STAT4

Chr 2AD

signal transducer and activator of transcription 4

Also known as: DPMC, SLEB11

NCBI Gene: 6775ENSG00000138378UniProt: Q14765

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]

Primary Disease Associations & Inheritance

{Systemic lupus erythematosus, susceptibility to, 11}MIM #612253
AD
Disabling pansclerotic morphea of childhoodMIM #620443
AD
UniProtRheumatoid arthritis
282
ClinVar variants
6
Pathogenic / LP
0.77
pLI score
0
Active trials
Clinical Summary— STAT4
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.77) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
6 Pathogenic / Likely Pathogenic· 144 VUS of 282 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.13–0.35)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.55–0.68)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.86
0≤1.21.6
LoF obs/exp: 10 / 48.8Missense obs/exp: 237 / 389.2Syn Z: 1.25

ClinVar Variant Classifications

282 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic1
VUS144
Likely Benign125
Benign6
Conflicting1
5
Pathogenic
1
Likely Pathogenic
144
VUS
125
Likely Benign
6
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
3
0
5
Likely Pathogenic
0
1
0
0
1
VUS
3
122
17
2
144
Likely Benign
0
1
67
57
125
Benign
0
0
6
0
6
Conflicting
—1
Total31269359282

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

View in ClinVar →

Protein Context — Lollipop Plot

STAT4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Systemic lupus erythematosus, susceptibility to, 11}

MIM #612253

Molecular basis of disorder known

Autosomal dominant

Disabling pansclerotic morphea of childhood

MIM #620443

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
JAK: Not Just Another Kinase.
Agashe RP et al.·Mol Cancer Ther
2022Review
Precision medicine in systemic lupus erythematosus.
Fasano S et al.·Nat Rev Rheumatol
2023Review
Classification of triple-negative breast cancers based on Immunogenomic profiling.
He Y et al.·J Exp Clin Cancer Res
2018
UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer.
Xiao J et al.·J Clin Invest
2023
Uveitis genetics.
Hou S et al.·Exp Eye Res
2020Review
IL-9 signaling redirects CAR T cell fate toward CD8(+) memory and CD4(+) cycling states, enhancing antitumor efficacy.
Castelli S et al.·Immunity
2026
Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation.
Scarno G et al.·Proc Natl Acad Sci U S A
2023
MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas.
Wang QW et al.·J Immunother Cancer
2021
Genetics of Antiphospholipid Syndrome.
Ortiz-Fernández L et al.·Curr Rheumatol Rep
2019Review
A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage.
Alexander MR et al.·Circ Res
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Molecular docking and dynamics simulations identify marine sponge-derived Halenaquinone as a promising STAT4 modulator for rheumatic heart disease.
Skariyachan S et al.·SAR QSAR Environ Res
2026
Deficiency of osteopontin in gut epithelial cells enhances intestinal integrity by promoting gut renewal through the JAK3/STAT4 pathway in acetaminophen (APAP)-induced acute liver injury.
Yu C et al.·Cell Commun Signal
2026🔓 Open Access
In Silico Functional and Structural Analysis of STAT4 Variants of Uncertain Significance.
Bravo-Villagra KM et al.·Genes (Basel)
2026🔓 Open AccessFunctional
Polymorphisms in STAT4 and PTPRC genes in rheumatoid arthritis: a Brazilian study and meta-analysis of susceptibility and TNFi response.
de Araújo JLF et al.·Immunol Res
2025
miR-197-y and novel-m0012-5p modulate Th cell differentiation via STAT4/STAT6 in flounder (Paralichthys olivaceus).
Ye M et al.·Fish Shellfish Immunol
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools