STAT1

Summary

STAT1 (signal transducer and activator of transcription 1, HGNC:11362) is a protein-coding gene on chromosome 2q32.2, encoding Signal transducer and activator of transcription 1-alpha/beta (P42224). Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors.

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.

Source: NCBI Gene 6772 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 31B (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 798 total — 58 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 82
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 458 downstream targets (CollecTRI)
• MANE Select transcript: NM_007315

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11362
Approved symbol	STAT1
Name	signal transducer and activator of transcription 1
Location	2q32.2
Locus type	gene with protein product
Status	Approved
Aliases	STAT91, ISGF-3
Ensembl gene	ENSG00000115415
Ensembl biotype	protein_coding
OMIM	600555
Entrez	6772

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 26 protein_coding, 13 nonsense_mediated_decay, 8 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000361099, ENST00000392322, ENST00000392323, ENST00000409465, ENST00000415035, ENST00000423282, ENST00000424722, ENST00000432058, ENST00000452281, ENST00000454414, ENST00000464072, ENST00000540176, ENST00000673638, ENST00000673734, ENST00000673762, ENST00000673777, ENST00000673816, ENST00000673832, ENST00000673841, ENST00000673847, ENST00000673858, ENST00000673859, ENST00000673863, ENST00000673885, ENST00000673942, ENST00000673952, ENST00000674028, ENST00000674080, ENST00000674081, ENST00000674153, ENST00000698141, ENST00000698142, ENST00000698143, ENST00000698144, ENST00000698145, ENST00000698146, ENST00000698147, ENST00000698148, ENST00000698149, ENST00000698150, ENST00000698151, ENST00000856926, ENST00000856927, ENST00000856928, ENST00000922629, ENST00000950377, ENST00000950378, ENST00000950379, ENST00000950380, ENST00000950381

RefSeq mRNA: 14 — MANE Select: NM_007315 NM_001384880, NM_001384881, NM_001384882, NM_001384883, NM_001384884, NM_001384885, NM_001384886, NM_001384887, NM_001384888, NM_001384889, NM_001384890, NM_001384891, NM_007315, NM_139266

CCDS: CCDS2309, CCDS42793, CCDS92917, CCDS92918

Canonical transcript exons

ENST00000361099 — 25 exons

Exon	Start	End
ENSE00000783935	191008963	191009107
ENSE00000783936	191007563	191007661
ENSE00000783937	191001074	191001163
ENSE00000783939	190998217	190998308
ENSE00001424647	191013525	191013678
ENSE00003467647	190976840	190977025
ENSE00003489660	190978856	190979001
ENSE00003492270	190975812	190975887
ENSE00003534511	190983642	190983740
ENSE00003570820	190997856	190998007
ENSE00003573841	190987039	190987068
ENSE00003609189	190989615	190989674
ENSE00003618712	190974830	190974932
ENSE00003626012	190991228	190991320
ENSE00003631268	190995061	190995219
ENSE00003631710	190985619	190985660
ENSE00003633846	190980620	190980669
ENSE00003649368	190986854	190986947
ENSE00003651802	190984310	190984393
ENSE00003653784	190979772	190979866
ENSE00003660292	191009876	191010004
ENSE00003683389	190982383	190982518
ENSE00003789252	190999626	190999704
ENSE00003972835	190969149	190970717
ENSE00003972850	191014018	191014171

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.5774 / max 665.8729, expressed in 1826 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32928	59.8967	1825
32929	0.3267	91
202514	0.2219	103
32926	0.1322	43

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	98.63	gold quality
vermiform appendix	UBERON:0001154	98.35	gold quality
mononuclear cell	CL:0000842	98.21	gold quality
monocyte	CL:0000576	98.20	gold quality
leukocyte	CL:0000738	98.20	gold quality
decidua	UBERON:0002450	97.88	gold quality
endothelial cell	CL:0000115	97.82	gold quality
lymph node	UBERON:0000029	97.81	gold quality
granulocyte	CL:0000094	97.78	gold quality
renal glomerulus	UBERON:0000074	97.78	gold quality
metanephric glomerulus	UBERON:0004736	97.73	gold quality
germinal epithelium of ovary	UBERON:0001304	97.62	gold quality
trigeminal ganglion	UBERON:0001675	97.41	gold quality
gall bladder	UBERON:0002110	97.36	gold quality
palpebral conjunctiva	UBERON:0001812	97.02	gold quality
caecum	UBERON:0001153	96.91	gold quality
stromal cell of endometrium	CL:0002255	96.90	gold quality
nasal cavity epithelium	UBERON:0005384	96.87	gold quality
pleura	UBERON:0000977	96.86	gold quality
parietal pleura	UBERON:0002400	96.85	gold quality
cervix squamous epithelium	UBERON:0006922	96.85	gold quality
visceral pleura	UBERON:0002401	96.78	gold quality
penis	UBERON:0000989	96.71	gold quality
epithelial cell of pancreas	CL:0000083	96.67	gold quality
blood	UBERON:0000178	96.59	gold quality
pericardium	UBERON:0002407	96.56	gold quality
thymus	UBERON:0002370	96.44	gold quality
periodontal ligament	UBERON:0008266	96.41	gold quality
nasal cavity mucosa	UBERON:0001826	96.35	gold quality
metanephros	UBERON:0000081	96.32	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-8	yes	787.45
E-CURD-114	yes	335.96
E-HCAD-13	yes	13.29
E-ANND-3	yes	9.64
E-CURD-89	no	924.19
E-MTAB-7606	no	678.13

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

458 targets.

Target	Regulation
A2M	Unknown
ABCA1	Unknown
ABCB1
ABCC8
ABL1
ACAT1	Unknown
ACSL1
ADAM2
ADAMTS4	Unknown
ADAR	Unknown
AGFG2	Repression
AGT	Unknown
AIM2	Unknown
AKT1
AOX1	Unknown
APOC2	Unknown
APOE	Unknown
APOL4	Unknown
APP	Unknown
ATG4C	Unknown
B3GAT3	Unknown
BACE1
BAX	Unknown
BCL2	Unknown
BCL2L14	Activation
BCL6	Activation
BCR
BIRC2
BRD8	Unknown
BST2	Unknown

JASPAR motifs

Motif	Name	Family
MA0137.3	STAT1	STAT factors
MA0137.4	STAT1	STAT factors
MA0517.1	STAT1::STAT2	STAT factors
MA0517.2	STAT1::STAT2	STAT factors

JASPAR matrix evidence (PMIDs): PMID:17558387, PMID:16319195

Upstream regulators (CollecTRI, top): ATF3, BHLHE40, BRCA1, CIITA, CREB5, DOT1L, EGF, ERCC6, ETS1, FOXC1, GATA1, GATA3, GTF3A, IKZF1, IRF1, IRF8, IRF9, MCM5, NR3C1, PIAS1, RARA, RELA, REST, SNAI2, SOCS1, STAT1, STAT2, STAT3, STAT6, TP53, TRIM24, ZNF148

miRNA regulators (miRDB)

91 targeting STAT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6515-3P	99.82	68.19	1933

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• soluble factor(s) secreted from CD8(+) T lymphocytes inhibits human immunodeficiency virus type 1 replication through STAT1 activation (PMID:11752148)
• We conclude that STAT1 activation is necessary but not sufficient for induction of transcription of IFN gamma-responsive genes (PMID:11777927)
• IFNtau effect on IRF-1 expression is primarily regulated by tyrosine-phosphorylated Stat1alpha or Stat1beta dimers (PMID:11804954)
• Cytokine signaling: STATS in plasma membrane rafts (PMID:11815625)
• STAT1 plays a minimal role in TNF-mediated cellular responses (PMID:11835405)
• phosphorylation on serine 727 by protein kinase C-delta (PMID:11839738)
• Stat1 and Stat3 may support cell growth in part via c-myc gene activation in primary erythroleukemia cells. (PMID:11843291)
• identification as a molecular target of IGFBP-3 during chondrogenesis (PMID:11886859)
• Isolation and characterization of a human STAT1 gene regulatory element. Inducibility by interferon (IFN) types I and II and role of IFN regulatory factor-1. (PMID:11909852)
• Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. (PMID:11909970)
• results constitute genetic and biochemical evidence supporting a paramyxovirus-induced, IFN-independent STAT protein degradation complex that contains at least STAT1 and STAT2 (PMID:11932384)
• Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-gamma (PMID:11972023)
• Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation. (PMID:11981818)
• arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5 (PMID:12048190)
• Distinct functions for STAT1 and PU.1 in transcriptional activation of Fc gamma receptor I promoter. (PMID:12130529)
• Excessive P-Tyr-STAT1 responses could induce inflammatory cytokines and demyelination in MS, as in motheaten mice, which have defects in SHP-1 function. Abnormal interferon signaling may predict the course of MS and responses to therapy. (PMID:12161037)
• Lipid microdomains are required sites for the phosphorylation and nuclear translocation of STAT1alpha. (PMID:12165521)
• STAT1 phosphorylation of TcPTP is regulated by arginine methylation (PMID:12171910)
• STAT-1, IRF-1, and RAR-beta expression were enhanced by IFN-gamma and ATRA in combination, and to a greater degree in BALM-3 cells than in BALM-1 cells, suggesting that these IFN-gamma related genes were involved in the induction of apoptosis. (PMID:12191570)
• requirement in interferon-gamma-mediated inhibition in human chondrocytes (PMID:12223098)
• STAT-dependent trans-activation is regulated by p38 MAPK and interferon gamma independent of serine phosphorylation (PMID:12232043)
• Cells lacking STAT-1 show reduced apoptosis in response to heat or ischaemia. Expression of STAT-1 in these cells does not enhance cell death but restores sensitivity to stress-induced death. (PMID:12232802)
• Stat1 phosphorylation is inhibited by SHP-2 and Stat1-dependent induction of luciferase activity is suppressed by SHP-2 (PMID:12270932)
• Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 activation and nuclear accumulation (PMID:12388709)
• Data suggest that down-regulation of interferon-gamma-mediated nuclear STAT1 binding in hepatocytes involves both dephosphorylation by mitogen-activated protein kinase phosphatase 1 and degradation by the ubiquitin-dependent proteasome pathway. (PMID:12459177)
• Amino-termnal extensions of Sendai Virus C proteins induce pY701-Stat1 formation (while decreasing bulk Stat1 levels) in a manner that does not require interferon signaling (PMID:12551969)
• We report two unrelated infants homozygous with respect to mutated STAT1 alleles. Both suffered from mycobacterial disease, but died of viral disease. (PMID:12590259)
• Epstein-Barr virus SM protein induces STAT1 mRNA levels (PMID:12610144)
• gp120 induces activation of STAT1, STAT3, and STAT5 in CD4+ cells of lymphocyte or monocyte/macrophage lineages. (PMID:12629155)
• role for NFkappaB in LMP-1-mediated STAT1 expression in Epstein-Barr virus-immortalized cells (PMID:12634403)
• results show that Ser727/Tyr701-phosphorylated Stat1 plays a key role as a prerequisite for the ATRA-induced down-regulation of c-Myc; cyclins A, B, D2, D3, and E; and simultaneous up-regulation of p27Kip1, associated with arrest in the G0/G1 phase (PMID:12637327)
• EGF-induced phosphorylation diminished the amount of this protein found in the clonal variants of A431 cells. (PMID:12722480)
• Results provide evidence that interleukin-13 induces p38 MAP kinase phosphorylation and activation, which regulates Stat1 and Stat3 serine 727 phosphorylation. (PMID:12748293)
• Data suggest that persistent STAT-1 activation can contribute to maintaining and expanding the local inflammatory response in Celiac Disease. (PMID:12759242)
• Data suggest there is no defect in the JAK/STAT pathway in the tested melanoma cell lines, and that interferon resistance must be mediated through other components. (PMID:12777975)
• a physical interaction between c-Fos and STAT-1 participates in NOS2 gene transcriptional activation in lung epithelium (PMID:12788789)
• Measles virus V protein blocks INF-alpha/beta signaling by inhibiting STAT1 phosphorylation. (PMID:12804771)
• STAT1-dependent transcription of pro-apoptotic and pro-inflammatory genes is regulated by IFN-gamma activated PI3K and mTOR pathways in a rapamycin-insensitive manner (PMID:12807916)
• Stat1 and Stat3 exist as stable homodimers prior to activation (PMID:12832402)
• STAT1 and STAT3 may, at least in part, mediate angiotensin II-induced TIMP-1 mRNA expression in human renal proximal tubular epithelial cells, implicating a role of the STAT signaling pathway in pathogenesis of renal tubulointerstitial fibrosis. (PMID:12846741)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	stat1a	ENSDARG00000006266
danio_rerio	stat1b	ENSDARG00000076182
mus_musculus	Stat1	ENSMUSG00000026104
rattus_norvegicus	Stat1	ENSRNOG00000014079
caenorhabditis_elegans		WBGENE00010251
caenorhabditis_elegans		WBGENE00013111

Paralogs (6): STAT5A (ENSG00000126561), STAT4 (ENSG00000138378), STAT6 (ENSG00000166888), STAT3 (ENSG00000168610), STAT2 (ENSG00000170581), STAT5B (ENSG00000173757)

Protein

Protein identifiers

Signal transducer and activator of transcription 1-alpha/beta — P42224 (reviewed: P42224)

Alternative names: Transcription factor ISGF-3 components p91/p84

All UniProt accessions (19): A0A669KB17, A0A669KB52, A0A669KB53, A0A669KB56, A0A669KB68, A0A669KB75, A0A669KBA4, A0A669KBI6, A0A669KBK4, A0A8V8TLI6, P42224, A0A8V8TMY9, A0A8V8TN81, D2KFR9, E7ENM1, E7EPD2, E9PH66, J3KPM9, Q67C41

UniProt curated annotations — full annotation on UniProt →

Function. Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated. It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Following bacterial lipopolysaccharide (LPS)-induced TLR4 endocytosis, phosphorylated at Thr-749 by IKBKB which promotes binding of STAT1 to the 5’-TTTGAGGC-3’ sequence in the ARID5A promoter, resulting in transcriptional activation of ARID5A and subsequent ARID5A-mediated stabilization of IL6. Phosphorylation at Thr-749 also promotes binding of STAT1 to the 5’-TTTGAGTC-3’ sequence in the IL12B promoter and activation of IL12B transcription. Involved in food tolerance in small intestine: associates with the Gasdermin-D, p13 cleavage product (13 kDa GSDMD) and promotes transcription of CIITA, inducing type 1 regulatory T (Tr1) cells in upper small intestine.

Subunit / interactions. Isoform alpha homodimerizes upon IFN-gamma induced phosphorylation. Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation. The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9. Interacts (phosphorylated at Ser-727) with PIAS1; the interaction results in release of STAT1 from its target gene. Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at ‘Tyr-466’. Interacts with IFNAR2. Found in a complex with NMI and CREBBP/CBP. Interacts with NMI which is required for CREBBP/CBP recruitment to the complex. Interacts with PTK2/FAK1. Interacts with SRC. Interacts with ERBB4 (phosphorylated). Interacts with PARP9 and DTX3L independently of IFN-beta or IFN-gamma-mediated STAT1 ‘Tyr-701’ phosphorylation. Interacts with histone acetyltransferase EP300/p300 in response to INF-gamma stimulation. Independently of its phosphorylation status, interacts with OTOP1. Interacts with IFNGR1. Interacts with STAT4. (Microbial infection) Interacts with Sendai virus C’, C, Y1 and Y2 proteins, preventing activation of ISRE and GAS promoter. (Microbial infection) Interacts with Nipah virus P, V and W proteins preventing activation of ISRE and GAS promoter. (Microbial infection) Interacts with Rabies virus phosphoprotein preventing activation of ISRE and GAS promoter. (Microbial infection) Interacts with HCV core protein; the interaction results in STAT1 degradation. (Microbial infection) Interacts with ebolavirus protein VP24. (Microbial infection) Interacts with Epstein-Barr virus (EBV) tegument protein BGLF2; this interaction leads to STAT1 dephosphorylation and inhibition. (Microbial infection) Interacts (via N-terminus) with measles V protein; this interaction inhibits STAT1 phosphorylation by Jak1 and thereby the type I interferon signaling pathway.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Deubiquitinated by USP13; leading to STAT1 stabilization and positive regulation of type I and type II IFN signalings. Phosphorylated on tyrosine and serine residues in response to a variety of cytokines/growth hormones including IFN-alpha, IFN-gamma, PDGF and EGF. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Upon EGF stimulation, phosphorylation on Tyr-701 (lacking in beta form) by JAK1, JAK2 or TYK2 promotes dimerization and subsequent translocation to the nucleus. Growth hormone (GH) activates STAT1 signaling only via JAK2. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylation on Ser-727 by several kinases including MAPK14, ERK1/2, CAMK2/CAMKII and CK2 in response to IFN-gamma stimulation, is required for maximal transcriptional activity. Phosphorylated on Ser-727 by CAMK2/CAMKII in response to IFN-gamma stimulation and calcium mobilization, promoting activity. Phosphorylated by CAMK2/CAMKII in response to IFN-beta stimulation and calcium mobilization in epithelial cells, promoting activity. Phosphorylation on Ser-727 promotes sumoylation though increasing interaction with PIAS. Phosphorylation on Ser-727 by PRKCD induces apoptosis in response to DNA-damaging agents. Phosphorylated on tyrosine residues when PTK2/FAK1 is activated; most likely this is catalyzed by a SRC family kinase. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates interferon-mediated signaling. Upon viral infection or IFN induction, phosphorylation on Ser-708 occurs much later than phosphorylation on Tyr-701 and is required for the binding of ISGF3 on the ISREs of a subset of IFN-stimulated genes IKBKE-dependent. Phosphorylation at Tyr-701 and Ser-708 are mutually exclusive, phosphorylation at Ser-708 requires previous dephosphorylation of Tyr-701. Phosphorylation at Thr-749 by IKBKB/IKKB promotes transcriptional activation of ARID5A and IL12B by STAT1. Phosphorylation at Thr-749 restricts interferon signaling and anti-inflammatory responses and promotes innate inflammatory responses. Sumoylated with SUMO1, SUMO2 and SUMO3. Sumoylation is enhanced by IFN-gamma-induced phosphorylation on Ser-727, and by interaction with PIAS proteins. Enhances the transactivation activity. ISGylated. Mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14; ADP-ribosylation prevents phosphorylation at Tyr-701. However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question and the lack of phosphorylation may be due to sumoylation of Lys-703. Monomethylated at Lys-525 by SETD2; monomethylation is necessary for phosphorylation at Tyr-701, translocation into the nucleus and activation of the antiviral defense. (Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22.

Disease relevance. Immunodeficiency 31B (IMD31B) [MIM:613796] A disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 31A (IMD31A) [MIM:614892] A form of Mendelian susceptibility to mycobacterial disease, a rare condition caused by impairment of interferon-gamma mediated immunity. It is characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. Clinical outcome severity depends on the degree of impairment of interferon-gamma mediated immunity. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. IMD31A has low penetrance, and affected individuals have relatively mild disease and good prognosis. IMD31A confers a predisposition to mycobacterial infections only, with no increased susceptibility to viral infections. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 31C (IMD31C) [MIM:614162] A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. The disease is caused by variants affecting the gene represented in this entry. STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin-17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa.

Similarity. Belongs to the transcription factor STAT family.

Isoforms (2)

UniProt ID	Names	Canonical?
P42224-1	Alpha, p91	yes
P42224-2	Beta, p84

RefSeq proteins (14): NP_001371809, NP_001371810, NP_001371811, NP_001371812, NP_001371813, NP_001371814, NP_001371815, NP_001371816, NP_001371817, NP_001371818, NP_001371819, NP_001371820, NP_009330, NP_644671 (=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
IPR022752	STAT1_TAZ2-bd_C	Domain
IPR035859	STAT1_SH2	Domain
IPR036535	STAT_N_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR038295	STAT1_C_sf	Homologous_superfamily
IPR048988	STAT_linker	Domain

Pfam: PF00017, PF01017, PF02864, PF02865, PF12162, PF21354

UniProt features (145 total): mutagenesis site 31, helix 29, sequence variant 28, strand 23, modified residue 15, turn 8, sequence conflict 3, cross-link 2, initiator methionine 1, chain 1, domain 1, splice variant 1, coiled-coil region 1, site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3WWT	X-RAY DIFFRACTION	2
7NUF	X-RAY DIFFRACTION	2
9IGA	X-RAY DIFFRACTION	2.8
1BF5	X-RAY DIFFRACTION	2.9
8D3F	X-RAY DIFFRACTION	2.97
1YVL	X-RAY DIFFRACTION	3
8YYV	ELECTRON MICROSCOPY	3.07
9IFX	X-RAY DIFFRACTION	3.64
8YYU	ELECTRON MICROSCOPY	3.84
2KA6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42224-F1	87.78	0.71

Functional residue map

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

Catalytic / active sites (1): 724 (required for recruitment of ep300/p300)

Post-translational modifications (17): 525, 637, 657, 665, 701, 705, 708, 727, 745, 749, 703, 703, 2, 114, 175, 296, 366

Mutagenesis-validated functional residues (31):

Position	Phenotype
110	sumoylated.
114	no effect on ifn-alpha-induced stat1 phosphorylation and nuclear translocation.
175	no effect on ifn-alpha-induced stat1 phosphorylation and nuclear translocation.
296	no effect on ifn-alpha-induced stat1 phosphorylation and nuclear translocation.
366	no effect on ifn-alpha-induced stat1 phosphorylation and nuclear translocation.
525	strongly reduced ifn-alpha-induced stat1 phosphorylation and nuclear translocation. does not affect ability to homodimer
636–637	no effect on ifn-alpha-induced stat1 phosphorylation and nuclear translocation.
656–658	enhances stat1 nuclear translocation and interferon (ifn)-stimulated gene (isg) expression in response to ifn-beta stimu
657	loss of adp-ribosylation and increased tyr-701 phosphorylation; when associated with q-705.
665	no effect on ifn-alpha-induced stat1 phosphorylation and nuclear translocation.
701	no effect on transcriptional activation of arid5a.
701	not phosphorylated at s-708 upon ifnb induction.
701	no effect on basal sumoylation. enhances sumoylation in the presence of mapk stimulation. phosphorylated at s-708 upon i
703	abolishes sumoylation by sumo1. increased ifn-gamma-mediated transactivation.
704	no effect on transcriptional activation of arid5a.
705	loss of adp-ribosylation and increased tyr-701 phosphorylation; when associated with q-657.
708	phosphorylated at y-701 upon ifnb induction. no effect on transcriptional activation of arid5a.
708	not phosphorylated at y-701 upon ifnb induction.
710	no effect on transcriptional activation of arid5a.
715	no effect on transcriptional activation of arid5a.
719	no effect on transcriptional activation of arid5a.
720	no effect on transcriptional activation of arid5a.
724	impaired phosphorylation at s-727.
727	decreased transcriptional activation. no effect on basal sumoylation. no enhancement of sumoylation on mapk stimulation.
727	no change in enhancement of mapk-induced sumoylation. basal interaction with pias1. interaction with pias1 increased on

Function

Pathways and Gene Ontology

Reactome pathways

64 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1839117	Signaling by cytosolic FGFR1 fusion mutants
R-HSA-186763	Downstream signal transduction
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8854691	Interleukin-20 family signaling
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-8984722	Interleukin-35 Signalling
R-HSA-8985947	Interleukin-9 signaling
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9020956	Interleukin-27 signaling
R-HSA-9020958	Interleukin-21 signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9670439	Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants
R-HSA-9673767	Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants
R-HSA-9673770	Signaling by PDGFRA extracellular domain mutants
R-HSA-9674555	Signaling by CSF3 (G-CSF)
R-HSA-9680350	Signaling by CSF1 (M-CSF) in myeloid cells
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-982772	Growth hormone receptor signaling
R-HSA-9833482	PKR-mediated signaling
R-HSA-9860927	Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells
R-HSA-9909649	Regulation of PD-L1(CD274) transcription
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-877300	Interferon gamma signaling
R-HSA-877312	Regulation of IFNG signaling
R-HSA-912694	Regulation of IFNA/IFNB signaling

MSigDB gene sets: 1052 (showing top): PID_SHP2_PATHWAY, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, REACTOME_INTERLEUKIN_6_SIGNALING, REACTOME_SIGNALING_BY_NOTCH, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION

GO Biological Process (52): negative regulation of transcription by RNA polymerase II (GO:0000122), negative regulation of endothelial cell proliferation (GO:0001937), positive regulation of mesenchymal cell proliferation (GO:0002053), positive regulation of defense response to virus by host (GO:0002230), negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis (GO:0003340), regulation of transcription by RNA polymerase II (GO:0006357), defense response (GO:0006952), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), response to nutrient (GO:0007584), blood circulation (GO:0008015), response to xenobiotic stimulus (GO:0009410), response to mechanical stimulus (GO:0009612), negative regulation of angiogenesis (GO:0016525), positive regulation of interferon-alpha production (GO:0032727), cellular response to insulin stimulus (GO:0032869), tumor necrosis factor-mediated signaling pathway (GO:0033209), response to type II interferon (GO:0034341), response to interferon-beta (GO:0035456), cellular response to interferon-beta (GO:0035458), interleukin-7-mediated signaling pathway (GO:0038111), interleukin-9-mediated signaling pathway (GO:0038113), regulation of cell population proliferation (GO:0042127), response to hydrogen peroxide (GO:0042542), regulation of apoptotic process (GO:0042981), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), response to peptide hormone (GO:0043434), positive regulation of nitric oxide biosynthetic process (GO:0045429), positive regulation of erythrocyte differentiation (GO:0045648), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation by virus of viral protein levels in host cell (GO:0046725), positive regulation of smooth muscle cell proliferation (GO:0048661), response to cAMP (GO:0051591), defense response to virus (GO:0051607), type II interferon-mediated signaling pathway (GO:0060333), type I interferon-mediated signaling pathway (GO:0060337), renal tubule development (GO:0061326), interleukin-27-mediated signaling pathway (GO:0070106), cellular response to type II interferon (GO:0071346), metanephric mesenchymal cell proliferation involved in metanephros development (GO:0072136)

GO Molecular Function (22): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II core promoter sequence-specific DNA binding (GO:0000979), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription corepressor binding (GO:0001222), transcription coactivator binding (GO:0001223), double-stranded DNA binding (GO:0003690), DNA-binding transcription factor activity (GO:0003700), tumor necrosis factor receptor binding (GO:0005164), enzyme binding (GO:0019899), CCR5 chemokine receptor binding (GO:0031730), histone acetyltransferase binding (GO:0035035), histone binding (GO:0042393), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ubiquitin-like protein ligase binding (GO:0044389), cadherin binding (GO:0045296), protein phosphatase 2A binding (GO:0051721), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (12): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), axon (GO:0030424), dendrite (GO:0030425), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471), ISGF3 complex (GO:0070721), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by Interleukins	2
Interleukin-12 family signaling	2
Interleukin-2 family signaling	2
Signaling by PDGFR in disease	2
Cytokine Signaling in Immune system	2
Interleukin-6 family signaling	1
Antimicrobial mechanism of IFN-stimulated genes	1
Signaling by Receptor Tyrosine Kinases	1
FGFR1 mutant receptor activation	1
Signaling by PDGF	1
Transcriptional regulation by RUNX2	1
Signaling by NOTCH3	1
Interferon Signaling	1
Signaling by KIT in disease	1
Signaling by CSF3 (G-CSF)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
protein binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
response to chemical	2
cytokine-mediated signaling pathway	2
response to cytokine	2
transcription cis-regulatory region binding	2
transcription coregulator binding	2
enzyme binding	2
nuclear lumen	2
cytoplasm	2
neuron projection	2
negative regulation of DNA-templated transcription	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
regulation of defense response to virus by host	1
mesenchymal to epithelial transition involved in metanephros morphogenesis	1
regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1
negative regulation of epithelial cell differentiation involved in kidney development	1
response to stress	1
cell surface receptor signaling pathway via STAT	1
response to nutrient levels	1
circulatory system process	1
response to external stimulus	1
response to abiotic stimulus	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
positive regulation of type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
response to insulin	1
cellular response to peptide hormone stimulus	1

Protein interactions and networks

STRING

5614 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAT1	JAK1	P23458	999
STAT1	IRF9	Q00978	999
STAT1	IRF1	P10914	997
STAT1	JAK2	O60674	996
STAT1	PIAS1	O75925	994
STAT1	KPNA1	P52294	993
STAT1	STAT2	P52630	985
STAT1	STAT3	P40763	982
STAT1	IFNAR1	P17181	982
STAT1	EP300	Q09472	977
STAT1	IFNGR1	P15260	977
STAT1	IFNG	P01579	972
STAT1	CREBBP	Q92793	964
STAT1	IFNAR2	P48551	957
STAT1	HDAC1	Q13547	957

IntAct

290 interactions, top by confidence:

A	B	Type	Score
STAT2	STAT1	psi-mi:“MI:0915”(physical association)	0.930
STAT1	STAT2	psi-mi:“MI:0914”(association)	0.930
STAT2	STAT1	psi-mi:“MI:0914”(association)	0.930
STAT1	STAT3	psi-mi:“MI:0915”(physical association)	0.910
STAT1	STAT3	psi-mi:“MI:0914”(association)	0.910
STAT3	STAT3	psi-mi:“MI:0914”(association)	0.840
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
EGFR	STAT1	psi-mi:“MI:0915”(physical association)	0.770
JAK1	STAT1	psi-mi:“MI:0915”(physical association)	0.760
STAT1	JAK1	psi-mi:“MI:0915”(physical association)	0.760
N	STAT1	psi-mi:“MI:0403”(colocalization)	0.710
N	STAT1	psi-mi:“MI:0915”(physical association)	0.710
STAT1	N	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
	STAT1	psi-mi:“MI:0914”(association)	0.670
EIF1AD	STAT1	psi-mi:“MI:0915”(physical association)	0.670
STAT1	EIF1AD	psi-mi:“MI:0915”(physical association)	0.670
	STAT1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (555): STAT1 (Affinity Capture-MS), STAT1 (Affinity Capture-Western), STAT1 (Two-hybrid), OTUD4 (Two-hybrid), EIF1AD (Two-hybrid), STAT1 (Affinity Capture-Western), STAT1 (Affinity Capture-Western), STAT1 (Affinity Capture-MS), STAT1 (Two-hybrid), STAT1 (Affinity Capture-MS), STAT1 (Affinity Capture-MS), STAT1 (Affinity Capture-MS), STAT1 (Two-hybrid), EIF1AD (Two-hybrid), STAT1 (Co-fractionation)

ESM2 similar proteins: A2A690, A2AWA9, A2RSQ0, A6QL63, F1LTE0, G3V7Q0, O60941, O70585, P40763, P42224, P42227, P42229, P42230, P42231, P52631, P52632, P84060, Q148V7, Q4V8I4, Q5R372, Q5R8N4, Q5RCW6, Q5ZJ17, Q62771, Q62784, Q6DFZ1, Q6DV79, Q6GQW0, Q6IQ26, Q6PAL8, Q6ZPY2, Q6ZUT9, Q7Z3J2, Q8BIK4, Q8CIQ7, Q8IZD9, Q8N122, Q8NFG4, Q92538, Q95115

Diamond homologs: O02799, P40763, P42224, P42225, P42227, P42228, P52630, P52631, P61635, Q14765, Q19S50, Q6DV79, Q764M5, Q7ZXK3, Q9PVX8, Q9WVL2, P42229, P42230, P42231, P42232, P51692, P52632, Q62771, Q95115, Q9TUM3, Q9TUZ0, Q9TUZ1, B5X561, Q24151, Q54BD4, O00910, Q70GP4, P42226, P52633, Q61AP6, Q7QDU4, Q9NAD6

SIGNOR signaling

77 interactions.

A	Effect	B	Mechanism
PIAS4	down-regulates	STAT1	binding
FANCC	up-regulates	STAT1
PIAS1	down-regulates	STAT1	binding
EGFR	up-regulates	STAT1	phosphorylation
PTPN2	“down-regulates activity”	STAT1	dephosphorylation
STAT1	down-regulates	RELA	binding
CAMK2B	up-regulates	STAT1	phosphorylation
IKBKE	up-regulates	STAT1	phosphorylation
MAPK14	“up-regulates activity”	STAT1	phosphorylation
PRKCD	up-regulates	STAT1	phosphorylation
STAT1	down-regulates	NfKb-p65/p50	binding
STAT2	“up-regulates activity”	STAT1	binding
STAT1	“up-regulates quantity by expression”	SOCS1	“transcriptional regulation”
SRC	“up-regulates activity”	STAT1	phosphorylation
JAK2	up-regulates	STAT1	phosphorylation
JAK1	“up-regulates activity”	STAT1	phosphorylation
PTPN11	“down-regulates activity”	STAT1	dephosphorylation
IFNGR2/INFGR1	“up-regulates activity”	STAT1	binding
STAT1	“up-regulates activity”	STAT1	binding
STAT1	up-regulates	M1_polarization
STAT1	“up-regulates quantity by expression”	NOS2	“transcriptional regulation”
STAT1	“up-regulates quantity by expression”	CIITA	“transcriptional regulation”
STAT1	“up-regulates quantity by expression”	IL12A	“transcriptional regulation”
STAT1	“up-regulates quantity by expression”	IL12B	“transcriptional regulation”
STAT6	“down-regulates activity”	STAT1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 161 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Interleukin-2 family signaling	5	27.6×	9e-05
Regulation of IFNA/IFNB signaling	7	26.7×	1e-06
Interleukin-20 family signaling	7	25.8×	1e-06
Evasion by RSV of host interferon responses	7	19.9×	7e-06
Interferon alpha/beta signaling	12	15.9×	7e-09
Antimicrobial mechanism of IFN-stimulated genes	6	10.3×	2e-03
Respiratory Syncytial Virus Infection Pathway	6	10.3×	2e-03
SARS-CoV-2 activates/modulates innate and adaptive immune responses	12	9.3×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor signaling pathway via JAK-STAT	9	18.9×	1e-06
type I interferon-mediated signaling pathway	7	17.4×	6e-05
cellular response to virus	9	13.1×	2e-05
defense response to virus	12	6.0×	3e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	58
Likely pathogenic	40
Uncertain significance	268
Likely benign	305
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074337	NM_007315.4(STAT1):c.1398C>A (p.Ser466Arg)	Pathogenic
1264351	NM_007315.4(STAT1):c.884C>A (p.Thr295Lys)	Pathogenic
1354984	NM_007315.4(STAT1):c.1999_2000del (p.Leu667fs)	Pathogenic
1403340	NM_007315.4(STAT1):c.1231_1232del (p.Glu411fs)	Pathogenic
1420518	NM_007315.4(STAT1):c.802G>T (p.Glu268Ter)	Pathogenic
144004	NM_007315.4(STAT1):c.537C>A (p.Asn179Lys)	Pathogenic
144005	NM_007315.4(STAT1):c.854A>G (p.Gln285Arg)	Pathogenic
144006	NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)	Pathogenic
1457465	NM_007315.4(STAT1):c.71_74dup (p.Ser25fs)	Pathogenic
1524110	NM_007315.4(STAT1):c.2102A>G (p.Tyr701Cys)	Pathogenic
155907	NM_007315.4(STAT1):c.2018A>G (p.Lys673Arg)	Pathogenic
155908	NM_007315.4(STAT1):c.1909A>G (p.Lys637Glu)	Pathogenic
1686231	NM_007315.4(STAT1):c.514T>C (p.Phe172Leu)	Pathogenic
1704320	NM_007315.4(STAT1):c.1398C>G (p.Ser466Arg)	Pathogenic
1710090	NM_007315.4(STAT1):c.373-2A>C	Pathogenic
208141	NM_007315.4(STAT1):c.832A>G (p.Lys278Glu)	Pathogenic
2097602	NM_007315.4(STAT1):c.200A>C (p.Gln67Pro)	Pathogenic
2203238	NM_007315.4(STAT1):c.1162A>G (p.Lys388Glu)	Pathogenic
2203239	NM_007315.4(STAT1):c.1159A>G (p.Thr387Ala)	Pathogenic
2424633	NC_000002.11:g.(?191835429)(192012929_?)del	Pathogenic
2500092	NM_007315.4(STAT1):c.25C>T (p.Gln9Ter)	Pathogenic
285493	NM_007315.4(STAT1):c.88del (p.Ile30fs)	Pathogenic
2925337	NM_007315.4(STAT1):c.961A>G (p.Arg321Gly)	Pathogenic
2936500	NM_007315.4(STAT1):c.1688A>T (p.Glu563Val)	Pathogenic
2942064	NM_007315.4(STAT1):c.861C>G (p.Tyr287Ter)	Pathogenic
2948670	NM_007315.4(STAT1):c.1127+1G>A	Pathogenic
2952404	NM_007315.4(STAT1):c.1286_1287del (p.Glu429fs)	Pathogenic
30082	NM_007315.4(STAT1):c.603G>T (p.Lys201Asn)	Pathogenic
30083	NM_007315.4(STAT1):c.820C>T (p.Arg274Trp)	Pathogenic
30084	NM_007315.4(STAT1):c.800C>T (p.Ala267Val)	Pathogenic

SpliceAI

5792 predictions. Top by Δscore:

Variant	Effect	Δscore
2:190921057:G:GG	donor_gain	1.0000
2:190921057:GT:G	donor_loss	1.0000
2:190921058:T:TC	donor_loss	1.0000
2:190921059:AAGT:A	donor_loss	1.0000
2:190921140:TCTA:T	acceptor_loss	1.0000
2:190921141:CTAG:C	acceptor_loss	1.0000
2:190921142:TAG:T	acceptor_loss	1.0000
2:190921143:A:AG	acceptor_gain	1.0000
2:190921144:G:GG	acceptor_gain	1.0000
2:190921144:GGTC:G	acceptor_gain	1.0000
2:190921199:GCAAC:G	donor_gain	1.0000
2:190921202:AC:A	donor_gain	1.0000
2:190921204:G:GG	donor_gain	1.0000
2:190923980:G:GT	donor_gain	1.0000
2:190923981:A:T	donor_gain	1.0000
2:190927300:T:TA	acceptor_gain	1.0000
2:190927302:TTA:T	acceptor_loss	1.0000
2:190927304:A:AG	acceptor_gain	1.0000
2:190927304:AGCT:A	acceptor_gain	1.0000
2:190927305:G:A	acceptor_loss	1.0000
2:190927305:G:GT	acceptor_gain	1.0000
2:190927305:GC:G	acceptor_gain	1.0000
2:190927305:GCT:G	acceptor_gain	1.0000
2:190927305:GCTG:G	acceptor_gain	1.0000
2:190927305:GCTGT:G	acceptor_gain	1.0000
2:190927483:G:GG	donor_gain	1.0000
2:190932825:T:TA	donor_gain	1.0000
2:190932826:A:AA	donor_gain	1.0000
2:190932840:A:T	donor_gain	1.0000
2:190954670:GAAC:G	donor_gain	1.0000

AlphaMissense

5036 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:190976880:T:A	K673N	1.000
2:190976880:T:G	K673N	1.000
2:190976908:A:G	L664P	1.000
2:190976908:A:T	L664Q	1.000
2:190976948:A:C	Y651D	1.000
2:190976983:A:G	L639P	1.000
2:190976999:A:C	Y634D	1.000
2:190977007:A:T	V631D	1.000
2:190978883:A:G	W616R	1.000
2:190978883:A:T	W616R	1.000
2:190978901:C:A	G610W	1.000
2:190978901:C:G	G610R	1.000
2:190978901:C:T	G610R	1.000
2:190978918:C:T	S604N	1.000
2:190978921:A:G	F603S	1.000
2:190978924:C:G	R602P	1.000
2:190978930:A:G	L600P	1.000
2:190978932:G:C	F599L	1.000
2:190978932:G:T	F599L	1.000
2:190978933:A:G	F599S	1.000
2:190978934:A:G	F599L	1.000
2:190978986:G:C	F581L	1.000
2:190978986:G:T	F581L	1.000
2:190978987:A:G	F581S	1.000
2:190978988:A:G	F581L	1.000
2:190978990:C:T	G580D	1.000
2:190978991:C:G	G580R	1.000
2:190979780:C:A	W573C	1.000
2:190979780:C:G	W573C	1.000
2:190979781:C:G	W573S	1.000

dbSNP variants (sampled 300 via entrez): RS1000200560 (2:191005408 G>T), RS1000215759 (2:190996307 C>T), RS1000283375 (2:190979607 G>A), RS1000310817 (2:191012087 T>C), RS1000356635 (2:190980037 C>A,T), RS1000357522 (2:190969543 C>T), RS1000557233 (2:191003308 T>A,C), RS1000614686 (2:191005667 G>C), RS1000699068 (2:190991437 G>C), RS1000830503 (2:190974465 C>T), RS1000841436 (2:191015509 C>G,T), RS1000998282 (2:190988159 C>T), RS1001039849 (2:190993694 C>G), RS1001100947 (2:190987689 G>A), RS1001214893 (2:191004260 G>A)

Disease associations

OMIM: gene MIM:600555 | disease phenotypes: MIM:613796, MIM:614162, MIM:614892, MIM:114580

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 31B	Definitive	Autosomal recessive
autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome	Definitive	Autosomal dominant
Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency 31B	Definitive	AR
Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	Definitive	AD
autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome	Definitive	AD

Mondo (4): immunodeficiency 31B (MONDO:0013427), autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (MONDO:0013599), Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (MONDO:0013956), chronic mucocutaneous candidiasis (MONDO:0015279)

Orphanet (4): Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (Orphanet:319595), Susceptibility to viral and mycobacterial infections due to STAT1 deficiency (Orphanet:391311), STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome (Orphanet:391487), Chronic mucocutaneous candidiasis (Orphanet:1334)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000009	Functional abnormality of the bladder
HP:0000818	Abnormality of the endocrine system
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty
HP:0000832	Primary hypothyroidism
HP:0000938	Osteopenia
HP:0000964	Eczematoid dermatitis
HP:0001324	Muscle weakness
HP:0001433	Hepatosplenomegaly
HP:0001510	Growth delay
HP:0001635	Congestive heart failure
HP:0001655	Patent foramen ovale
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001904	Autoimmune neutropenia
HP:0001920	Renal artery stenosis
HP:0001945	Fever
HP:0001973	Autoimmune thrombocytopenia
HP:0002014	Diarrhea
HP:0002092	Pulmonary arterial hypertension
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002242	Abnormal intestine morphology

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001725_73	Inflammatory bowel disease	3.000000e-11
GCST003103_1	Systemic lupus erythematosus	4.000000e-07
GCST003129_7	Primary biliary cholangitis	2.000000e-14
GCST004032_11	JT interval (sulfonylurea treatment interaction)	5.000000e-08
GCST004302_7	Primary biliary cholangitis	4.000000e-13
GCST004623_164	Neutrophil percentage of granulocytes	2.000000e-09
GCST005334_1	Limited cutaneous systemic scleroderma	8.000000e-08
GCST005554_1	Systemic sclerosis	4.000000e-11
GCST005555_3	Limited cutaneous systemic scleroderma	2.000000e-08
GCST005581_23	Primary biliary cirrhosis	5.000000e-18
GCST005581_24	Primary biliary cirrhosis	3.000000e-09
GCST005581_25	Primary biliary cirrhosis	9.000000e-25
GCST005581_42	Primary biliary cirrhosis	3.000000e-18
GCST005581_43	Primary biliary cirrhosis	1.000000e-13
GCST006866_1	Lung cancer (SNP x SNP interaction)	1.000000e-13
GCST008362_205	Birth weight	7.000000e-10
GCST008839_514	Height	1.000000e-08
GCST009391_1034	Metabolite levels	3.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007885	JT interval
EFO:0007922	response to sulfonylurea
EFO:0007994	neutrophil percentage of granulocytes
EFO:1001017	limited scleroderma
EFO:0004344	birth weight
EFO:0009775	threonine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002178	Candidiasis, Chronic Mucocutaneous	C01.150.703.160.088; C01.150.703.302.100; C01.800.200.100; C17.800.838.208.165; C23.550.291.500.250

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4523693 (PROTEIN-PROTEIN INTERACTION), CHEMBL5291972 (PROTEIN COMPLEX), CHEMBL6101 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 34,608 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3301607	FILGOTINIB	4	2,905
CHEMBL4435170	DEUCRAVACITINIB	4	679
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL413376	SURAMIN HEXASODIUM	3	2,743
CHEMBL165790	IPRIFLAVONE	2	5,477

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — STAT transcription factors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
ZDZ-553	Inhibition	6.06	pIC50

Binding affinities (BindingDB)

88 measured of 302 human assays (304 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
4-(3,4-dihydro-2H-quinolin-1-yl)-[1,2,4]triazolo[4,3-a]quinoxaline	EC50	0.00483 nM
1-(1-acetyl-2,3-dihydroindol-5-yl)-4-hydroxy-3-pyrazolecarboxylic acid methyl ester	EC50	610 nM
1-(3-chlorophenyl)-3-(2-pyridin-3-ylpyrimidin-4-yl)urea	EC50	1110 nM
2-[(3,5-dimethyl-1,2-oxazol-4-yl)methylsulfanyl]-1-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethanone	IC50	1120 nM
MLS000569713	EC50	1260 nM
MLS000729575	EC50	2000 nM
1-[[5-[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]sulfanyl-1,3,4-oxadiazol-2-yl]methyl]azepan-2-one	IC50	3460 nM
4-[4-(4-keto-2-thioxo-1H-quinazolin-3-yl)benzoyl]piperazine-1-carboxylic acid ethyl ester	IC50	3470 nM
2-(4-methylphenyl)-5-pyridin-4-yl-4H-benzo[i][1,3,4]benzotriazepine	IC50	3520 nM
3-[[4-(2-fluorophenyl)-1,3-thiazol-2-yl]methyl]-2-[(4-methylpiperazin-1-yl)methyl]quinazolin-4-one	IC50	4240 nM
2-[(7-hydroxy-2-keto-chromen-4-yl)methylthio]-1H-quinazolin-4-one	IC50	4360 nM
Isonicotinic acid N’-(1,3-diethyl-4,6-dioxo-2-thioxo-tetrahydro-pyrimidin-5-ylidenemethyl)-hydrazide	IC50	4420 nM
2-hydroxy-4-(2-{[(4-methylbenzene)sulfonyl]oxy}acetamido)benzoic acid	IC50	4640 nM
(4-methoxy-1,3-benzothiazol-2-yl)-[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]amine	IC50	5160 nM
3-(3,4-dimethylphenyl)-4-keto-phthalazine-1-carboxylic acid	IC50	5200 nM
(2E)-2-(1,3-benzothiazol-2-yl)-2-(2-ketoindolin-3-ylidene)acetonitrile	IC50	5660 nM
2-[[(5-methyl-2-phenyl-3-pyrazolyl)amino]methylidene]propanedioic acid diethyl ester	IC50	6370 nM
4-(6-methyl-5-imidazo[2,1-b]thiazolyl)-N-(phenylmethyl)-2-thiazolamine	IC50	6740 nM
1H-indazole-3-carboxylic acid [2-keto-2-(4-pyrrolidinosulfonylanilino)ethyl] ester	IC50	6770 nM
4-(2-furanyl)-2-methylsulfonyl-6-(trifluoromethyl)pyrimidine	IC50	6980 nM
MLS000394345	IC50	7870 nM
3-[oxo(1-pyrrolidinyl)methyl]-5-(phenylmethyl)-6-benzo[b][1,4]benzothiazepinone	IC50	8430 nM
3-[(5-bromothiophene-2-carbonyl)amino]thiophene-2-carboxylic acid methyl ester	EC50	8670 nM
(E)-(7S,11S)-2,4,11-Trihydroxy-7-methyl-7,8,9,10,11,12,13,14-octahydro-6-oxa-benzocyclotetradecen-5-one	EC50	9220 nM
MLS000526191	IC50	9250 nM
2-(5-methylpyridin-2-yl)-3-oxidanyl-3H-isoindol-1-one	IC50	9270 nM
2-[2-(2,4-dihydroxyphenyl)-2-oxoethyl]sulfanyl-1H-quinazolin-4-one	IC50	9380 nM
2-[(4-methyl-1-piperazinyl)methyl]-3-[[4-(2-naphthalenyl)-2-thiazolyl]methyl]-4-quinazolinone	IC50	9580 nM
5-[(1,3-dimethyl-2-oxo-5-benzimidazolyl)sulfamoyl]-3-methyl-2-benzofurancarboxylic acid ethyl ester	IC50	9710 nM
2-[(4-methyl-1-piperazinyl)methyl]-3-[[4-(3-nitrophenyl)-2-thiazolyl]methyl]-4-quinazolinone	IC50	10400 nM
MLS000692834	IC50	10500 nM
1-(4-acetyl-3,5-dimethyl-1H-pyrrol-2-yl)-2-(2-methoxyphenoxy)ethanone	IC50	10600 nM
3-(4-Phenyl-6-trifluoromethyl-pyrimidine-2-sulfonyl)-propionic acid methyl ester	IC50	10600 nM
4-[(E)-3-[5-chloro-1-(4-fluorophenyl)-3-methyl-4-pyrazolyl]-1-oxoprop-2-enyl]-1-piperazinecarboxylic acid ethyl ester	IC50	11400 nM
2-(methylsulfonyl)-4-phenyl-6-(trifluoromethyl)pyrimidine	IC50	11600 nM
2-(6-methoxy-2-naphthalenyl)-4-quinolinecarboxylic acid [2-[(1,5-dimethyl-3-oxo-2-phenyl-4-pyrazolyl)amino]-2-oxoethyl] ester	IC50	11700 nM
3-[(2-bromanylphenoxy)methyl]benzohydrazide	IC50	11700 nM
(2R,3R,4S)-2-ethoxy-4-(4-ethynylphenyl)-3-(3-hydroxypropyl)-3,4-dihydro-2H-pyran-6-carboxylic acid allyl ester	IC50	11800 nM
3-[4-(4-methoxyphenyl)-6-(trifluoromethyl)pyrimidin-2-yl]sulfonyl-N-(1-methoxypropan-2-yl)propanamide	IC50	11900 nM
4-(4-fluorophenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine	IC50	12000 nM
MLS000086269	IC50	12500 nM
11,11-dimethyl-3-(pyrrolidine-1-carbonyl)-10H-naphth[1,2-g]indolizine-1,2-quinone	IC50	13300 nM
1-methyl-2-[4-(4-nitrophenyl)piperazin-1-yl]carbonyl-5H-pyrrolo[3,2-c]quinolin-4-one	IC50	13500 nM
2-[3-(4-fluorophenyl)-2,4-diketo-thieno[3,2-d]pyrimidin-1-yl]-N-homoveratryl-acetamide	IC50	14000 nM
5-ethyl-2-(pyrrolidine-1-carbonyl)thieno[3,2-c]quinolin-4-one	IC50	14800 nM
3-[4-phenyl-6-(trifluoromethyl)pyrimidin-2-yl]sulfonylpropionic acid ethyl ester	EC50	15700 nM
MLS000700815	IC50	15900 nM
MLS000052445	IC50	16200 nM
MLS000062293	IC50	16800 nM
1-[(3,4-dimethoxyphenyl)methyl]-4-thiophen-2-yl-4H-pyridine-3,5-dicarboxylic acid dimethyl ester	IC50	16800 nM

ChEMBL bioactivities

134 potent at pChembl≥5 of 223 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.47	IC50	34	nM	DEUCRAVACITINIB
7.30	IC50	50	nM	CHEMBL4747591
7.25	IC50	56	nM	CHEMBL6146315
7.19	EC50	64.3	nM	CHEMBL1398377
7.16	EC50	69	nM	CHEMBL1332452
7.15	EC50	71	nM	CHEMBL5397297
7.13	IC50	74	nM	CHEMBL4747591
7.07	IC50	85	nM	CHEMBL4747591
7.06	EC50	87	nM	CHEMBL1333621
7.03	EC50	93	nM	CHEMBL1328302
6.94	EC50	114	nM	CHEMBL1523697
6.90	EC50	126	nM	CHEMBL1535921
6.75	EC50	179	nM	CHEMBL1604696
6.72	IC50	191	nM	CHEMBL5282944
6.70	IC50	200	nM	CHEMBL4747591
6.68	EC50	210	nM	CHEMBL1450911
6.64	EC50	229	nM	CHEMBL1577902
6.63	EC50	233	nM	CHEMBL1559414
6.61	IC50	247	nM	CHEMBL6146315
6.57	IC50	270	nM	CHEMBL6144023
6.50	IC50	320	nM	CHEMBL4846365
6.48	EC50	331	nM	CHEMBL1465006
6.47	EC50	341	nM	CHEMBL1571018
6.46	IC50	350	nM	CHEMBL4864495
6.45	EC50	356	nM	CHEMBL1334210
6.39	EC50	409	nM	CHEMBL1543167
6.38	EC50	418	nM	IPRIFLAVONE
6.38	EC50	420	nM	CHEMBL1543182
6.37	EC50	431	nM	CHEMBL1531634
6.36	EC50	436	nM	CHEMBL1453960
6.33	EC50	463	nM	CHEMBL1406726
6.32	IC50	480	nM	CHEMBL6146315
6.29	EC50	516	nM	CHEMBL1563821
6.28	EC50	525	nM	CHEMBL1430765
6.20	IC50	629	nM	FILGOTINIB
6.18	IC50	660	nM	DEUCRAVACITINIB
6.17	EC50	669	nM	CHEMBL1366272
6.16	Kd	700	nM	EPIGALOCATECHIN GALLATE
6.13	EC50	741	nM	CHEMBL1458453
6.12	EC50	751	nM	CHEMBL1496911
6.09	EC50	811	nM	CHEMBL1518405
6.08	EC50	834.7	nM	CHEMBL1316867
6.08	EC50	832	nM	CHEMBL1381396
6.08	EC50	825	nM	CHEMBL1408441
6.07	IC50	851	nM	DEUCRAVACITINIB
6.07	EC50	851	nM	CHEMBL1501717
6.06	IC50	880	nM	CHEMBL4846078
6.04	EC50	920	nM	CHEMBL1423409
6.00	Kd	1000	nM	CHEMBL4452527
6.00	EC50	1002	nM	CHEMBL1610388

PubChem BioAssay actives

21 with measured affinity, of 343 total; 20 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
N-methyl-4-[[(2S,4S)-2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]piperidin-4-yl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide	2023977: Inhibition of STAT1 phosphorylation in human SK-MES-1 cells pretreated for 30 mins followed by IL-6 stimulation by Western blot analysis	ec50	0.0710	uM
(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,15Z,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-5-amino-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(3-amino-3-oxopropyl)-2-[(2S)-butan-2-yl]-8-[3-(diaminomethylideneamino)propyl]-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carbonyl]amino]-4-methylpentanoyl]-naphthalen-2-ylamino]propanoic acid	1924304: Inhibition of JAK/STAT (unknown origin)	ic50	0.1910	uM
2-methoxy-N-[2-[2-[[(1S)-1-(4-methoxyphenyl)ethyl]amino]-2-oxoethyl]sulfanyl-1,3-benzothiazol-6-yl]-3-methyl-4-pentan-2-yloxybenzamide	1757415: Inhibition of IFN-gamma-induced STAT1 transcriptional activity in human HepG2 cells by luciferase reporter gene assay	ic50	0.3200	uM
2-methoxy-3-methyl-N-[2-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethyl]sulfanyl-1,3-benzothiazol-6-yl]-4-pentan-2-yloxybenzamide	1757415: Inhibition of IFN-gamma-induced STAT1 transcriptional activity in human HepG2 cells by luciferase reporter gene assay	ic50	0.3500	uM
[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate	1070486: Binding affinity to STAT1 (unknown origin) by surface plasmon resonance assay	kd	0.7000	uM
2-acetyl-3a,9a-dihydrobenzo[f][1]benzofuran-4,9-dione	1757415: Inhibition of IFN-gamma-induced STAT1 transcriptional activity in human HepG2 cells by luciferase reporter gene assay	ic50	0.8800	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	1559100: Binding affinity to recombinant human His/SUMO-tagged STAT1 (132 to 713 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	kd	1.0000	uM
(1S,3R,4S,6S,8R,9S,12R,13R)-4,9,12-trimethyl-13-propan-2-yl-7-oxapentacyclo[7.6.0.01,12.03,8.06,8]pentadecane-5,11-dione	1333813: Inhibition of Stat1 (unknown origin) expressed in LPS/INF-gamma-stimulated human MONO-MAC-6 cells assessed as reduction in GAS dependent transcription activity measured after 4 hrs by luciferase reporter gene assay	ic50	2.0000	uM
(1R,3R,4S,6S,8R,9S,11S,12R,13R)-13-ethenyl-11-hydroxy-4,9,12-trimethyl-7-oxapentacyclo[7.6.0.01,12.03,8.06,8]pentadecan-5-one	1333813: Inhibition of Stat1 (unknown origin) expressed in LPS/INF-gamma-stimulated human MONO-MAC-6 cells assessed as reduction in GAS dependent transcription activity measured after 4 hrs by luciferase reporter gene assay	ic50	2.0000	uM
2-hydroxy-4-[[4-[4-(3-methoxycarbonylphenyl)phenyl]phenyl]methyl-[2-[methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]benzoic acid	658687: Displacement of radioligand from the STAT1 after 15 mins by fluorescent polarization assay	ki	3.2000	uM
(1S,3E,5R,7S)-3-[(3,4-dihydroxyphenyl)-hydroxymethylidene]-1-[(2E)-3,7-dimethylocta-2,6-dienyl]-6,6-dimethyl-5,7-bis(3-methylbut-2-enyl)bicyclo[3.3.1]nonane-2,4,9-trione	1070486: Binding affinity to STAT1 (unknown origin) by surface plasmon resonance assay	kd	4.6700	uM
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[[2-(trifluoromethyl)phenyl]methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	772671: Binding affinity to Stat1 (unknown origin) using 5-FAM-GpYLPQTV-NH2 as probe assessed as phosphopetide complex formation after 30 mins by fluorescence polarization assay	ic50	5.8000	uM
4,6,8-trimethyl-N-(4,4,6-trimethyl-1H-pyrimidin-2-yl)quinazolin-2-amine	1167943: Inhibition of IFNgamma-induced STAT1 phosphorylation in human Cal33 cells by Western blot analysis	ic50	5.9000	uM
(1S,3R,4S,6S,8R,9R,10R,12R,13R)-10-hydroxy-4,9,12-trimethyl-13-propan-2-yl-7-oxapentacyclo[7.6.0.01,12.03,8.06,8]pentadecane-5,11-dione	1333813: Inhibition of Stat1 (unknown origin) expressed in LPS/INF-gamma-stimulated human MONO-MAC-6 cells assessed as reduction in GAS dependent transcription activity measured after 4 hrs by luciferase reporter gene assay	ic50	7.0000	uM
octasodium;4-[[3-[[3,5-bis[(2,4-disulfonatophenyl)carbamoyl]phenyl]carbamoylamino]-5-[(2,4-disulfonatophenyl)carbamoyl]benzoyl]amino]benzene-1,3-disulfonate	1486490: Inhibition of 5-carboxyfluorescein-GpYDKPHVL-OH binding to STAT1 (unknown origin) pre-incubated for 1 hr before fluorescent-labelled peptide addition by fluorescence polarization assay	ic50	7.9000	uM
4-[(4-cyclohexylphenyl)methyl-[2-[methyl-(4-phenylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	658687: Displacement of radioligand from the STAT1 after 15 mins by fluorescent polarization assay	ki	8.8000	uM
hexasodium;8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonatonaphthalen-1-yl)carbamoyl]phenyl]carbamoyl]phenyl]carbamoylamino]benzoyl]amino]benzoyl]amino]naphthalene-1,3,5-trisulfonate	1486490: Inhibition of 5-carboxyfluorescein-GpYDKPHVL-OH binding to STAT1 (unknown origin) pre-incubated for 1 hr before fluorescent-labelled peptide addition by fluorescence polarization assay	ic50	9.1000	uM
4-[[4-[4-(4-carbamoylphenyl)phenyl]phenyl]methyl-[2-[methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	658687: Displacement of radioligand from the STAT1 after 15 mins by fluorescent polarization assay	ki	9.5000	uM
4-[(4-cyclohexylphenyl)methyl-[2-[methyl-(2,4,6-trimethylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	658687: Displacement of radioligand from the STAT1 after 15 mins by fluorescent polarization assay	ki	9.7000	uM
10,20-diphenyl-21,22-dihydroporphyrin	702252: Inhibition of STAT1 SH2 domain assessed as inhibition of STAT1 SH2-phosphotyrosine interaction by AlphaScreen assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
tofacitinib	increases activity, decreases expression, decreases phosphorylation, affects localization, decreases reaction (+1 more)	9
Tretinoin	increases expression, increases phosphorylation, increases reaction, decreases reaction, increases activity (+2 more)	8
Lipopolysaccharides	affects expression, increases expression, increases activity, affects reaction, affects response to substance (+2 more)	7
bisphenol A	increases expression, affects cotreatment, decreases expression, decreases methylation	5
sodium arsenite	decreases phosphorylation, decreases reaction, increases abundance, increases phosphorylation, increases expression (+1 more)	5
Benzo(a)pyrene	affects activity, affects expression, increases expression, increases methylation, decreases reaction	5
Cadmium Chloride	affects localization, increases abundance, decreases reaction, increases phosphorylation, decreases expression	5
Acetylcysteine	decreases reaction, increases phosphorylation	4
Estradiol	affects cotreatment, increases expression, decreases expression, increases phosphorylation	4
Hydrogen Peroxide	increases phosphorylation, decreases reaction, affects localization, affects reaction, increases activity	4
Nickel	decreases expression, increases expression, affects reaction, decreases reaction, increases stability	4
Quercetin	affects binding, decreases reaction, decreases expression, decreases phosphorylation	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	4
chromium hexavalent ion	increases stability, decreases expression, increases activity, affects localization, increases phosphorylation (+5 more)	3
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide	decreases reaction, increases phosphorylation	3
monomethylarsonous acid	affects expression, decreases expression	3
(+)-JQ1 compound	decreases expression	3
Resveratrol	affects cotreatment, increases expression, decreases expression	3
Arsenic Trioxide	increases reaction, increases expression, increases phosphorylation, decreases activity, decreases phosphorylation (+1 more)	3
Acetaminophen	decreases expression, increases expression	3
Air Pollutants	decreases reaction, increases phosphorylation, decreases expression, affects cotreatment, increases abundance	3
Diclofenac	affects cotreatment, decreases reaction, increases phosphorylation, increases reaction, affects expression (+1 more)	3
Doxorubicin	increases expression, decreases response to substance	3
Plant Extracts	decreases expression, affects expression, affects reaction, affects cotreatment, increases expression	3
Aflatoxin B1	affects expression, affects cotreatment, increases expression	3
Simvastatin	decreases phosphorylation, decreases reaction, increases expression, decreases activity, decreases expression	3
bisphenol F	decreases methylation, increases expression	2
N’-nitrosonornicotine	decreases reaction, increases activity, increases expression	2
arsenite	affects expression, decreases reaction, increases abundance, increases phosphorylation	2
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases activity, increases expression, decreases reaction	2

ChEMBL screening assays

147 unique, capped per target: 137 binding, 8 functional, 2 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4356747	Binding	Protac activity at CRBN/STAT1 in human MOLM16 cells assessed as degradation of STAT1 at 0.01 to 10 uM incubated for 4 hrs by Western blot analysis	Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein. — J Med Chem
CHEMBL4715507	Functional	In vivo protac activity at CRBN/STAT1 degradation in SCID mouse xenografted with human MOLM16 cells assessed as reduction in STAT1 in tumor tissue at 50 mg/kg, iv measured after 24 hrs by immunoblotting analysis	SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression. — ACS Med Chem Lett
CHEMBL1738384	Unclassified	PUBCHEM_BIOASSAY: Late stage results from the probe development effort to identify activators of signal transducer and activator of transcription 3 (STAT3). (Class of assay: screening) [Related pubchem assays (depositor defined):AID1267, AI	PubChem BioAssay data set

Cellosaurus cell lines

24 cell lines: 19 cancer cell line, 4 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A126	Ma-Mel-102a	Cancer cell line	Male
CVCL_A8CY	HEK-Dual IFN-gamma	Transformed cell line	Female
CVCL_B0NB	293.STAT1 BAX KO	Transformed cell line	Female
CVCL_B2HI	Abcam HeLa STAT1 KO	Cancer cell line	Female
CVCL_B9BY	Abcam MCF-7 STAT1 KO	Cancer cell line	Female
CVCL_C2UW	Huh-7.5 STAT1 KO #1	Cancer cell line	Male
CVCL_C2UX	Huh-7.5 STAT1 KO #2	Cancer cell line	Male
CVCL_C9AT	A549-deltaSTAT1	Cancer cell line	Male
CVCL_C9AU	A549-deltaSTAT1-SunTag	Cancer cell line	Male
CVCL_C9AV	A549-deltaSTAT1-SunTag ACE2	Cancer cell line	Male

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01386437	Not specified	RECRUITING	Natural History of Individuals With Immune System Problems That Lead to Fungal Infections
NCT03736252	Not specified	COMPLETED	Effectiveness of a Neoprene CMC Joint Orthosis
NCT05896410	Not specified	UNKNOWN	3D-Printed Hand Orthosis Versus Thermoplastic Orthosis