STAT4

Summary

STAT4 (signal transducer and activator of transcription 4, HGNC:11365) is a protein-coding gene on chromosome 2q32.2-q32.3, encoding Signal transducer and activator of transcription 4 (Q14765). Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response.

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.

Source: NCBI Gene 6775 — RefSeq curated summary.

At a glance

• Gene–disease (curated): disabling pansclerotic morphea of childhood (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 94 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 532 total — 1 pathogenic, 1 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 34 tissues, sQTL in 9 (q < 0.05)
• Phenotypes (HPO): 193
• Constraint (gnomAD): pLI 0.93 (loss-of-function intolerant), LOEUF 0.50 (moderately constrained)
• Transcription factor: yes — 33 downstream targets (CollecTRI)
• MANE Select transcript: NM_003151
• Interaction hub: 1,992 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11365
Approved symbol	STAT4
Name	signal transducer and activator of transcription 4
Location	2q32.2-q32.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138378
Ensembl biotype	protein_coding
OMIM	600558
Entrez	6775

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 17 protein_coding, 4 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 3 retained_intron

MANE Select: ENST00000392320

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 2, TSL 4: 1, TSL 5: 4

ENST00000392320, ENST00000358470, ENST00000409995, ENST00000413064, ENST00000432798, ENST00000450994, ENST00000463951, ENST00000470708, ENST00000495326, ENST00000495849, ENST00000647167, ENST00000714286, ENST00000714287, ENST00000714288, ENST00000714335, ENST00000714336, ENST00000960212, ENST00000960213, ENST00000960214, ENST00000960215, ENST00000960216, ENST00000960217, ENST00000960218, ENST00000999200, ENST00001049366, ENST00001049367, ENST00001102107, ENST00001145365

RefSeq mRNA: 2 — MANE Select: NM_003151 NM_001243835, NM_003151

CCDS: CCDS2310

Canonical transcript exons

ENST00000392320 — 24 exons

Exon	Start	End
ENSE00001372547	191029576	191029866
ENSE00001616842	191030972	191031080
ENSE00001788358	191031450	191031516
ENSE00001845053	191150947	191150994
ENSE00003459083	191054490	191054534
ENSE00003481696	191073098	191073190
ENSE00003487965	191033490	191033626
ENSE00003497169	191069693	191069771
ENSE00003498179	191032958	191033149
ENSE00003516088	191041065	191041148
ENSE00003523522	191034548	191034597
ENSE00003543489	191036164	191036299
ENSE00003563758	191148076	191148204
ENSE00003581307	191039199	191039297
ENSE00003584777	191062762	191062920
ENSE00003591717	191033911	191034005
ENSE00003601043	191061729	191061821
ENSE00003603366	191064807	191064958
ENSE00003610045	191058202	191058219
ENSE00003640858	191146613	191146757
ENSE00003652296	191066430	191066515
ENSE00003684846	191058018	191058111
ENSE00003688547	191058710	191058769
ENSE00003788940	191076227	191076325

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 96.60.

FANTOM5 (CAGE): breadth broad, TPM avg 10.9745 / max 558.7582, expressed in 734 samples.

Highest expression (Bgee): granulocyte, sperm, middle temporal gyrus, male germ cell, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

STAT4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 34 tissues and its splicing (sQTL) in 9 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 43 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	eqtl	6.2e-61	-0.46	2:191243882:C:T
Nerve Tibial	eqtl	1.4e-37	-0.50	2:191241877:C:T
Muscle Skeletal	eqtl	1.0e-34	-0.51	2:191243882:C:T
Testis	sqtl	1.3e-31	+0.93	2:191129374:G:A
Artery Tibial	eqtl	4.6e-30	-0.35	2:191241877:C:T
Cells EBV-transformed lymphocytes	eqtl	4.0e-27	-0.66	2:191155892:A:C
Breast Mammary Tissue	eqtl	4.2e-21	-0.32	2:191243882:C:T
Skin Sun Exposed Lower leg	eqtl	9.7e-19	-0.26	2:191243882:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.7e-15	+0.27	2:191242980:T:C
Thyroid	eqtl	5.7e-14	-0.19	2:191241877:C:T
Pancreas	eqtl	1.1e-12	+0.50	2:191249952:A:C
Colon Sigmoid	eqtl	2.7e-12	-0.30	2:191243882:C:T
Adipose Visceral Omentum	eqtl	6.0e-12	-0.26	2:191240909:C:T
Esophagus Muscularis	eqtl	2.9e-10	-0.23	2:191240909:C:T
Artery Aorta	eqtl	3.1e-10	-0.28	2:191241877:C:T
Whole Blood	sqtl	1.6e-09	-0.37	2:191131792:T:C
Ovary	eqtl	4.1e-09	-0.46	2:191243882:C:T
Lung	eqtl	1.5e-07	-0.12	2:191237092:C:T
Prostate	eqtl	4.8e-07	+0.30	2:191249952:A:C
Thyroid	sqtl	1.4e-06	+0.41	2:191240909:C:T

FANTOM5 promoters

10 alternative TSS:

Promoter ID	TPM avg	Samples expressed
32938	6.7085	515
32939	3.1743	477
32937	0.6096	103
32936	0.2539	69
32935	0.0879	38
32931	0.0743	25
32930	0.0374	9
32941	0.0113	3
32940	0.0099	3
32942	0.0074	4

Top tissues by expression

showing 100 of 281 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.60	gold quality
sperm	CL:0000019	93.37	gold quality
middle temporal gyrus	UBERON:0002771	93.17	gold quality
male germ cell	CL:0000015	91.69	gold quality
blood	UBERON:0000178	90.24	gold quality
right atrium auricular region	UBERON:0006631	89.56	gold quality
cardiac atrium	UBERON:0002081	89.50	gold quality
cardiac muscle of right atrium	UBERON:0003379	88.85	gold quality
left testis	UBERON:0004533	88.26	gold quality
right testis	UBERON:0004534	88.23	gold quality
pituitary gland	UBERON:0000007	87.71	gold quality
right frontal lobe	UBERON:0002810	87.04	gold quality
spleen	UBERON:0002106	86.78	gold quality
adenohypophysis	UBERON:0002196	86.64	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.52	gold quality
testis	UBERON:0000473	85.83	gold quality
Brodmann (1909) area 10	UBERON:0013541	85.77	gold quality
lymph node	UBERON:0000029	85.39	gold quality
primary visual cortex	UBERON:0002436	85.13	gold quality
prefrontal cortex	UBERON:0000451	85.10	gold quality
right lobe of liver	UBERON:0001114	84.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.51	gold quality
frontal cortex	UBERON:0001870	84.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.39	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.03	gold quality
bone marrow cell	CL:0002092	83.02	gold quality
neocortex	UBERON:0001950	82.59	gold quality
vermiform appendix	UBERON:0001154	81.84	gold quality
colonic epithelium	UBERON:0000397	81.53	gold quality
right lung	UBERON:0002167	80.80	gold quality
occipital lobe	UBERON:0002021	80.72	gold quality
cingulate cortex	UBERON:0003027	80.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.64	gold quality
anterior cingulate cortex	UBERON:0009835	80.56	gold quality
superior frontal gyrus	UBERON:0002661	80.15	gold quality
orbitofrontal cortex	UBERON:0004167	80.04	gold quality
omental fat pad	UBERON:0010414	79.78	gold quality
peritoneum	UBERON:0002358	79.68	gold quality
islet of Langerhans	UBERON:0000006	79.55	gold quality
bone marrow	UBERON:0002371	79.33	gold quality
upper lobe of left lung	UBERON:0008952	79.30	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.16	gold quality
cerebral cortex	UBERON:0000956	79.05	gold quality
gall bladder	UBERON:0002110	79.05	gold quality
apex of heart	UBERON:0002098	78.99	gold quality
superficial temporal artery	UBERON:0001614	78.97	silver quality
nucleus accumbens	UBERON:0001882	78.72	gold quality
amniotic fluid	UBERON:0000173	77.82	gold quality
small intestine	UBERON:0002108	77.74	gold quality
forebrain	UBERON:0001890	77.05	gold quality
postcentral gyrus	UBERON:0002581	76.96	gold quality
hypothalamus	UBERON:0001898	76.87	gold quality
frontal pole	UBERON:0002795	76.81	gold quality
caecum	UBERON:0001153	76.66	gold quality
heart	UBERON:0000948	76.65	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.63	gold quality
upper lobe of lung	UBERON:0008948	76.53	gold quality
telencephalon	UBERON:0001893	76.36	gold quality
parietal lobe	UBERON:0001872	75.90	gold quality
ileal mucosa	UBERON:0000331	75.55	silver quality
rectum	UBERON:0001052	75.49	gold quality
left ventricle myocardium	UBERON:0006566	75.49	gold quality
caudate nucleus	UBERON:0001873	75.16	gold quality
calcaneal tendon	UBERON:0003701	74.90	gold quality
adipose tissue	UBERON:0001013	74.77	gold quality
myocardium	UBERON:0002349	74.62	gold quality
liver	UBERON:0002107	74.41	gold quality
connective tissue	UBERON:0002384	74.09	gold quality
brain	UBERON:0000955	73.95	gold quality
central nervous system	UBERON:0001017	73.66	gold quality
leukocyte	CL:0000738	73.64	gold quality
jejunal mucosa	UBERON:0000399	73.59	gold quality
endothelial cell	CL:0000115	73.58	silver quality
pancreas	UBERON:0001264	73.48	gold quality
mucosa of transverse colon	UBERON:0004991	73.12	gold quality
epithelium of nasopharynx	UBERON:0001951	72.92	silver quality
lung	UBERON:0002048	72.73	gold quality
tonsil	UBERON:0002372	72.66	gold quality
right coronary artery	UBERON:0001625	72.54	gold quality
decidua	UBERON:0002450	72.50	silver quality
heart left ventricle	UBERON:0002084	72.28	gold quality
mucosa of stomach	UBERON:0001199	72.12	gold quality
left uterine tube	UBERON:0001303	72.10	gold quality
anatomical system	UBERON:0000467	71.83	gold quality
mononuclear cell	CL:0000842	71.77	gold quality
material anatomical entity	UBERON:0000465	71.67	gold quality
multicellular organism	UBERON:0000468	71.67	gold quality
transverse colon	UBERON:0001157	71.67	gold quality
body of stomach	UBERON:0001161	71.49	gold quality
cardiac ventricle	UBERON:0002082	71.30	gold quality
intestine	UBERON:0000160	71.08	gold quality
monocyte	CL:0000576	71.01	gold quality
body of pancreas	UBERON:0001150	70.80	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.71	gold quality
lower esophagus	UBERON:0013473	70.65	gold quality
stromal cell of endometrium	CL:0002255	70.59	gold quality
pancreatic ductal cell	CL:0002079	70.56	silver quality
left lobe of thyroid gland	UBERON:0001120	70.54	gold quality
adult organism	UBERON:0007023	70.51	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	29.69
E-MTAB-6678	yes	27.01
E-CURD-46	yes	20.91
E-MTAB-9067	yes	4.78
E-CURD-112	yes	3.41
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Testis	tissue	27.2	high
Postcentral gyrus	tissue	23.0
Heart muscle	tissue	19.6	not detected
Lymph node	tissue	16.9	low
Pituitary gland	tissue	15.8
Bone marrow	tissue	14.8	low
Spleen	tissue	14.6	low
Appendix	tissue	10.9	low
Tonsil	tissue	9.8	low
Nucleus accumbens	tissue	8.9
Thymus	tissue	8.4
Liver	tissue	7.1	low
Lung	tissue	5.8	low
Locus coeruleus	tissue	5.7
Urinary bladder	tissue	5.5	medium
Small intestine	tissue	5.5	medium
Gallbladder	tissue	4.7	low
Adipose tissue	tissue	4.4	not detected
Duodenum	tissue	4.2	low
Stomach 1	tissue	4.1	medium
Basal ganglia	tissue	3.9	low
Adrenal gland	tissue	3.8	low
Putamen	tissue	3.3
Rectum	tissue	3.2	low
Hippocampus	tissue	3.2	medium
Choroid plexus	tissue	3.1
Ventral forebrain	tissue	2.8
Colon	tissue	2.6	low
Placenta	tissue	2.5	low
Septum	tissue	2.5
Epididymis	tissue	2.4	low
Superior colliculi	tissue	2.4
Breast	tissue	2.3	low
Salivary gland	tissue	2.1	not detected
Pancreas	tissue	2.1	low
Pons	tissue	2.0
Vagina	tissue	2.0	not detected
Retina	tissue	1.9
Thalamus	tissue	1.9
Endometrium 1	tissue	1.8	not detected
Midbrain	tissue	1.6
Medulla oblongata	tissue	1.6
Spinal cord	tissue	1.5
Hippocampal formation	tissue	1.5
Ovary	tissue	1.4	not detected
Prostate	tissue	1.4	low
Periaqueductal gray	tissue	1.4
Fallopian tube	tissue	1.4	low
Cerebral cortex	tissue	1.3	medium
Esophagus	tissue	1.3	not detected
Smooth muscle	tissue	1.3	not detected
Temporal cortex	tissue	1.3
Cervix	tissue	1.2	not detected
Seminal vesicle	tissue	1.2	not detected
Parathyroid gland	tissue	1.1	medium
Skeletal muscle	tissue	1.1	not detected
Frontal cortex	tissue	1.1
Amygdala	tissue	1.1
Kidney	tissue	1.1	low
Tongue	tissue	1.0

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Postcentral gyrus, middle (21.9), Precentral gyrus, ventral (21.4), Precentral gyrus, middle (20.8), Transversal temporal gyrus, anterior (20.8), Frontal eye field (20.6).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 33 targets:

Target	Regulation
AKT1
CD4	Activation
CD8A	Activation
CREBBP
CSF2	Activation
FATE1
FCGRT
HAND1
IFNA1
IFNG	Unknown
IL10	Activation
IL12B
IL12RB2	Activation
IL13	Unknown
IL17A	Unknown
IL21	Activation
IL2RA	Unknown
IRF1	Unknown
IRF4
LTA	Repression
MYC	Activation
NOS2	Activation
NOX1	Unknown
NOX4	Unknown
PIK3R1
PIM1	Unknown
PRF1	Activation
PRKCQ
S100A4	Activation
SOCS3	Repression

Upstream regulators (CollecTRI, top): CREB1, DNMT3A, GATA3, NFKB1, NFKB, PITX2, POU2F1, REL, RELA, SMAD3, SP1, STAT4, STAT6, TBX21

miRNA regulators (miRDB)

Targeting STAT4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-2115-5P	98.66	68.07	1191
HSA-MIR-4704-3P	98.28	69.33	1300

Functional genomics

gnomAD constraint: pLI 0.935, LOEUF 0.503, missense Z 3.21 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000392320 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:191,029,843–191,031,485	32 / 67.6	0.47	no
2:191,031,486–191,033,006	38 / 33.2	1.15	no
2:191,033,007–191,034,559	74 / 154.3	0.48	no
2:191,034,560–191,148,203	488 / 632.8	0.77	no

Literature-anchored findings (GeneRIF, showing 40)

• STAT4 regulates IL-12-induced expression of the perforin gene in NK cells (PMID:12372421)
• Active STAT4, essential for IL-12-mediated Th1 differentiation, is readily detectable in biopsies from Peyer’s patches and ileal mucosa, and STAT4-DNA binding activity is demonstrable by electrophoretic mobility-shift assay of lamina propria lymphocytes. (PMID:12496413)
• STAT4 is constitutively activated in Crohn’s patients but not in healthy volunteers (PMID:12615922)
• STAT4 is repressed by PIASx (PMID:12716907)
• requires the N-terminal domain for efficient phosphorylation (PMID:12805384)
• STAT4 signaling in human vascular endothelial cells is activated by interferon alpha but not by IL-12 (PMID:15087447)
• The STAT4 is transactivated by Ikaros (Ik) and Ik binding elements were revealed in its promoter. (PMID:16081070)
• identify and characterize the transcriptional regulatory elements in the promoter region of the human STAT4 gene. (PMID:16301617)
• these results indicate that STAT-4 can be finely tuned along with DC maturation through NF-kappaB activation and that its induction may be involved in preparing the DC to be receptive to the cytokine environment present in lymphoid organs. (PMID:17046972)
• IFNAR2 cytoplasmic domain serves to link STAT4 to the IFNAR as a pre-assembled complex that facilitates cytokine-driven STAT4 activation. (PMID:17095088)
• STAT-4 T90089C polymorphism might be the genetic factor for the risk of asthma in the Chinese population (PMID:17532201)
• A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses. (PMID:17804842)
• A haplotype of the STAT4 gene shows consistent association with rheumatoid arthritis susceptibility across Whites and Asians. (PMID:17932559)
• Single nucleotide polymorphisms in the STAT4 gene are associated with primary Sjogren’s syndrome. (PMID:18273036)
• STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians. (PMID:18432273)
• STAT4 and the TRAF1/C5 loci are associated with rheumatoid arthritis susceptibility. (PMID:18434327)
• STAT4 contributes to the phenotypic heterogeneity of systemic lupus erythematosus, predisposing specifically to more severe disease. (PMID:18516230)
• We conclude that STAT4 is associated with RA and SLE in the Japanese. (PMID:18576330)
• Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data. (PMID:18576336)
• The SNP rs7582694 in STAT4 displayed a increased risk of systemic lupus erythematosus with two independent risk alleles of the IRF5. (PMID:18579578)
• study concludes that mutant alleles or genotypes of both TRAF1 and STAT4 polymorphisms are associated with the development of Rheumatoid arthritis in our population. (PMID:18625278)
• in a genetically homogeneous population, the STAT4 rs7574865 G/T polymorphism, which has been shown to be associated with several autoimmune diseases, is associated with susceptibility to type 1 diabetes (T1D) (PMID:18703106)
• The association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin and described for the first time in both clinical forms of inflammatory bowel disease, Crohn’s disease, ulcerative colitis and type 1 diabetes mellitus. (PMID:18759272)
• T helper (Th) type 1 cells expressing transgenic STAT4 beta (an isoform lacking the C-terminal transactivation domain) secrete significantly more tumor necrosis factor-alpha upon T cell receptor stimulation than transgenic STAT4alpha-expressing Th1 cells. (PMID:18802110)
• The same STAT4 risk allele is associated with SLE in Caucasian and Japanese populations. (PMID:18803832)
• Data confirm STAT4 as a susceptibility gene for systemic lupus erythematosus and suggest the presence of at least two functional variants affecting levels of STAT4 and also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE (PMID:19019891)
• Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogren’s syndrome are reported. (PMID:19092842)
• The risk allele of STAT4 is associated with increased sensitivity to IFN-alpha signaling in systemic lupus erythematosus. (PMID:19109131)
• The age at diagnosis is lowest in the patients carrying the homozygotes of a minor allele, middle in the heterozygotes, and highest in the homozygotes of a major allele, suggesting the dosage effects of risk alleles on the age of onset of disease. (PMID:19120275)
• Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) =1.71, P=3.55 x 10(-23)) and BLK (rs13277113, OR=0.77, P=1.34 x 10(-5)) with SLE (PMID:19225526)
• Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients. (PMID:19282076)
• STAT4 influences the genetic predisposition to systemic sclerosis phenotype. (PMID:19286670)
• Our results do not support a major role of the STAT4 rs7574865 gene polymorphism in susceptibility to or clinical manifestations of giant cell arteritis. (PMID:19332627)
• STAT4 is likely to be a crucial component in systemic lupus erythematosus pathogenesis in multiple racial groups (PMID:19333953)
• STAT4 is required for optimal human Th1 lineage development (PMID:19359411)
• Focusing on how STAT4 work in concert with other transcription factors will hopefully provide a better mechanistic understanding of the pathogenesis of various autoimmune diseases. (PMID:19362457)
• STAT4 is not associated with type 2 diabetes in the genetically homogeneous population of Crete. (PMID:19371230)
• Our results replicate and firmly establish the association of STAT4 and CTLA4 with RA and provide highly suggestive evidence for IL2/IL21 loci as a risk factor for RA. (PMID:19404967)
• The results of this meta-analysis demonstrated that STAT4 rs7574865 single nucleotide polymorphism is significantly associated with rheumatoid arthritis and systemic lupus erythematosus. (PMID:19479340)
• single nucleotide polymorphism is associated with psoriasis in population of Crete, Greece (PMID:19500629)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	stat4	ENSDARG00000028731
mus_musculus	Stat4	ENSMUSG00000062939
drosophila_melanogaster	Stat92E	FBGN0016917
caenorhabditis_elegans		WBGENE00010251
caenorhabditis_elegans		WBGENE00013111

Paralogs (6): STAT1 (ENSG00000115415), STAT5A (ENSG00000126561), STAT6 (ENSG00000166888), STAT3 (ENSG00000168610), STAT2 (ENSG00000170581), STAT5B (ENSG00000173757)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103062) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 25 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating interferon-gamma level	4
increased susceptibility to bacterial infection	2
decreased susceptibility to autoimmune diabetes	2
decreased interferon-gamma secretion	2
increased susceptibility to bacterial infection induced morbidity/mortality	2
abnormal NK cell physiology	2
abnormal circulating glucose level	1
cataract	1
cornea opacity	1
abnormal inflammatory response	1
abnormal kidney morphology	1
abnormal kidney physiology	1
abnormal vitreous body morphology	1
small kidney	1
abnormal cytokine secretion	1
abnormal insulin secretion	1
abnormal lymphocyte physiology	1
abnormal T cell proliferation	1
abnormal pancreatic beta cell morphology	1
abnormal T-helper 1 physiology	1
abnormal T-helper 2 physiology	1
abnormal CD4-positive T cell differentiation	1
decreased circulating interleukin-2 level	1
increased circulating interleukin-12 level	1
increased interleukin-4 secretion	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Rattus norvegicus	P52631	99.9%	Diamond
Sus scrofa	Q19S50	99.7%	Diamond
Bos taurus	P61635	99.4%	Diamond
Gallus gallus	Q6DV79	97.5%	Diamond
Xenopus laevis	Q7ZXK3	96.1%	Diamond
Arabidopsis thaliana	B5X561	67.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
STAT4-AS1	ncRNA	105373805
GLS	protein-coding	2744
STAT1	protein-coding	6772
MYO1B-AS1	ncRNA	122152331
MYO1B	protein-coding	4430

Protein

Protein identifiers

Signal transducer and activator of transcription 4 — Q14765 (reviewed: Q14765)

All UniProt accessions (8): A0A2R8Y693, A0AAQ5BHR1, A0AAQ5BHW3, C9JFG0, C9JM11, E9PBE2, E9PG69, Q14765

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response. Plays a key role in the differentiation of T-helper 1 cells and the production of interferon-gamma. Also participates in multiple neutrophil functions including chemotaxis and production of the neutrophil extracellular traps. After IL12 binding to its receptor IL12RB2, STAT4 interacts with the intracellular domain of IL12RB2 and becomes tyrosine phosphorylated. Phosphorylated STAT4 then homodimerizes and migrates to the nucleus where it can recognize STAT target sequences present in IL12 responsive genes. Although IL12 appears to be the predominant activating signal, STAT4 can also be phosphorylated and activated in response to IFN-gamma stimulation via JAK1 and TYK2 and in response to different interleukins including IL23, IL2 and IL35. Transcription activation of IFN-gamma gene is mediated by interaction with JUN that forms a complex that efficiently interacts with the AP-1-related sequence of the IFN-gamma promoter. In response to IFN-alpha/beta signaling, acts as a transcriptional repressor and suppresses IL5 and IL13 mRNA expression during response to T-cell receptor (TCR) activation.

Subunit / interactions. Forms a homodimer or a heterodimer with a related family member. Interacts with ARL2BP. The SH2 domain interacts, in vitro, with IL12RB2 via a short cytoplasmic domain. Interacts with STAT1. Interacts with JUN; this complex efficiently interacts with the AP-1-related sequence of the IFN-gamma.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Acetylation at Lys-667 is required for JAK2-mediated phosphorylation and activation of STAT4. Tyrosine phosphorylated upon IL12 and IFN-alpha activation, but not by IFN-gamma in T-lymphocytes and NK cells. Serine phosphorylation is required for maximal transcriptional activity but not for DNA binding. Phosphorylation by MAP2K6 at Ser-721 is required for full transcriptional activity induced by IL12. However this serine phosphorylation is not required for cell proliferation although critical for IFN-gamma production.

Disease relevance. Systemic lupus erythematosus 11 (SLEB11) [MIM:612253] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. Rheumatoid arthritis (RA) [MIM:180300] An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Disease susceptibility is associated with variants affecting the gene represented in this entry. Disabling pansclerotic morphea of childhood (DPMC) [MIM:620443] An autosomal dominant, severe systemic inflammatory disorder that is part of the juvenile localized scleroderma spectrum. DPMC is characterized by poor wound healing with rapidly progressive deep fibrosis involving the mucous membranes, dermis, subcutaneous fat, fascia, muscles, and bone, leading to contractures, musculoskeletal atrophy, and articular ankylosis. Systemic manifestations include cytopenias and hypogammaglobulinemia, but scleroderma-associated autoantibodies are usually not present. The disorder is associated with high morbidity and mortality due to squamous-cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the transcription factor STAT family.

RefSeq proteins (2): NP_001230764, NP_003142* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001217	STAT	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR012345	STAT_TF_DNA-bd_N	Homologous_superfamily
IPR013799	STAT_TF_prot_interaction	Domain
IPR013800	STAT_TF_alpha	Domain
IPR013801	STAT_TF_DNA-bd	Domain
IPR015988	STAT_TF_CC	Homologous_superfamily
IPR029839	STAT4_DBD	Domain
IPR035856	STAT4_SH2	Domain
IPR036535	STAT_N_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR046991	STAT4_CC	Domain
IPR048988	STAT_linker	Domain

Pfam: PF00017, PF01017, PF02864, PF02865, PF21354

UniProt features (14 total): sequence variant 6, modified residue 3, mutagenesis site 2, chain 1, domain 1, sequence conflict 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14765-F1	86.87	0.65

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Immunoglobulin fold, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; nucleoplasm; flagellar centriole

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3)

Type	Positions
N6-acetyllysine	667
Phosphotyrosine	693
Phosphoserine	721

Mutagenesis-validated functional residues (2)

Position	Phenotype
693	abrogates phosphorylation and transcriptional activity.
721	about 50% loss of transcriptional activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 12; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	curated
R-HSA-8854691	Interleukin-20 family signaling	curated
R-HSA-9020958	Interleukin-21 signaling	curated
R-HSA-9020933	Interleukin-23 signaling	curated
R-HSA-8984722	Interleukin-35 Signalling	curated
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-9942503	Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	electronic
R-HSA-168256	Immune System	—
R-HSA-447115	Interleukin-12 family signaling	—
R-HSA-9020591	Interleukin-12 signaling	electronic
R-HSA-451927	Interleukin-2 family signaling	—
R-HSA-449147	Signaling by Interleukins	—

MSigDB gene sets: 696 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, AGGAAGC_MIR5163P, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, LU_IL4_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, MODULE_45, MODULE_64, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, NIKOLSKY_OVERCONNECTED_IN_BREAST_CANCER, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE

GO Biological Process (14): DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), defense response (GO:0006952), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), cytokine-mediated signaling pathway (GO:0019221), interleukin-12-mediated signaling pathway (GO:0035722), regulation of cell population proliferation (GO:0042127), response to peptide hormone (GO:0043434), T-helper 1 cell differentiation (GO:0045063), positive regulation of transcription by RNA polymerase II (GO:0045944), response to interleukin-6 (GO:0070741), regulation of DNA-templated transcription (GO:0006355), immune response (GO:0006955), signal transduction (GO:0007165)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), identical protein binding (GO:0042802), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear body (GO:0016604), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Signaling by Interleukins	3
Interleukin-12 family signaling	3
Interleukin-12 signaling	1
Interleukin-2 family signaling	1
Differentiation of T cells	1
Immune System	1
Cytokine Signaling in Immune system	1

GO top-level categories

50 GO namespaces:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of cellular process	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
gene expression	1
RNA biosynthetic process	1
response to stress	1
cell surface receptor signaling pathway via STAT	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-12	1
cell population proliferation	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
alpha-beta T cell activation involved in immune response	1
T cell differentiation involved in immune response	1
T-helper 1 type immune response	1
T-helper cell differentiation	1
positive regulation of DNA-templated transcription	1
response to cytokine	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
protein binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1
transcription regulator complex	1
nuclear protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 27 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
T-helper 1 cell differentiation	BP	direct assay
interleukin-12-mediated signaling pathway	BP	direct assay
response to interleukin-6	BP	mutant phenotype
nuclear body	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
DNA-binding transcription factor activity	MF	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,992 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAT4	IL12RB2	Q99665	883
STAT4	IFNG	P01579	878
STAT4	TBX21	Q9UL17	877
STAT4	TYK2	P29597	877
STAT4	IL12RB1	P42701	868
STAT4	CD4	P01730	808
STAT4	IRF5	Q13568	801
STAT4	GATA3	P23771	780
STAT4	IL23R	Q5VWK5	774
STAT4	IL4	P05112	773
STAT4	IFNA13	P01562	771
STAT4	IL10	P22301	770
STAT4	JAK1	P23458	769
STAT4	IL17A	Q16552	762
STAT4	CD8A	P01732	749

IntAct

Human interaction partners of STAT4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

16 partners by confidence:

Partner	Interaction type	MIscore	Records
KLF11	physical association	0.560	3
NUP58	physical association	0.560	3
STAT1	physical association	0.540	1
IL12RB2	association	0.530	2
CRK	physical association	0.490	2
SH2D1B	physical association	0.490	2
LAMTOR5	physical association	0.400	2
NMI	physical association	0.400	1
FLOT1	association	0.350	1
ZNF136	association	0.350	1
FBXW7	proximity	0.270	4
SMAD4	proximity	0.270	4
SPOP	proximity	0.270	4
AKT1	proximity	0.270	1
BRAF	proximity	0.270	1
KMT2D	proximity	0.270	1

BioGRID (36 interactions; top human partners by supporting records): STAT1 (Reconstituted Complex; 3 records), ADRB2 (PCA; 2 records), ALMS1 (Proximity Label-MS), BCL7A (Proximity Label-MS), BICD2 (Affinity Capture-Western), C2orf44 (Proximity Label-MS), CRK (Two-hybrid), DIS3L (Proximity Label-MS), ECH1 (Proximity Label-MS), FLOT1 (Affinity Capture-MS), FLOT2 (Affinity Capture-MS), IL12RB2 (Protein-peptide), JUN (Affinity Capture-Western), KMT2D (Proximity Label-MS), NUP62 (Proximity Label-MS)

SIGNOR signaling

10 signaling interactions:

A	Effect	B	Mechanism
JAK2	up-regulates	STAT4	phosphorylation
MAPK14	up-regulates	STAT4	phosphorylation
STAT4	“up-regulates quantity by expression”	PRF1	“transcriptional regulation”
STAT4	“up-regulates quantity by expression”	S100A4	“transcriptional regulation”
STAT4	“up-regulates activity”	LAMTOR5	binding
TYK2	“up-regulates activity”	STAT4	phosphorylation
IL12A	“up-regulates activity”	STAT4	binding
STAT4	“up-regulates activity”	IFNG	“transcriptional regulation”
IL23R	up-regulates	STAT4
MAP2K6	“up-regulates activity”	STAT4	phosphorylation

Disease & clinical

Genetic variants

Variant evidence for STAT4: 532 ClinVar records (2 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 94 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

532 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	230
Likely benign	250
Benign	20

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2572046	NM_003151.4(STAT4):c.1904C>T (p.Ala635Val)	Likely pathogenic	criteria provided, single submitter	2
2572048	NM_003151.4(STAT4):c.1867C>T (p.His623Tyr)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore STAT4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 2,156):

Position(s)	Effect	Δscore	Sites
2:191032956	donor_gain	1.0000
2:191033151	acceptor_gain	1.0000
2:191033909–191033910	donor_loss	1.0000	5
2:191034006–191034007	acceptor_loss	1.0000	6
2:191034010	acceptor_gain	1.0000
2:191036162–191036163	donor_loss	1.0000	5
2:191041063–191041064	donor_loss	1.0000	3
2:191041149	acceptor_gain	1.0000
2:191041150	acceptor_loss	1.0000
2:191054537	acceptor_gain	1.0000

AlphaMissense

1,892 missense substitutions predicted likely pathogenic (of 4,973 scored), across 482 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M324	9	0.964	0.997
F577	8	0.993	1.000
F595	8	0.992	1.000
S600	8	0.990	0.999
F599	8	0.983	1.000
F671	8	0.978	0.999
H427	8	0.977	0.998
F502	8	0.973	0.999
F340	8	0.970	0.999
F483	8	0.966	0.995
F431	8	0.965	0.996
F375	8	0.955	0.999
D291	8	0.953	0.986
F399	8	0.947	0.998
F538	8	0.939	0.998
H401	8	0.933	0.989
F609	8	0.922	0.998
F26	8	0.912	0.997
D364	8	0.910	0.979
H81	8	0.879	0.988

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (TCGA)	favorable	3.11e-05
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000836

Disease associations

OMIM: gene MIM:600558 | disease phenotypes: MIM:620443

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
disabling pansclerotic morphea of childhood	Strong	Autosomal dominant	2
systemic lupus erythematosus	Supportive	Unknown

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (2): disabling pansclerotic morphea of childhood (MONDO:0957497), systemic lupus erythematosus (MONDO:0007915)

HPO phenotypes

showing 60 of 193 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000031	Epididymitis
HP:0000079	Abnormality of the urinary system
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000099	Glomerulonephritis
HP:0000100	Nephrotic syndrome
HP:0000123	Nephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000554	Uveitis
HP:0000572	Visual loss
HP:0000585	Band keratopathy
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000707	Abnormality of the nervous system
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000737	Irritability
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000951	Abnormality of the skin
HP:0000969	Edema
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity
HP:0001061	Acne
HP:0001094	Iridocyclitis
HP:0001097	Keratoconjunctivitis sicca
HP:0001155	Abnormality of the hand
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001269	Hemiparesis
HP:0001287	Meningitis
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001369	Arthritis
HP:0001370	Rheumatoid arthritis
HP:0001371	Flexion contracture
HP:0001382	Joint hypermobility
HP:0001384	Abnormal hip joint morphology
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001433	Hepatosplenomegaly
HP:0001482	Subcutaneous nodule
HP:0001508	Failure to thrive
HP:0001530	Mild postnatal growth retardation
HP:0001541	Ascites
HP:0001596	Alopecia
HP:0001637	Abnormal myocardium morphology
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001659	Aortic regurgitation
HP:0001698	Pericardial effusion
HP:0001701	Pericarditis
HP:0001733	Pancreatitis

GWAS associations

showing 30 of 94 associations:

Study	Trait	p-value
GCST011956_104	Systemic lupus erythematosus	5e-123
GCST003155_41	Systemic lupus erythematosus	6e-122
GCST005752_34	Systemic lupus erythematosus	1e-77
GCST003156_4	Systemic lupus erythematosus	2e-76
GCST007400_55	Systemic lupus erythematosus	4e-69
GCST003622_3	Systemic lupus erythematosus	1e-65
GCST007278_9	Systemic seropositive rheumatic diseases (Systemic sclerosis or systemic lupus erythematosus or rheumatoid arthritis or idiopathic inflammatory myopathies)	3e-42
GCST000507_11	Systemic lupus erythematosus	5e-42
GCST004867_27	Systemic lupus erythematosus	1e-41
GCST007932_44	Medication use (thyroid preparations)	3e-39
GCST010571_48	Autoimmune thyroid disease	5e-39
GCST005581_3	Primary biliary cirrhosis	9e-25
GCST009131_5	Systemic sclerosis	2e-23
GCST003622_26	Systemic lupus erythematosus	4e-22
GCST001795_19	Systemic lupus erythematosus	1e-21
GCST000996_2	Systemic lupus erythematosus	2e-20
GCST006959_32	Rheumatoid arthritis	5e-20
GCST001010_12	Primary biliary cholangitis	2e-19
GCST003599_6	Systemic lupus erythematosus	2e-19
GCST90010715_4	Arthritis (juvenile idiopathic)	2e-19
GCST002318_60	Rheumatoid arthritis	4e-19
GCST005581_21	Primary biliary cirrhosis	3e-18
GCST005581_1	Primary biliary cirrhosis	5e-18
GCST002217_2	Sjögren’s syndrome	2e-17
GCST007278_8	Systemic seropositive rheumatic diseases (Systemic sclerosis or systemic lupus erythematosus or rheumatoid arthritis or idiopathic inflammatory myopathies)	3e-17
GCST006048_46	Rheumatoid arthritis (ACPA-positive)	4e-17
GCST003156_35	Systemic lupus erythematosus	9e-17
GCST006019_45	Gamma glutamyl transferase levels	3e-16
GCST005752_104	Systemic lupus erythematosus	6e-16
GCST011426_4	Systemic lupus erythematosus	8e-16

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0004267	biliary liver cirrhosis
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:1001017	limited scleroderma
EFO:0008536	anti-centromere-antibody-positive systemic scleroderma
EFO:0009087	non-typhoidal Salmonella bacteremia
EFO:0009933	Thyroid preparation use measurement
EFO:0004842	eosinophil count

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523296 (SINGLE PROTEIN), CHEMBL4523706 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs7574865	Efficacy	3	etanercept	Rheumatoid arthritis

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7574865	STAT4	3	2.50	1	etanercept

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

3 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs7574865	ustekinumab	Efficacy	Genotypes GT + TT is associated with increased response to ustekinumab in people with Psoriasis as compared to genotype GG.	PMID:27977334
rs7574865	HMG-CoA reductase inhibitors	Toxicity	Allele T is associated with increased likelihood of drug-induced liver injury when treated with hmg coa reductase inhibitors in people with drug-induced liver injury as compared to allele G.	PMID:22968431
rs7574865	etanercept	Efficacy	Allele T is associated with decreased response to etanercept in people with Arthritis, Rheumatoid as compared to allele G.	PMID:28107378

Binding affinities (BindingDB)

2 measured of 3 human assays (3 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL6144023	IC50	270 nM
CHEMBL4452527	IC50	1300 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.44	IC50	360	nM	CHEMBL6144023
6.00	Kd	1000	nM	CHEMBL4452527
5.96	IC50	1100	nM	CHEMBL4452527

PubChem BioAssay actives

4 with measured affinity, of 27 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[[2-[[(5S,8S,10aR)-8-[[(2S)-5-amino-1-[[(2S)-3-(3,4-difluorophenyl)-1-[4-[4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]but-3-ynyl]piperidin-1-yl]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]-3-methoxycarbonyl-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1-benzothiophen-5-yl]-difluoromethyl]phosphonic acid	2225399: Binding affinity to STAT4 (unknown origin) by FP assay	ic50	0.3600	uM
[[2-[[(5S,8S,10aR)-8-[[(2S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl]carbamoyl]-3-[8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oct-7-ynoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indol-5-yl]-difluoromethyl]phosphonic acid	1559101: Binding affinity to recombinant human His/SUMO-tagged STAT4 (133 to 705 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	kd	1.0000	uM

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	4
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	3
Benzene	increases expression	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, affects response to substance	3
perfluorooctanoic acid	increases activity, increases expression	2
nickel sulfate	increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Arsenic	increases methylation, affects cotreatment, decreases expression, increases abundance	2
Estradiol	decreases expression, affects binding, increases expression, affects cotreatment	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
leptomycin B	affects localization	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
arsenic disulfide	decreases expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acetaminophen	increases expression	1
Allergens	increases expression	1

ChEMBL screening assays

20 unique, capped per target: 20 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4356793	Binding	Binding affinity to recombinant human His/SUMO-tagged STAT4 (133 to 705 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein. — *J Med Chem*

Cellosaurus cell lines

11 cell lines: 5 cancer cell line, 3 embryonic stem cell, 2 transformed cell line, 1 telomerase immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6U5	SEES3-1V human STAT4, clone1	Embryonic stem cell	Male
CVCL_A6U6	SEES3-1V human STAT4, clone2	Embryonic stem cell	Male
CVCL_A6U7	SEES3-1V human STAT4, clone3	Embryonic stem cell	Male
CVCL_B7ZM	Abcam Raji STAT4 KO	Cancer cell line	Male
CVCL_C0AF	Abcam THP-1 STAT4 KO	Cancer cell line	Male
CVCL_C3KJ	N/Tert-1 STAT4	Telomerase immortalized cell line	Male
CVCL_C7C3	Abcam PC-3 STAT4 KO	Cancer cell line	Male
CVCL_D8BL	Ubigene A-549 STAT4 KO	Cancer cell line	Male
CVCL_D8WG	Ubigene HCT 116 STAT4 KO	Cancer cell line	Male
CVCL_D9T9	Ubigene HEK293 STAT4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00120887	Phase 4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	Phase 4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	Phase 4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	Phase 4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	Phase 4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	Phase 4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	Phase 4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	Phase 4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	Phase 4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	Phase 4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	Phase 4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	Phase 4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	Phase 4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	Phase 4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	Phase 4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	Phase 4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	Phase 4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	Phase 4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	Phase 4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	Phase 4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	Phase 4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	Phase 4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	Phase 4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	Phase 4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	Phase 4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	Phase 4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	Phase 4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	Phase 4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	Phase 4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	Phase 4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	Phase 4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	Phase 4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	Phase 4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	Phase 4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	Phase 4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	Phase 4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	Phase 4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	Phase 4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	Phase 4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	Phase 4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients
NCT05828147	Phase 4	UNKNOWN	Anti-CD20 Antibodies for Treatment of SLE-PAH
NCT05879419	Phase 4	ACTIVE_NOT_RECRUITING	Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases
NCT05899907	Phase 4	UNKNOWN	Efficacy and Safety of Telitacicept in Early SLE
NCT05916781	Phase 4	UNKNOWN	Effectiveness of Mycophenolate Mofetil Combined With Tacrolimus for Steroid Tapering in Systemic Lupus Erythematosus
NCT06411249	Phase 4	ACTIVE_NOT_RECRUITING	A Study Describing the Efficacy and Safety of Belimumab Administered in Adult Participants With Early Systemic Lupus Erythematosus (SLE)
NCT06594068	Phase 4	RECRUITING	Prospective Registry Investigating Maternal, Infant, and Lactation Outcomes in Anifrolumab Users
NCT06677801	Phase 4	ACTIVE_NOT_RECRUITING	Immune Cell Subsets in SLE Patients Treated with Telitacicept
NCT06763783	Phase 4	ENROLLING_BY_INVITATION	Vaccination Against Herpes Zoster in Patients With Inflammatory Rheumatic Diseases
NCT06875960	Phase 4	RECRUITING	A Study to Continue the Administration of Deucravacitinib in Participants With Systemic Lupus Erythematosus (SLE) or Discoid and/or Subacute Cutaneous Lupus Erythematosus (DLE/SCLE) Who Have Completed Study IM011074 or Study IM011132
NCT07077486	Phase 4	RECRUITING	Effects of Telitacicept vs Cyclophosphamide on Lupus Related Interstitial Lung Disease
NCT07087912	Phase 4	RECRUITING	Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases
NCT07381465	Phase 4	ACTIVE_NOT_RECRUITING	Efficacy and Safety of IL-1 Inhibitors in Mild to Moderate Systemic Lupus Erythematosus
NCT07611747	Phase 4	RECRUITING	Carotid Ultrasound-Based Strategy for Primary Prevention of Cardiovascular Events in Inflammatory Rheumatic Disease (PREVENER)
NCT07760480	Phase 4	RECRUITING	Assessing Residual Inflammation and Macrophage Presence in Lupus Nephritis After 3 Months of Intensified Treatment With Prednisolone, Mycofenolate Mofetil and Voclosporin as Compared to Mycofenolate Mofetil and Prednisolone
NCT00000419	Phase 3	TERMINATED	Safety of Estrogens in Lupus: Hormone Replacement Therapy
NCT00000420	Phase 3	COMPLETED	Safety of Estrogens in Lupus: Birth Control Pills
NCT00004662	Phase 3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Dehydroepiandrosterone in Women With Active Systemic Lupus Erythematosus
NCT00005778	Phase 3	COMPLETED	High-Dose Intravenous (IV) Cyclophosphamide Versus Monthly IV Cyclophosphamide
NCT00025818	Phase 3	COMPLETED	Six Month Clinical Research Study for Patients With Moderate or Severe Dry Eye Syndrome
NCT00035308	Phase 3	COMPLETED	Safety and Efficacy Study of LJP 394 (Abetimus Sodium) to Treat Lupus Kidney Disease

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for STAT4 across ~30M SureChEMBL compounds — explore on Sugi Predict.