STAT1

Chr 2ADAR

signal transducer and activator of transcription 1

Also known as: CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91

NCBI Gene: 6772 ENSG00000115415 UniProt: P42224 OMIM: 600555

STAT1 encodes a signal transducer and transcription activator that mediates cellular responses to interferons and other cytokines, playing a crucial role in immune responses to viral, fungal, and mycobacterial pathogens. Mutations cause three distinct immunodeficiency syndromes: autosomal dominant immunodeficiency 31A with mycobacteriosis, autosomal recessive immunodeficiency 31B with mycobacterial and viral infections, and autosomal dominant immunodeficiency 31C with chronic mucocutaneous candidiasis. The gene is highly constrained against loss-of-function variants (pLI >0.99), reflecting its essential role in immune function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.193 OMIM phenotypes

Clinical Summary— STAT1

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Gene-Disease Validity (ClinGen)

immunodeficiency 31B · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.19LOEUF

pLI 1.000

Z-score 5.95

OE 0.08 (0.04–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

5.15Z-score

OE missense 0.28 (0.24–0.33)

114 obs / 406.0 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.08 (0.04–0.19)

0≤0.351.4

Missense OE0.28 (0.24–0.33)

0≤0.61.4

Synonymous OE1.02

0≤1.21.6

LoF obs/exp: 4 / 48.9Missense obs/exp: 114 / 406.0Syn Z: -0.23

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSTAT1-related immunodeficiencyOTHERAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.3793th %ile

GOF

0.4184th %ile

LOF

0.67top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNA heterozygous dominant-negative mutation in the coiled-coil domain of STAT1 is the cause of autosomal-dominant Mendelian susceptibility to mycobacterial diseases.PMID:27856304

GOFThe FCM findings provided strong evidence for the diagnosis of severe combined immunodeficiency (n = 6), X-linked chronic granulomatous diseases (CGD) (n = 6), leukocyte adhesion deficiency type 1 (n = 3), X-linked agammaglobulinemia (n = 11), autoimmune lymphoproliferative syndrome-FASLG (n = 1), aPMID:32009323

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.