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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the STAT protein family. 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. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

99 unique Pathogenic / Likely Pathogenic· 276 VUS of 810 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — STAT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.08 (0.04–0.19)

0≤0.351.4

Missense OE?0.28 (0.24–0.33)

0≤0.61.4

Synonymous OE?1.02

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

This gene — mechanism propensity

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.1

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), a2

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

References

ClinVar Variant Classifications

810 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57

Likely Pathogenic42

VUS276

Likely Benign319

Benign49

Conflicting21

Pathogenic

Likely Pathogenic

276

VUS

319

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	38	1	0	57
Likely Pathogenic	11	31	0	0	42
VUS	4	192	69	11	276
Likely Benign	0	5	163	151	319
Benign	0	0	45	4	49
Conflicting	—				21
Total	33	266	278	166	764

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

29 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap STAT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →