STAT2

Summary

STAT2 (signal transducer and activator of transcription 2, HGNC:11363) is a protein-coding gene on chromosome 12q13.3, encoding Signal transducer and activator of transcription 2 (P52630). Signal transducer and activator of transcription that mediates signaling by type I interferons (IFN-alpha and IFN-beta).

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. In response to interferon (IFN), this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly. The protein mediates innate antiviral activity. Mutations in this gene result in Immunodeficiency 44.

Source: NCBI Gene 6773 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 613 total — 28 pathogenic, 3 likely-pathogenic (top 5% of genes corpus-wide)
• GTEx eGene: eQTL in 18 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 34
• Constraint (gnomAD): pLI 0.81 (intermediate), LOEUF 0.50 (moderately constrained)
• Transcription factor: yes — 58 downstream targets (CollecTRI)
• MANE Select transcript: NM_005419
• Interaction hub: 2,200 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11363
Approved symbol	STAT2
Name	signal transducer and activator of transcription 2
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	STAT113
Ensembl gene	ENSG00000170581
Ensembl biotype	protein_coding
OMIM	600556
Entrez	6773

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 24 retained_intron, 14 protein_coding, 13 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

MANE Select: ENST00000314128

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

ENST00000314128, ENST00000418572, ENST00000555488, ENST00000555519, ENST00000555646, ENST00000556140, ENST00000556539, ENST00000557156, ENST00000557199, ENST00000557235, ENST00000557252, ENST00000557417, ENST00000650805, ENST00000651078, ENST00000651301, ENST00000651339, ENST00000651805, ENST00000651915, ENST00000651934, ENST00000651967, ENST00000652091, ENST00000652398, ENST00000652624, ENST00000652741, ENST00000698178, ENST00000698179, ENST00000698180, ENST00000698181, ENST00000698182, ENST00000698183, ENST00000698184, ENST00000698185, ENST00000698186, ENST00000698187, ENST00000698188, ENST00000698189, ENST00000698190, ENST00000698191, ENST00000698192, ENST00000698193, ENST00000698194, ENST00000698195, ENST00000878609, ENST00000878610, ENST00000878611, ENST00000922389, ENST00000922390, ENST00000960655, ENST00000960656, ENST00000960657, ENST00000991652, ENST00001028262, ENST00001065389, ENST00001065390, ENST00001109982

RefSeq mRNA: 7 — MANE Select: NM_005419 NM_001385110, NM_001385111, NM_001385113, NM_001385114, NM_001385115, NM_005419, NM_198332

CCDS: CCDS55836, CCDS8917, CCDS91707

Canonical transcript exons

ENST00000314128 — 24 exons

Exon	Start	End
ENSE00001232848	56350412	56350432
ENSE00001232934	56350097	56350190
ENSE00001232989	56354778	56354863
ENSE00001232997	56355276	56355351
ENSE00002444103	56360058	56360107
ENSE00003496341	56350829	56350888
ENSE00003508547	56349163	56349261
ENSE00003522195	56349589	56349636
ENSE00003539855	56356132	56356285
ENSE00003542351	56349426	56349509
ENSE00003546895	56348752	56348804
ENSE00003551187	56346146	56346203
ENSE00003552882	56346819	56346955
ENSE00003561376	56351292	56351450
ENSE00003609916	56355443	56355532
ENSE00003616942	56346442	56346624
ENSE00003638811	56348529	56348623
ENSE00003642392	56356441	56356578
ENSE00003647379	56351098	56351190
ENSE00003665088	56343825	56344135
ENSE00003666203	56355708	56355803
ENSE00003672218	56348924	56349059
ENSE00003681102	56354466	56354614
ENSE00003847657	56341597	56343531

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 98.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.7708 / max 987.8589, expressed in 1821 samples.

Highest expression (Bgee): granulocyte, stromal cell of endometrium, monocyte, sural nerve, pituitary gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

STAT2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

19 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Liver	eqtl	3.2e-20	+0.90	12:56295751:G:A
Adipose Subcutaneous	eqtl	4.5e-18	-0.45	12:56350638:G:A
Brain Cerebellum	eqtl	4.2e-16	-0.60	12:56295941:G:C
Nerve Tibial	eqtl	2.3e-15	-0.40	12:56273820:T:C
Brain Cerebellar Hemisphere	eqtl	7.5e-14	+0.46	12:56349583:T:C
Cells EBV-transformed lymphocytes	eqtl	4.0e-09	+0.61	12:56302761:T:G
Adipose Visceral Omentum	eqtl	8.1e-07	-0.34	12:56357088:G:C
Brain Cortex	eqtl	1.7e-04	+1.15	12:55434111:A:C
Lung	eqtl	1.1e-03	-0.22	12:56241296:G:C
Artery Coronary	eqtl	1.7e-03	+0.70	12:56454623:G:T
Artery Tibial	eqtl	5.5e-03	-0.17	12:56360038:C:A
Skin Not Sun Exposed Suprapubic	eqtl	7.7e-03	-0.22	12:56302761:T:G
Thyroid	eqtl	9.2e-03	-0.19	12:56350307:A:C
Brain Frontal Cortex BA9	eqtl	1.7e-02	+0.48	12:56294021:C:T
Skin Sun Exposed Lower leg	eqtl	2.8e-02	-0.14	12:56233835:A:G
Uterus	eqtl	2.8e-02	-0.84	12:56765945:A:G
Colon Sigmoid	sqtl	3.5e-02	-0.67	12:56487830:G:A
Esophagus Mucosa	eqtl	4.1e-02	+0.27	12:57168210:C:T
Cells Cultured fibroblasts	eqtl	4.7e-02	+0.18	12:56380240:G:T

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
131518	49.9823	1821
131519	1.1884	784
131520	0.4274	193
131517	0.1728	13

Top tissues by expression

showing 100 of 300 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.14	gold quality
stromal cell of endometrium	CL:0002255	98.04	gold quality
monocyte	CL:0000576	97.62	gold quality
sural nerve	UBERON:0015488	97.56	gold quality
pituitary gland	UBERON:0000007	97.52	gold quality
adenohypophysis	UBERON:0002196	97.51	gold quality
nerve	UBERON:0001021	97.30	gold quality
tibial nerve	UBERON:0001323	97.30	gold quality
right ovary	UBERON:0002118	97.19	gold quality
right lobe of liver	UBERON:0001114	97.16	gold quality
tendon of biceps brachii	UBERON:0008188	97.14	gold quality
endocervix	UBERON:0000458	97.10	gold quality
germinal epithelium of ovary	UBERON:0001304	96.98	gold quality
epithelium of nasopharynx	UBERON:0001951	96.97	gold quality
mucosa of stomach	UBERON:0001199	96.95	gold quality
nasopharynx	UBERON:0001728	96.95	gold quality
mononuclear cell	CL:0000842	96.89	gold quality
leukocyte	CL:0000738	96.86	gold quality
inferior vagus X ganglion	UBERON:0005363	96.72	gold quality
left ovary	UBERON:0002119	96.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.66	gold quality
endothelial cell	CL:0000115	96.64	gold quality
gall bladder	UBERON:0002110	96.60	gold quality
medial globus pallidus	UBERON:0002477	96.57	gold quality
spleen	UBERON:0002106	96.56	gold quality
ectocervix	UBERON:0012249	96.54	gold quality
cardia of stomach	UBERON:0001162	96.47	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.23	gold quality
ovary	UBERON:0000992	96.20	gold quality
amniotic fluid	UBERON:0000173	96.19	gold quality
upper lobe of left lung	UBERON:0008952	96.10	gold quality
metanephros cortex	UBERON:0010533	96.00	gold quality
upper lobe of lung	UBERON:0008948	95.98	gold quality
right lung	UBERON:0002167	95.97	gold quality
globus pallidus	UBERON:0001875	95.95	gold quality
vagina	UBERON:0000996	95.94	gold quality
right lobe of thyroid gland	UBERON:0001119	95.87	gold quality
body of uterus	UBERON:0009853	95.87	gold quality
right uterine tube	UBERON:0001302	95.84	gold quality
right coronary artery	UBERON:0001625	95.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.80	gold quality
spinal cord	UBERON:0002240	95.77	gold quality
minor salivary gland	UBERON:0001830	95.68	gold quality
lymph node	UBERON:0000029	95.63	gold quality
adipose tissue	UBERON:0001013	95.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.50	gold quality
corpus callosum	UBERON:0002336	95.42	gold quality
apex of heart	UBERON:0002098	95.40	gold quality
connective tissue	UBERON:0002384	95.40	gold quality
visceral pleura	UBERON:0002401	95.37	gold quality
saliva-secreting gland	UBERON:0001044	95.36	gold quality
skin of leg	UBERON:0001511	95.35	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.35	gold quality
pylorus	UBERON:0001166	95.33	gold quality
left lobe of thyroid gland	UBERON:0001120	95.30	gold quality
peritoneum	UBERON:0002358	95.28	gold quality
omental fat pad	UBERON:0010414	95.28	gold quality
descending thoracic aorta	UBERON:0002345	95.24	gold quality
subthalamic nucleus	UBERON:0001906	95.21	gold quality
left uterine tube	UBERON:0001303	95.19	gold quality
cerebellar hemisphere	UBERON:0002245	95.17	gold quality
tonsil	UBERON:0002372	95.14	gold quality
right adrenal gland	UBERON:0001233	95.12	gold quality
body of pancreas	UBERON:0001150	95.06	gold quality
cerebellar cortex	UBERON:0002129	95.06	gold quality
right adrenal gland cortex	UBERON:0035827	95.05	gold quality
trigeminal ganglion	UBERON:0001675	94.98	gold quality
coronary artery	UBERON:0001621	94.97	gold quality
small intestine	UBERON:0002108	94.95	gold quality
trabecular bone tissue	UBERON:0002483	94.95	gold quality
mouth mucosa	UBERON:0003729	94.87	gold quality
left coronary artery	UBERON:0001626	94.86	gold quality
parotid gland	UBERON:0001831	94.85	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.85	gold quality
thyroid gland	UBERON:0002046	94.85	gold quality
skin of abdomen	UBERON:0001416	94.76	gold quality
parietal pleura	UBERON:0002400	94.66	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.63	gold quality
ascending aorta	UBERON:0001496	94.61	gold quality
thoracic aorta	UBERON:0001515	94.61	gold quality
fundus of stomach	UBERON:0001160	94.57	gold quality
transverse colon	UBERON:0001157	94.52	gold quality
endometrium	UBERON:0001295	94.50	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.48	gold quality
adrenal cortex	UBERON:0001235	94.38	gold quality
penis	UBERON:0000989	94.37	gold quality
pericardium	UBERON:0002407	94.22	gold quality
left adrenal gland cortex	UBERON:0035825	94.21	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.20	gold quality
aorta	UBERON:0000947	94.19	gold quality
body of stomach	UBERON:0001161	94.16	gold quality
left adrenal gland	UBERON:0001234	94.16	gold quality
blood	UBERON:0000178	94.10	gold quality
colonic epithelium	UBERON:0000397	94.02	gold quality
lower esophagus	UBERON:0013473	94.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.00	gold quality
rectum	UBERON:0001052	93.96	gold quality
pleura	UBERON:0000977	93.90	gold quality
popliteal artery	UBERON:0002250	93.89	gold quality
tibial artery	UBERON:0007610	93.89	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.24
E-MTAB-7052	no	424.65
E-GEOD-124858	no	387.28

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spleen	tissue	26.9	low
Cerebral cortex	tissue	24.4	low
Somatosensory cortex	tissue	24.4
Spinal cord	tissue	24.2
Hippocampal formation	tissue	23.9
Entorhinal cortex	tissue	23.9
Superior colliculi	tissue	23.7
Substantia nigra	tissue	23.2
Occipital cortex	tissue	23.0
Lung	tissue	22.9	medium
Temporal cortex	tissue	22.7
Prefrontal cortex	tissue	22.5
Medulla oblongata	tissue	22.0
Midbrain	tissue	21.9
Motor cortex	tissue	21.8
Thalamus	tissue	21.8
Smooth muscle	tissue	21.6	medium
Hypothalamus	tissue	21.6
Pons	tissue	21.1
Appendix	tissue	20.9	medium
Tonsil	tissue	20.7	high
Liver	tissue	20.5	not detected
Retrosplenial and cingulate cortex	tissue	20.5
Periaqueductal gray	tissue	20.5
Gallbladder	tissue	20.4	medium
Lymph node	tissue	20.3	medium
Insular cortex	tissue	19.9
Septum	tissue	19.2
Retrosplenial cortex	tissue	19.1
Amygdala	tissue	19.0
Salivary gland	tissue	18.7	medium
Thymus	tissue	18.7
Cervix	tissue	18.6	medium
Olfactory bulb	tissue	18.0
Urinary bladder	tissue	17.9	high
Adipose tissue	tissue	17.5	not detected
Ovary	tissue	17.1	low
Ventral forebrain	tissue	17.1
Putamen	tissue	17.0
Placenta	tissue	16.6	medium
Basal ganglia	tissue	16.1	medium
Corpus callosum	tissue	15.8
Choroid plexus	tissue	15.5
Hippocampus	tissue	14.8	medium
Locus coeruleus	tissue	14.5
Small intestine	tissue	13.6	medium
Rectum	tissue	13.0	medium
Fallopian tube	tissue	12.9	low
Postcentral gyrus	tissue	12.5
Parathyroid gland	tissue	12.1	medium
Endometrium 1	tissue	11.7	low
Duodenum	tissue	11.7	low
Stomach 1	tissue	11.4	medium
Thyroid gland	tissue	11.3	low
Nucleus accumbens	tissue	11.1
Esophagus	tissue	10.9	medium
Colon	tissue	10.9	medium
Cerebellum	tissue	10.6	low
Pancreas	tissue	10.5	medium
Prostate	tissue	10.5	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Lateral funiculus (white matter) (26.6), Dorsal spinal cord (24.2), Ventral spinal cord (24.1), Cervical spinal cord, dorsal horn (24.0), Dorsal hippocampus (22.4).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 58 targets:

Target	Regulation
ANKRD1
BST2	Unknown
CBL
CCL19	Activation
CCL2	Unknown
CD74
CFB	Activation
CLDN4	Activation
CREBBP
CXCL8	Repression
DES	Activation
DGKE	Activation
EIF2AK2
GFAP
HGF	Unknown
HLA-E
IFIT2	Activation
IFIT3	Unknown
IFNA1	Unknown
IFNB1
IFNG
IGF1	Activation
IGF2	Unknown
IL12A	Activation
IL20RA	Activation
IL21	Activation
IL27	Activation
IL6
IRF1	Activation
IRF7	Activation

JASPAR motifs

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

JASPAR matrix evidence (PMIDs): PMID:16319195

Upstream regulators (CollecTRI, top): BRCA1, ERCC6, STAT1

miRNA regulators (miRDB)

Targeting STAT2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 85 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7F-5P	99.98	72.56	1784
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832

Functional genomics

gnomAD constraint: pLI 0.807, LOEUF 0.497, missense Z 3.65 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000314128 — one region, missense o/e 0.73.

Literature-anchored findings (GeneRIF, showing 40)

