STAT6
protein-codingsignal transducer and activator of transcription 6, the group of SH2 domain containing
Gene summary
The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2) cells, expression of cell surface markers, and class switch of immunoglobulins. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~36.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0957807
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0957807
Submitter: ClinGen
*STAT6* was first reported in relation to autosomal dominant hyper-IgE syndrome 6 in 2023 (Suratannon N, et al., 2023, PMID: 36216080). This is an immunologic disorder characterized by early-childhood onset of severe refractory atopic dermatitis, IgE-mediated food and drug allergies, asthma, and eosinophilic esophagitis. Laboratory studies show increased serum IgE levels and eosinophilia. Additional features may include allergic rhinitis, recurrent secondary infections (bacterial, viral, fungal), and short stature. It is caused by caused by heterozygous gain of function mutations; 11 missense variants reported in 12 probands in 3 publications (PMIDs: 36216080, 36884218, 36758835). This gene-disease relationship is further supported by experimental evidence including its biochemical function in mediating the effects of IL4 (PMID: 8085155), a key cytokine necessary for type 2 differentiation of CD4+ T cells (TH2) and B cells, cell proliferation, and class switching to IgE. Functional alteration in patient cells confirmed a significant increase of TH2 lymphocytes and increased IL-4 production, while transcriptomic changes were found in D419G-transducted cells (PMID: 36884218). A protein interaction with STAT3 (definitively related to hyper-IgE syndrome 1) has been reported (PMID: 20211142). In addition, a gain of function mouse model shares a number of key features of the allergic diathesis, including elevated serum IgE and chronic atopic dermatitis (PMID: 12646608). In summary, there is strong evidence to support the relationship between *STAT6* and autosomal dominant hyper-IgE syndrome 6. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Musculoskeletal; Pulmonary
Intervention: Allergy/Immunology/Infectious
Rationale: The condition can manifest with multisystem immunologic features, incluidng frequent infections, and medical management (eg, with IL4 inhibitors or JAK inhibitors) as well as early and aggressive treatment of infections, may be beneficial; Individuals have been described with anaphylactic allergic reactions, and awareness may allow identification and triggers and avoidance and prompt management of allergic reactions; The condition can involve cerebrovascular anomalies, and early identification may improve outcomes;
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STAT6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003153.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 6 | 1 | 9 | ||
| missense | 5 | 1 | 110 | 6 | 1 | 123 |
| nonsense | 3 | 3 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 5 | 1 | 121 | 12 | 2 | 141 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003144.3 | 21 | MANE Select | |
| Ensembl | ENSP00000300134.3 | 21 | MANE Select | |
| RefSeq | NP_001171549.1 | 21 | Standard | |
| RefSeq | NP_001171550.1 | 21 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Jak-STAT signaling pathway - Homo sapiens (human)
- Inflammatory bowel disease (IBD) - Homo sapiens (human)
- Necroptosis - Homo sapiens (human)
- Th17 cell differentiation - Homo sapiens (human)
- Th1 and Th2 cell differentiation - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- T-helper 1 cell lineage commitment
- negative regulation of type 2 immune response
- regulation of transcription by RNA polymerase II
- signal transduction
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
Cellular Component
- nuclear chromatin
- nucleoplasm
- cytosol
- nuclear membrane
- membrane raft
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000300134
- Coding exons
- 21
- Length
- 36732
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 125748
- p
- 0.0000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.41 | 336 | 486 | 0.692 | 0.0000271 | 5516 |
| Missense (PolyPhen) | 93 | 198.98 | 0.46739 | 2347 | ||
| Synonymous | 0.204 | 190 | 194 | 0.981 | 0.0000106 | 1715 |
| Loss of Function | 5.41 | 8 | 48.7 | 0.164 | 0.00000261 | 499 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Carries out a dual function: signal transduction and activation of transcription. Involved in IL4/interleukin-4- and IL3/interleukin-3-mediated signaling. {ECO:0000269|PubMed:17210636}.;
Recessive Scores
- pRec
- 0.752
Intolerance Scores
- LoFtool
- 0.0386
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 15.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |