STAT4

Chr 2AD

signal transducer and activator of transcription 4

Also known as: DPMC, SLEB11

NCBI Gene: 6775 ENSG00000138378 UniProt: Q14765 OMIM: 600558

STAT4 encodes a transcription factor that mediates responses to IL-12 and other cytokines, playing a critical role in T-helper cell differentiation and interferon-gamma production in immune responses. Mutations cause disabling pansclerotic morphea of childhood, a severe skin and connective tissue disorder, and increase susceptibility to systemic lupus erythematosus. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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 is essential for mediating responses to IL12 in lymphocytes, and regulating the differentiation of T helper cells. Mutations in this gene may be associated with systemic lupus erythematosus and rheumatoid arthritis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

ADLOEUF 0.352 OMIM phenotypes

Clinical Summary— STAT4

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.77) — some intolerance to loss-of-function variants.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 230 VUS of 536 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.766

Z-score 5.15

OE 0.20 (0.13–0.35)

Highly constrained

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

Missense Constraint?

2.74Z-score

OE missense 0.61 (0.55–0.68)

237 obs / 389.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.20 (0.13–0.35)

0≤0.351.4

Missense OE?0.61 (0.55–0.68)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 10 / 48.8Missense obs/exp: 237 / 389.2Syn Z: 1.25

ClinVar Variant Classifications

536 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS230

Likely Benign257

Benign22

Conflicting6

Pathogenic

Likely Pathogenic

230

VUS

257

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	1	0	2
Likely Pathogenic	0	1	0	0	1
VUS	8	201	17	4	230
Likely Benign	0	7	135	115	257
Benign	0	1	17	4	22
Conflicting	—				6
Total	8	211	170	123	518

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

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29 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap STAT4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →