Information on STAT3

Basic details

Alt. symbols: APRF

Approved name: signal transducer and activator of transcription 3
Alt. names: signal transducer and activator of transcription 3 (acute-phase response factor)

Location: 17q21.2: 42313324 - 42388568 (-)
Gene type: protein_coding, 51 transcripts.

Scores: LoFtool: 0.035900 | pLI: 0.99998919 | LOEUF: 0.095

HGNC: 11364

NCBI: 6774, RefSeq: NG_007370.1

Ensembl: ENSG00000168610.17

LRG_112 | Status: public

OMIM: 102582

Expression | ProteinAtlas

Normal function

STAT3 encodes an important and widely expressed developmental transcription factor (TF) with key roles in many aspects of cellular immunity, proliferation, apoptosis and differentiation. All STAT family TFs share a common structure consisting of N-terminal, coiled-coil, DNA-binding, linker, Src homology 2 (SH2), and C-terminal transactivation domains. The N-terminal and SH2 domains mediate homo- or hetero-dimerization, while the coiled-coil domain partially functions as a nuclear localization signal (NLS) and the DNA-binding and transactivation domains direct DNA targeting and transcriptional activity, respectively. STAT3 is activated in response to cytokines, such as interferons and interleukins, epidermal growth factors or other mitogens. Ligand stimulation leads to intracellular receptor-associated Janus kinase (JAK) activation, which in turn promotes STAT3 phosphorylation on key residues such as Tyr705. In addition, STAT3 phosphorylation of Ser727 by Mitogen-activated protein kinases (MAPK) can occur through Src (non-receptor tyrosine kinase) activation. Once phosphorylated, STAT3 dimerizes and translocates to the nucleus to regulate target gene expression. In epithelial cells, STAT3 controls the expression of genes important for cell survival and proliferation, cell migration and oncogenic transformation. In immune cells, it regulates the expression of genes involved in immune evasion, cell survival, cytokine signaling, and pre-metastatic niche formation. STAT3 modulates the inflammatory response by regulating the differentiation of naive T-cells into specific subsets of T-helper (Th) or regulatory T-cells (Tregs). In the skeletal system, STAT3 is involved in the formation of osteoclasts, which are essential for bone development and maintenance. Unrestrained activity of STAT3 is implicated in tumorigenesis, as it can upregulate the expression of genes involved in proliferation and angiogenesis, promote the expression of oncogenes, and downregulate the expression of genes mediating immune surveillance and apoptosis.

Dysfunction and disease

Mutations in STAT3 have been associated with a variety of clinical phenotypes. All inherited conditions known thus far show an autosomal dominant mode of transmission. Germline STAT3 gain-of-function mutations (STAT3 GOF) are associated with early-onset multi-organ autoimmunity, while germline dominant-negative loss-of-function (STAT3 DN LOF) mutations develop autosomal-dominant Hyper-IgE syndrome (AD-HIES). Unlike STAT3 GOF, which is thought in part to arise from increased Th17 polarization, ST AT3 LOF leading to AD-HIES is thought to be due to an enhanced Th2 skewing at the cost of Th1 and Th17 lineages. The overactivity of STAT3, in STAT3 GOF, can be explained by increased intrinsic transcriptional activity of the STAT3 dimer rather than by enhanced phosphorylation. STAT3 GOF patients show a broad spectrum of phenotypes, often with infantile or childhood onset, including many autoimmune phenotypes, such as type I diabetes mellitus (T1D), hypothyroidism, and other endocrinopathies; hepatitis, enteropathy, and achalasia; arthritis, interstitial lung disease, cytopenias, lymphoproliferation, and vasculitis, in addition to short stature, growth failure, and recurrent infections (PMID: 30825606). Laboratory studies usually show hypogammaglobulinemia, along with T and/or B cell lymphopenia (PMID: 25359994). Predominantly missense mutations are distributed in important functional domains through the protein, including within N-terminal, coiled-coil, DNA binding, linker, Src-homology 2 (SH2), and transactivation (TA) domains (PMID: 30825606). Increasing evidence suggests that combined use of tocilizumab (an anti-IL-6 agent) and JAK inhibitors such as ruxolitinib and tofacitinib may be effective for controlling disease activity in STAT3 GOF patients (PMID: 30092289, 33731004, 30825606). On the other hand, AD-HIES due to STAT3 DN LOF is characterized by cutaneous and sinopulmonary infections (bacterial, viral and fungal, oral candidiasis, atopic manifestations including eczema, peripheral eosinophilia and high IgE levels, along with vascular, skeletal and connective tissue abnormalities (PMID: 17881745, 20159255, 30466772). Most of the autosomal-dominant loss-of-function mutations lay in the DNA-binding domain or SH2 domain and impair STAT3 homodimers´ ability to bind to DNA in order to activate transcription. As STAT3 forms homodimers, mutant STAT3 molecules can exert a dominant-negative effect on the wild-type STAT3 molecules and hence weaken the cytokine signalling via STAT3. Finally, somatic GOF mutations, mostly in the SH2 domain, have been found in 30-40% of large granular lymphocytic leukemia (LGLL) patients (PMID: 22591296, 22859607). LGLL is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T cells, often found in association with a history of autoimmune disorders and immune-mediated cytopenias. [Load More]

[Reviewed by Virginia Andreani on 2022-05-24 13:04:40]

Associated conditions

Acronym Condition's_name MOI Mode_of_actionwww icon OMIM_ID No.cases
HIES1 Hyper-IgE recurrent infection syndrome 1 ADdict. icon Negative Dominance 147060www icon 404 (327 fams)
IMAD1 Infantile-Onset Multisystem Autoimmune Disease 1 ADdict. icon Gain of Function 615952www icon 61 (53 fams)
NKTCL1 NK/T-cell lymphomas 1 Sodict. icon Gain of Function - 9 (9 fams)
BCL1 B-cell lymphomas 1 Sodict. icon Gain of Function - 11 (11 fams)
T-LGLL1 T-cell LGL leukemia 1 Sodict. icon Gain of Function - 112 (112 fams)
IHCA1 Inflammatory hepatocellular adenomas 1 Sodict. icon Gain of Function - 6 (6 fams)
CLPD-NK1 Chronic lymphoproliferative disorder of NK-cells 1 Sodict. icon Gain of Function - 18 (18 fams)

Transcripts of STAT3

Name ENSEMBL_ID LRG_ID CCDS_ID MANE Transcript.type Exons Canonical CDS_length REFSEQ_ID
236 ENST00000678535.1 protein_coding 23 No 3288 NM_001384988
243 ENST00000678905.1 protein_coding 24 No 4768 NM_001384986
223 ENST00000677442.1 protein_coding 24 No 4829 NM_001384991
239 ENST00000678674.1 protein_coding 23 No 4703 NM_001384989
237 ENST00000678572.1 protein_coding 24 No 4739 NM_001384990
249 ENST00000679185.1 protein_coding 24 No 4782 NM_001369520
217 ENST00000677152.1 protein_coding 24 No 3395 NM_001384993
227 ENST00000677723.1 CCDS32657 protein_coding 24 No 4834 NM_001369514,NM_001369516,NM_003150
224 ENST00000677479.1 protein_coding 24 No 4731 NM_001369519
201 ENST00000264657.10 1 CCDS32656 Select protein_coding 24 Yes 4921 NM_001369512,NM_001369513,NM_001384985,NM_001384992,NM_139276
232 ENST00000678048.1 protein_coding 23 No 4740 NM_001384984
211 ENST00000585517.5 CCDS59288 protein_coding 24 No 3319 XM_047436585
216 ENST00000677030.1 CCDS59288 protein_coding 24 No 4812 NM_001369518,NM_213662
202 ENST00000389272.7 protein_coding 23 No 2615 XM_047436586
230 ENST00000678043.1 protein_coding 24 No 4837 NM_001384987
242 ENST00000678827.1 CCDS59288 protein_coding 24 No 4800 NM_001369517

Published variants

Found 233 variants

Var.name Exon/Intron cDNA_pos. CDS_change Prot.change Var.type Var.class. Patients
A744V EX23 2418 c.2231C>T p.Ala744Val missense_variant Uncertain significance 0
IN21_EX23DEL IN21-EX23 2288-2416 c.2102-28_2230del p.? exon_loss_variant Pathogenic 0
R729Pfs*12 EX23 2372-2373 c.2185dup p.Arg729ProfsTer12 frameshift_variant Pathogenic 0
T716M EX23 2334 c.2147C>T p.Thr716Met missense_variant Pathogenic 9
EX22+1G>A IN22 c.2144+1G>A p.(Ser701LysfsTer17) splice_donor_variant Pathogenic 2
P715L EX22 2331 c.2144C>T p.Pro715Leu missense_variant Pathogenic 4
T714I EX22 2328 c.2141C>T p.Thr714Ile missense_variant Pathogenic 2
T714A EX22 2327 c.2140A>G p.Thr714Ala missense_variant Pathogenic 1
V713L EX22 2324 c.2137G>C p.Val713Leu missense_variant Pathogenic 1
V713M EX22 2324 c.2137G>A p.Val713Met missense_variant Pathogenic 2
C712R EX22 2321 c.2134T>C p.Cys712Arg missense_variant Pathogenic 0
I711T EX22 2319 c.2132T>C p.Ile711Thr missense_variant Pathogenic 0
I711V EX22 2318 c.2131A>G p.Ile711Val missense_variant Pathogenic 0
F710C EX22 2316 c.2129T>G p.Phe710Cys missense_variant Pathogenic 1
K709E EX22 2312 c.2125A>G p.Lys709Glu missense_variant Pathogenic 4
T708S EX22 2310 c.2123C>G p.Thr708Ser missense_variant Pathogenic 2
T708TT EX22 2309-2310 c.2123_2125dup p.Thr708dup inframe_insertion Pathogenic 0
T708N EX22 2310 c.2123C>A p.Thr708Asn missense_variant Pathogenic 1
L706P EX22 2304 c.2117T>C p.Leu706Pro missense_variant Pathogenic 2
L706M EX22 2303 c.2116C>A p.Leu706Met missense_variant Pathogenic 0
Y705F EX22 2301 c.2114A>T p.Tyr705Phe missense_variant Pathogenic 0
Y705C EX22 2301 c.2114A>G p.Tyr705Cys missense_variant Pathogenic 0
Y705H EX22 2300 c.2113T>C p.Tyr705His missense_variant Pathogenic 1
Y705N EX22 2300 c.2113T>A p.Tyr705Asn missense_variant Pathogenic 0
A703T EX22 2294 c.2107G>A p.Ala703Thr missense_variant Pathogenic 3
A702T EX22 2291 c.2104G>A p.Ala702Thr missense_variant Uncertain significance 1
E690_P699del EX21 2256-2285 c.2069_2098del p.Glu690_Pro699del inframe_deletion Pathogenic 4
D698Tfs*9 EX21 2278 c.2091del p.Asp698ThrfsTer9 frameshift_variant Pathogenic 2
D698Efs*6 EX21 2277-2278 c.2069_2090dup p.Asp698GlufsTer6 stop_gained Pathogenic 1
S668F EX21 2190 c.2003C>T p.Ser668Phe missense_variant Pathogenic 2
S668Y EX21 2190 c.2003C>A p.Ser668Tyr missense_variant Pathogenic 2
V667L EX21 2186 c.1999G>T p.Val667Leu missense_variant Likely Pathogenic 1
L666R EX21 2184 c.1997T>G p.Leu666Arg missense_variant Pathogenic 1
I665N EX21 2181 c.1994T>A p.Ile665Asn missense_variant Pathogenic 3
T663I EX21 2175 c.1988C>T p.Thr663Ile missense_variant Pathogenic 2
T663S EX21 2175 c.1988C>G p.Thr663Ser missense_variant Pathogenic 0
D661V EX21 2169 c.1982A>T p.Asp661Val missense_variant Pathogenic 11
D661I EX21 2168-2169 c.1981_1982delinsAT p.Asp661Ile missense_variant Pathogenic 1
G656_M660del EX21 2154-2168 c.1967_1981del p.Gly656_Met660del inframe_deletion Pathogenic 0
D661Y EX21 2168 c.1981G>T p.Asp661Tyr missense_variant Pathogenic 43
Y657_M660dup EX21 2167-2168 c.1969_1980dup p.Tyr657_Met660dup inframe_insertion Pathogenic 1
D661H EX21 2168 c.1981G>C p.Asp661His missense_variant Likely Pathogenic 2
G656_M660del EX21 2153-2167 c.1967_1981del p.Gly656_Met660del inframe_deletion Pathogenic 0
M660R EX21 2166 c.1979T>G p.Met660Arg missense_variant Pathogenic 0
M660T EX21 2166 c.1979T>C p.Met660Thr missense_variant Pathogenic 0
I659L EX21 2162 c.1975A>C p.Ile659Leu missense_variant Likely Pathogenic 1
K658N EX21 2161 c.1974G>T p.Lys658Asn missense_variant Likely Pathogenic 1
K658N EX21 2161 c.1974G>C p.Lys658Asn missense_variant Pathogenic 1
K658Y EX21 2159-2161 c.1972_1974delinsTAT p.Lys658Tyr missense_variant Pathogenic 1
K658M EX21 2160 c.1973A>T p.Lys658Met missense_variant Pathogenic 1
K658R EX21 2160 c.1973A>G p.Lys658Arg missense_variant Likely Pathogenic 1
K658E EX21 2159 c.1972A>G p.Lys658Glu missense_variant Pathogenic 0
Y657dup EX21 2158-2159 c.1969_1971dup p.Tyr657dup inframe_insertion Likely Pathogenic 2
Y657* EX21 2158 c.1971del p.Tyr657Ter stop_gained Pathogenic 1
Y657C EX21 2157 c.1970A>G p.Tyr657Cys missense_variant Pathogenic 6
Y657S EX21 2157 c.1970A>C p.Tyr657Ser missense_variant Pathogenic 1
Y657N EX21 2156 c.1969T>A p.Tyr657Asn missense_variant Pathogenic 0
G656GF EX21 2155 c.1968delinsTTTT p.Gly656_Tyr657insPhe inframe_insertion Pathogenic 1
I654del EX21 2149-2151 c.1962_1964del p.Ile654del inframe_deletion Pathogenic 0
E652K EX21 2141 c.1954G>A p.Glu652Lys missense_variant Pathogenic 3
S649L EX21 2133 c.1946C>T p.Ser649Leu missense_variant Likely Pathogenic 1
N647I EX21 2127 c.1940A>T p.Asn647Ile missense_variant Pathogenic 15
N647D EX21 2126 c.1939A>G p.Asn647Asp missense_variant Pathogenic 4
N646K EX21 2125 c.1938C>G p.Asn646Lys missense_variant Pathogenic 2
L645Q EX21 2121 c.1934T>A p.Leu645Gln missense_variant Pathogenic 0
Q644del EX21 2118-2120 c.1931_1933del p.Gln644del inframe_deletion Pathogenic 1
Q644del EX21 2117-2119 c.1931_1933del p.Gln644del inframe_deletion Pathogenic 0
Q644P EX21 2118 c.1931A>C p.Gln644Pro missense_variant Pathogenic 1
K642E EX21 2111 c.1924A>G p.Lys642Glu missense_variant Pathogenic 2
Y640F EX21 2106 c.1919A>T p.Tyr640Phe missense_variant Pathogenic 57
Y640N EX21 2105 c.1918T>A p.Tyr640Asn missense_variant Pathogenic 2
P639R EX21 2103 c.1916C>G p.Pro639Arg missense_variant Pathogenic 1
P639Q EX21 2103 c.1916C>A p.Pro639Gln missense_variant Pathogenic 0
P639S EX21 2102 c.1915C>T p.Pro639Ser missense_variant Pathogenic 2
P639A EX21 2102 c.1915C>G p.Pro639Ala missense_variant Pathogenic 1
P639T EX21 2102 c.1915C>A p.Pro639Thr missense_variant Pathogenic 1
E638G EX21 2100 c.1913A>G p.Glu638Gly missense_variant Pathogenic 2
V637A EX21 2097 c.1910T>C p.Val637Ala missense_variant Pathogenic 1
V637L EX21 2096 c.1909G>T p.Val637Leu missense_variant Pathogenic 2
V637M EX21 2096 c.1909G>A p.Val637Met missense_variant Pathogenic 49
S636F EX21 2094 c.1907C>T p.Ser636Phe missense_variant Pathogenic 2
S636Y EX21 2094 c.1907C>A p.Ser636Tyr missense_variant Pathogenic 1
Q633* EX21 2084 c.1897C>T p.Gln633Ter stop_gained Pathogenic 2
W623L EX20 2055 c.1868G>T p.Trp623Leu missense_variant Pathogenic 0
T622I EX20 2052 c.1865C>T p.Thr622Ile missense_variant Pathogenic 5
F621L EX20 2050 c.1863C>G p.Phe621Leu missense_variant Likely Pathogenic 1
F621S EX20 2049 c.1862T>C p.Phe621Ser missense_variant Pathogenic 0
F621V EX20 2048 c.1861T>G p.Phe621Val missense_variant Pathogenic 2
F621I EX20 2048 c.1861T>A p.Phe621Ile missense_variant Pathogenic 0
T620S EX20 2046 c.1859C>G p.Thr620Ser missense_variant Pathogenic 0
T620A EX20 2045 c.1858A>G p.Thr620Ala missense_variant Pathogenic 3
G618A EX20 2040 c.1853G>C p.Gly618Ala missense_variant Pathogenic 2
G618D EX20 2040 c.1853G>A p.Gly618Asp missense_variant Pathogenic 2
G618R EX20 2039 c.1852G>C p.Gly618Arg missense_variant Pathogenic 2
G617V EX20 2037 c.1850G>T p.Gly617Val missense_variant Pathogenic 1
G617E EX20 2037 c.1850G>A p.Gly617Glu missense_variant Pathogenic 1
E616del EX20 2034-2036 c.1847_1849del p.Glu616del inframe_deletion Likely Pathogenic 1
G617R EX20 2036 c.1849G>A p.Gly617Arg missense_variant Likely Pathogenic 1
E616G EX20 2034 c.1847A>G p.Glu616Gly missense_variant Likely Pathogenic 1
K615E EX20 2030 c.1843A>G p.Lys615Glu missense_variant Pathogenic 2
S614R EX20 2029 c.1842C>G p.Ser614Arg missense_variant Pathogenic 0
S614R EX20 2029 c.1842C>A p.Ser614Arg missense_variant Pathogenic 3
S614G EX20 2027 c.1840A>G p.Ser614Gly missense_variant Pathogenic 1
S614R EX20 2027 c.1840A>C p.Ser614Arg missense_variant Pathogenic 1
S611I EX20 2019 c.1832G>T p.Ser611Ile missense_variant Pathogenic 0
S611N EX20 2019 c.1832G>A p.Ser611Asn missense_variant Pathogenic 1
S611G EX20 2018 c.1831A>G p.Ser611Gly missense_variant Pathogenic 2
R609G EX20 2012 c.1825A>G p.Arg609Gly missense_variant Pathogenic 0
E594K EX20 1967 c.1780G>A p.Glu594Lys missense_variant Pathogenic 0
R593P EX20 1965 c.1778G>C p.Arg593Pro missense_variant Pathogenic 0
K591M EX20 1959 c.1772A>T p.Lys591Met missense_variant Pathogenic 1
K591E EX20 1958 c.1771A>G p.Lys591Glu missense_variant Pathogenic 1
D570N EX19 1895 c.1708G>A p.Asp570Asn missense_variant Pathogenic 2
I568M EX19 1891 c.1704C>G p.Ile568Met missense_variant Pathogenic 0
I568F EX19 1889 c.1702A>T p.Ile568Phe missense_variant Pathogenic 2
N567D EX19 1886 c.1699A>G p.Asn567Asp missense_variant Pathogenic 0
W562* EX19 1872 c.1685G>A p.Trp562Ter stop_gained Pathogenic 2
F561del EX19 1869-1871 c.1682_1684del p.Phe561del inframe_deletion Pathogenic 1
S560del EX19 1866-1868 c.1679_1681del p.Ser560del inframe_deletion Pathogenic 6
K531N EX17 1780 c.1593A>T p.Lys531Asn missense_variant Pathogenic 0
K531E EX17 1778 c.1591A>G p.Lys531Glu missense_variant Pathogenic 2
R518* EX17 1739 c.1552C>T p.Arg518Ter stop_gained Pathogenic 1
D502Y EX17 1691 c.1504G>T p.Asp502Tyr missense_variant Likely Benign 0
F493Lfs*16 EX17 1666 c.1479del p.Phe493LeufsTer16 frameshift_variant Pathogenic 0
W479C EX16 1624 c.1437G>T p.Trp479Cys missense_variant Uncertain significance 2
S476F EX16 1614 c.1427C>T p.Ser476Phe missense_variant Pathogenic 0
N472D EX16 1601 c.1414A>G p.Asn472Asp missense_variant Pathogenic 5
Q469H EX16 1594 c.1407G>T p.Gln469His missense_variant Pathogenic 3
Q469R EX16 1593 c.1406A>G p.Gln469Arg missense_variant Pathogenic 0
I467F EX16 1586 c.1399A>T p.Ile467Phe missense_variant Pathogenic 0
N466K EX16 1585 c.1398C>G p.Asn466Lys missense_variant Pathogenic 1
N466I EX16 1584 c.1397A>T p.Asn466Ile missense_variant Pathogenic 0
N466S EX16 1584 c.1397A>G p.Asn466Ser missense_variant Likely Pathogenic 4
N466T EX16 1584 c.1397A>C p.Asn466Thr missense_variant Pathogenic 1
N466D EX16 1583 c.1396A>G p.Asn466Asp missense_variant Pathogenic 1
S465F EX16 1581 c.1394C>T p.Ser465Phe missense_variant Pathogenic 0
S465A EX16 1580 c.1393T>G p.Ser465Ala missense_variant Pathogenic 1
V463del EX16 1574-1576 c.1387_1389del p.Val463del inframe_deletion Pathogenic 20
V463E EX16 1575 c.1388T>A p.Val463Glu missense_variant Pathogenic 0
V461L EX16 1568 c.1381G>C p.Val461Leu missense_variant Benign 0
H447Y EX15 1526 c.1339C>T p.His447Tyr missense_variant Likely Pathogenic 1
H437P EX15 1497 c.1310A>C p.His437Pro missense_variant Pathogenic 2
H437Y EX15 1496 c.1309C>T p.His437Tyr missense_variant Pathogenic 1
V432L EX15 1481 c.1294G>C p.Val432Leu missense_variant Pathogenic 0
V432M EX15 1481 c.1294G>A p.Val432Met missense_variant Pathogenic 2
EX15-89C>T IN14 c.1282-89C>T p.(D427ins17) intron_variant Pathogenic 7
EX14+1del IN14 c.1281+1del splice_donor_variant Pathogenic 0
C426R EX14 1463 c.1276T>C p.Cys426Arg missense_variant Likely Pathogenic 1
N425Y EX14 1460 c.1273A>T p.Asn425Tyr missense_variant Pathogenic 0
R423Q EX14 1455 c.1268G>A p.Arg423Gln missense_variant Pathogenic 8
G421R EX14 1448 c.1261G>A p.Gly421Arg missense_variant Pathogenic 2
N420K EX14 1447 c.1260T>G p.Asn420Lys missense_variant Pathogenic 1
G419R EX14 1442 c.1255G>A p.Gly419Arg missense_variant Pathogenic 1
E415G EX14 1431 c.1244A>G p.Glu415Gly missense_variant Pathogenic 1
E415L EX14 1430-1431 c.1243_1244delinsCT p.Glu415Leu missense_variant Pathogenic 1
E415K EX14 1430 c.1243G>A p.Glu415Lys missense_variant Pathogenic 1
T412S EX14 1421 c.1234A>T p.Thr412Ser missense_variant Pathogenic 4
T412A EX14 1421 c.1234A>G p.Thr412Ala missense_variant Pathogenic 1
H410R EX13 1416 c.1229A>G p.His410Arg missense_variant Pathogenic 2
N395Y EX13 1370 c.1183A>T p.Asn395Tyr missense_variant Pathogenic 0
M394T EX13 1368 c.1181T>C p.Met394Thr missense_variant Pathogenic 1
V393A EX13 1365 c.1178T>C p.Val393Ala missense_variant Pathogenic 1
K392R EX13 1362 c.1175A>G p.Lys392Arg missense_variant Pathogenic 1
T389I EX13 1353 c.1166C>T p.Thr389Ile missense_variant Pathogenic 4
F384F EX13 1339 c.1152T>C p.Phe384= synonymous_variant Uncertain significance 0
F384L EX13 1339 c.1152T>A p.Phe384Leu missense_variant Pathogenic 13
F384C EX13 1338 c.1151T>G p.Phe384Cys missense_variant Pathogenic 0
F384S EX13 1338 c.1151T>C p.Phe384Ser missense_variant Pathogenic 1
F384V EX13 1337 c.1150T>G p.Phe384Val missense_variant Pathogenic 0
R382L EX13 1332 c.1145G>T p.Arg382Leu missense_variant Pathogenic 3
R382Q EX13 1332 c.1145G>A p.Arg382Gln missense_variant Pathogenic 41
R382W EX13 1331 c.1144C>T p.Arg382Trp missense_variant Pathogenic 75
R382G EX13 1331 c.1144C>G p.Arg382Gly missense_variant Pathogenic 4
S381Y EX13 1329 c.1142C>A p.Ser381Tyr missense_variant Benign 0
EX13-2A>G IN12 c.1140-2A>G p.(Ser381Ter) splice_acceptor_variant Pathogenic 0
EX13-2A>C IN12 c.1140-2A>C p.(Ser381Ter) splice_acceptor_variant Pathogenic 1
EX13-3C>G IN12 c.1140-3C>G p.(Ser381Ter) ALTERS SPLICING! Pathogenic 1
EX12+5G>A IN12 c.1139+5G>A splice_donor_5th_base_variant Pathogenic 0
EX12+2dup IN12 c.1139+2dup splice_region_variant Pathogenic 1
EX12+2dup IN12 c.1139+2dup splice_donor_variant Pathogenic 0
EX12+1G>T IN12 c.1139+1G>T splice_donor_variant Pathogenic 1
EX12+1G>A IN12 c.1139+1G>A splice_donor_variant Pathogenic 5
V375I EX12 1310 c.1123G>A p.Val375Ile missense_variant Uncertain significance 1
D374G EX12 1308 c.1121A>G p.Asp374Gly missense_variant Pathogenic 0
D371Lfs*14 EX12 1298-1299 c.1111_1112del p.Asp371LeufsTer14 frameshift_variant Pathogenic 1
EX12-1G>T IN11 c.1110-1G>T splice_acceptor_variant Pathogenic 1
EX12-2A>G IN11 c.1110-2A>G p.(Asp371-Gly380del) ALTERS SPLICING! Pathogenic 6
EX12-2A>C IN11 c.1110-2A>C splice_acceptor_variant Pathogenic 0
EX12-3C>A IN11 c.1110-3C>A splice_region_variant Pathogenic 0
EX11+1G>T IN11 c.1109+1G>T splice_donor_variant Pathogenic 2
DK369-370E EX11 1294-1296 c.1107_1109del p.Asp369_Lys370delinsGlu inframe_deletion Pathogenic 0
P356R EX11 1254 c.1067C>G p.Pro356Arg missense_variant Pathogenic 2
V353F EX11 1244 c.1057G>T p.Val353Phe missense_variant Pathogenic 1
K348E EX10 1229 c.1042A>G p.Lys348Glu missense_variant Pathogenic 1
Q344H EX10 1219 c.1032G>C p.Gln344His missense_variant Pathogenic 2
V343F EX10 1214 c.1027G>T p.Val343Phe missense_variant Pathogenic 2
V343L EX10 1214 c.1027G>C p.Val343Leu missense_variant Pathogenic 1
G342D EX10 1212 c.1025G>A p.Gly342Asp missense_variant Pathogenic 4
KT340-341N EX10 1207-1209 c.1020_1022del p.Lys340_Thr341delinsAsn inframe_deletion Pathogenic 1
T341N EX10 1209 c.1022C>A p.Thr341Asn missense_variant Pathogenic 1
K340E EX10 1205 c.1018A>G p.Lys340Glu missense_variant Likely Pathogenic 0
K340Q EX10 1205 c.1018A>C p.Lys340Gln missense_variant Pathogenic 0
R335W EX10 1190 c.1003C>T p.Arg335Trp missense_variant Pathogenic 2
H332L EX10 1182 c.995A>T p.His332Leu missense_variant Pathogenic 0
H332R EX10 1182 c.995A>G p.His332Arg missense_variant Uncertain significance 0
H332P EX10 1182 c.995A>C p.His332Pro missense_variant Pathogenic 0
H332Y EX10 1181 c.994C>T p.His332Tyr missense_variant Pathogenic 4
C328_P330dup EX10 1177-1178 c.982_990dup p.Cys328_Pro330dup inframe_insertion Pathogenic 0
P330PCMP EX10 1176-1177 c.982_990dup p.Cys328_Pro330dup inframe_insertion Pathogenic 1
P330R EX10 1176 c.989C>G p.Pro330Arg missense_variant Pathogenic 1
M329K EX10 1173 c.986T>A p.Met329Lys missense_variant Pathogenic 1
F313L EX9 1124 c.937T>C p.Phe313Leu missense_variant Likely Pathogenic 2
K290N EX9 1057 c.870A>T p.Lys290Asn missense_variant Pathogenic 1
Q288P EX9 1050 c.863A>C p.Gln288Pro missense_variant Pathogenic 1
L287V EX9 1046 c.859T>G p.Leu287Val missense_variant Likely Pathogenic 1
E286G EX9 1044 c.857A>G p.Glu286Gly missense_variant Pathogenic 3
E286A EX9 1044 c.857A>C p.Glu286Ala missense_variant Pathogenic 1
Q280P EX9 1026 c.839A>C p.Gln280Pro missense_variant Pathogenic 0
R278H EX9 1020 c.833G>A p.Arg278His missense_variant Likely Pathogenic 1
R246Q EX8 924 c.737G>A p.Arg246Gln missense_variant Likely Pathogenic 1
V218A EX8 840 c.653T>C p.Val218Ala missense_variant Likely Pathogenic 1
M206K EX7 804 c.617T>A p.Met206Lys missense_variant Pathogenic 1
F174S EX6 708 c.521T>C p.Phe174Ser missense_variant Pathogenic 2
E166Q EX6 683 c.496G>C p.Glu166Gln missense_variant Pathogenic 1
R152W EX5 641 c.454C>T p.Arg152Trp missense_variant Pathogenic 3
Q125* EX5 560 c.373C>T p.Gln125Ter stop_gained Pathogenic 1
R107W EX4 506 c.319C>T p.Arg107Trp missense_variant Likely Pathogenic 2
R103W EX4 494 c.307C>T p.Arg103Trp missense_variant Likely Pathogenic 1
R84Q EX3 438 c.251G>A p.Arg84Gln missense_variant Pathogenic 0
L78R EX3 420 c.233T>G p.Leu78Arg missense_variant Pathogenic 1
S69R EX3 394 c.207C>A p.Ser69Arg missense_variant Likely Pathogenic 1
H58Y EX3 359 c.172C>T p.His58Tyr missense_variant Likely Pathogenic 2
R13Vfs*11 EX2 224-225 c.37_38del p.Arg13ValfsTer11 frameshift_variant Pathogenic 0

Diagnostic pitfalls & paradigms

Considerations to take into account when analyzing this gene

Year Paradigm ⓘ PMID Notes
- Regions of Homology -
2013Mosaicism23623265[gonosomal] Report of 2 AD-HIES families in which mildly affected (HIES scores: 41-44) and mosaic fathers transmitted their mutations to their respective children. All affected children (HIES scores: 59-82) were germline heterozygotes. The percentage of mosaicism in father of family J017 was ~33% in PBMCs and granulocytes; and in father of family J149 the mutation was present in ~50-60% cells when compared to one of his heterozygous sons.
2023Mosaicism36917542[gonadal] Report of 2 maternal half-sisters with a HIES phenotype, who were found to carry the same DN p.P356R variant, which was absent in their mother (at least in blood cells). They suspect that the variant was present in the mother's gametes, but they could not confirm this.
-Cryptic splicing-Unreported or not recorded in our DB.
-Uniparental disomy-Unreported or not recorded in our DB.
-Incomplete penetrance-Unreported or not recorded in our DB.
-Di-/oligo-genic inheritance-Unreported or not recorded in our DB.
-Somatic reversion-Unreported or not recorded in our DB.

References linked to variants in STAT3

ID Year Title Journal PMID Variants
36 2016 Genetic Diagnosis Using Whole Exome Sequencing in Common Var... Front. Immunol. 27379089 3
118 2021 Establishing the Molecular Diagnoses in a Cohort of 291 Pati... Front. Immunol. 34975878 7
304 2010 Mutations in STAT3 and diagnostic guidelines for hyper-IgE s... JACI 20159255 31
310 2016 Protein stabilization improves STAT3 function in autosomal d... Blood 27799162 77
315 2018 Oncogenic activation of the STAT3 pathway drives PD-L1 expre... Blood 30054295 1
317 2012 Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: ... Medicine 22751495 24
319 2021 Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE ... JoCI 34390440 1
320 2014 Activating germline mutations in STAT3 cause early-onset mul... Nat. Genet. 25038750 6
321 2015 Early-onset lymphoproliferation and autoimmunity caused by g... Blood 25359994 11
322 2020 Distinct molecular response patterns of activating STAT3 mut... Clin. Immunol. 31770611 4
336 2008 Novel and recurrent STAT3 mutations in hyper-IgE syndrome pa... Mol. Immunol. 18706697 4
337 2007 STAT3 mutations in the hyper-IgE syndrome... N. Engl. J. Med. 17881745 18
339 2016 Distinct mutations at the same positions of STAT3 cause eith... JACI 27345172 18
340 2007 Dominant-negative mutations in the DNA-binding domain of STA... Nature 17676033 5
348 2009 A novel mutation in the linker domain of the signal transduc... JACI 19348930 1
349 2017 Molecular typing of Staphylococcus aureus isolated from pati... Pathogens 28587312 14
350 2010 Rapid molecular analysis of the STAT3 gene in job syndrome o... JMD 20093388 6
354 2017 Tocilizumab Promotes Regulatory T-cell Alleviation in STAT3 ... Clin. Therap. 28153428 1
356 2018 Visualization and quantification of dynamic STAT3 homodimeri... Sci. Rep. 29402895 3
377 2018 Invasive dermatophyte infection with Trichophyton interdigit... BJD 28667753 1
457 2019 STAT3 gain of function: a new aetiology of severe rheumatic ... Rheumatology 30299506 1
458 2020 Successful treatment of interstitial lung disease in STAT3 g... Am. J. Respir. 32392079 4
459 2019 Clinical Aspects of STAT3 Gain-of-Function Germline Mutation... JACI: In Practice 30825606 1
531 2018 Clinical, immunologic, and genetic spectrum of 696 patients ... JACI 28916186 1
538 2019 The first cohort of Iranian patients with hyper immunoglobul... PAI 30801830 1
759 2015 Activating mutations of STAT5B and STAT3 in lymphomas derive... Nat. Commun. 25586472 5
761 2013 A novel missense (M206K) STAT3 mutation in diffuse large B c... Plos one 23861822 1
762 2012 Discovery and prioritization of somatic mutations in diffuse... PNAS 22343534 5
763 2008 Novel signal transducer and activator of transcription 3 (ST... JACI 18602572 15
784 2009 Hyperimmunoglobulin E syndrome with a novel STAT3 mutation... Dermatol. Online J. 19891924 1
785 2018 Aspergillosis, eosinophilic esophagitis, and allergic rhinit... JACI 29803798 1
790 2007 STAT3 mutation in the original patient with Job's syndrome... N. Engl. J. Med. 17942886 1
794 2021 Human STAT3 variants underlie autosomal dominant hyper-IgE s... JEM 34137790 151
796 2014 Genetic and functional characterisation of the autosomal dom... UCL library 39
802 2012 Frequent and widespread vascular abnormalities in human sign... Circ. Cardiovasc. Genet. 22084479 13
803 2010 Milder clinical hyperimmunoglobulin E syndrome phenotype is ... Clin. Exp. Immunol. 19878510 3
804 2011 Paucity of genotype-phenotype correlations in STAT3 mutation... Clin. Immunol. 21288777 23
805 2010 Destructive pulmonary staphylococcal infection in a boy with... Eur. J. Pediatr. 21107604 1
806 2013 Lung parenchyma surgery in autosomal dominant hyper-IgE synd... JoCI 23584561 16
807 2010 A novel mutation in the signal transducer and activator of t... Mol. Immunol. 20149460 1
808 2008 Deficiency of Th17 cells in hyper IgE syndrome due to mutati... JEM 18591410 4
809 2009 Coccidioides immitis meningitis in a patient with hyperimmun... Pediatr. Infect. Dis. J. 19483664 1
814 2014 STAT3 mutations are present in aggressive B-cell lymphomas i... Haematol. J. 24837465 5
815 2015 Endemic mycoses in patients with STAT3-mutated hyper-IgE (Jo... JACI 26292779 7
816 2011 Case report of a young child with disseminated histoplasmosi... Clin. Mol. Allergy 22126402 1
869 2022 Molecular diagnosis of childhood immune dysregulation, polye... JACI 33864888 4
871 2019 A deep intronic splice mutation of STAT3 underlies hyper IgE... PNAS 31346092 3
886 2018 STAT3 Gain of Function: A New Kid on the Block in Interstiti... Am. J. Respir. 29590538 1
887 2018 Jakinibs for the treatment of immune dysregulation in patien... JACI 30092289 6
888 2015 Autoimmunity, hypogammaglobulinemia, lymphoproliferation, an... Blood 25349174 3
889 2018 A novel de novo activating mutation in STAT3 identified in a... Clin. Immunol. 29180260 3
890 2017 Short Stature in a Boy with Multiple Early-Onset Autoimmune ... Horm. Res. Paediatr. 28253502 1
895 2017 Autoimmunity/inflammation in a monogenic primary immunodefic... Clin. Transl. Immunology 28983403 2
1011 2020 Identification of Novel Genetic Variants in CVID Patients Wi... Front. Immunol. 32047491 1
1116 2021 Diagnostic Yield and Therapeutic Consequences of Targeted Ne... Int. Arch. Allergy Immunol. 34619682 5
1124 2023 Germline Mosaicism in STAT3: A Pitfall for Genetic Diagnosis... Dermatitis 36917542 1
1350 2016 Activating somatic mutations outside the SH2-domain of STAT3... Leukemia 26419508 4
1351 2012 Somatic STAT3 mutations in large granular lymphocytic leukem... N. Engl. J. Med. 22591296 7
1352 2022 A Novel STAT3 Gain-of-Function Mutation in Fatal Infancy-Ons... Front. Immunol. 35677041 1
1353 2021 Clinical and Immunological Heterogeneity in Japanese Patient... JoCI 33501615 7
1354 2013 STAT3 mutations are highly specific for large granular lymph... Leukemia 23207521 6
1355 2012 STAT3 mutations unify the pathogenesis of chronic lymphoprol... Blood 22859607 8
1383 2013 STAT3 mutations are frequent in CD30+ T-cell lymphomas and T... Leukemia 23563237 4
1384 2011 Somatic mutations activating STAT3 in human inflammatory hep... JEM 21690253 7
1433 2015 Immunosuppressive therapy of LGL leukemia: prospective multi... Leukemia 25306898 4
1498 2021 Pulmonary Histopathology Findings in Patients With STAT3 Gai... Pediatr. Dev. Pathol. 33651637 1

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