• In this study we have characterized the Stat2-IFNaR2 interaction and examined its role in IFNalpha signaling (PMID:11786546)
• IFNtau did not affect IRF-1 expression in Stat2-deficient cells (PMID:11804954)
• 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)
• arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5 (PMID:12048190)
• acts as a host range determinant for species-specific paramyxovirus interferon antagonism and simian virus 5 replication (PMID:12050355)
• Stat2 binds more avidly to subunit 2 of the interferon alpha receptor (IRNaR2) than to phosphorylated IFNaR1. (PMID:12220192)
• Nipah virus V protein evades alpha and gamma interferons by preventing STAT2 activation and nuclear accumulation (PMID:12388709)
• results suggest that the STAT2 activation process is a crucial target for the blockade of IFN-alpha signaling (PMID:12610111)
• 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)
• Measles virus V protein blocks INF-alpha/beta by inhibiting STAT2 phosphorylation. (PMID:12804771)
• Hendra virus V protein inhibits cellular responses to IFN through binding and cytoplasmic sequestration of STAT2. (PMID:14557668)
• there is a critical motif in Stat2 required for its transcriptional activity, and resistance to type one IFNs can be mediated by mutations in Stat2 (PMID:14722125)
• expression of STAT-2 induced by Epstein-Barr virus (EBV) LMP-1 (latent membrane protein) and may be part of the viral programming that regulates viral latency and cellular transformation (PMID:15165826)
• The regulation of STAT2 nuclear trafficking is distinct from the previously characterized STAT1 factor. (PMID:15175343)
• IFNalpha-induced nuclear accumulation of STAT2 was partially blocked in cell lines expressing high levels of HCV core protein. Subsequently (PMID:15221897)
• STAT2 activation and interferon signaling blocked by West Nile Virus nonstructural proteins (PMID:15650219)
• the conserved DNA-binding domain of STAT2 has a role specific to the activity of ISGF3-independent STAT2-containing complexes (PMID:15668228)
• IFNaR2 intracellular domain transcriptional modulation is dependent upon the carboxyl-terminal transactivation domain of Stat2. (PMID:15717316)
• Rabies virus P protein inhibits interferon signaling via activation-dependent binding to STAT1 and STAT2 (PMID:16501077)
• Data reveal the existence of a collection of GAS-regulated target genes whose expression is interferon-inducible and independent of ISGF3 but highly dependent on the STAT2 DNA binding domain. (PMID:16689942)
• Our data suggest that ATRA-induced regulation of Stat2, ICSBP and C/EBPepsilon is dependent on active Stat1, and that a failure to correctly regulate these transcription factors is associated with the inhibition of monocytic differentiation. (PMID:16918696)
• These results suggest that RSV can inhibit the phosphorylation of IFN-alpha-inducible STAT1 and STAT2 by inducing the expression of SOCS proteins in PMA-treated U937 cells. (PMID:16978698)
• A mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I interferons, is described. (PMID:17442890)
• presence of intracellular HCV antigens led to transcriptional and protein expression of IL-8 (CXCL-8), and impaired interferon induction of signal transducers and activators of transcription 1 (STAT1) serine and tyrosine and STAT2 tyrosine phosphorylation (PMID:17538964)
• These data define the role of the ISGF3 members in IFN-beta inhibitory signaling. (PMID:18370868)
• The data suggest that liberation of the IFNaR2-ICD by regulated proteolysis could trigger a novel mechanism for moving the transcription factor Stat2 to the nucleus. (PMID:18456457)
• STAT2 is a primary target for measles virus V protein-mediated alpha/beta interferon signaling inhibition. (PMID:18579593)
• The results provide genetic evidence that IE1 binding to STAT2 requires the 55-amino-acid acidic domain and promotes viral growth by interfering with interferon signaling (PMID:18701593)
• ISRE, STAT1, and STAT2 have essential roles in the regulation of constitutive and IFN-alpha-mediated PD-1 expression in macrophages (PMID:18771758)
• Human cytomegalovirus infections downregulates STAT2 protein levels and interferes with tyrosine phosphorylation of STAT2. (PMID:18796709)
• The interaction of measles virus V protein with STAT2 is carried by the cysteine-constrained peptide of 49 amino acids localized in the VCT region, and is essential to the inhibition of IFN-alpha/beta signaling. (PMID:19007958)
• Data show that STAT2*C related genotypes and alleles are associated with asthma susceptibilities and pathogenesis. (PMID:19159017)
• the mature form of NS5, when not expressed as a precursor, was able to bind to STAT2 but was unable to target it for degradation, establishing a unique role for viral polyprotein processing in providing an additional function to a viral polypeptide (PMID:19279106)
• Results provide evidence of the significance of IRF-9/STAT2 complex, and of an alternative pathway modulating the expression of IFN-stimulated genes. (PMID:19351818)
• Palmitoylation of interferon-alpha (IFN-alpha) receptor subunit IFNAR1 is required for the activation of Stat1 and Stat2 by IFN-alpha. (PMID:19561067)
• This study showed that expression of dengue virus nonstructural protein 5 alone inhibits interferon-alpha signaling and thus signal transducer and activator of transcription 2 phosphorylation. (PMID:19754307)
• Defects in the expression or nuclear localization of STAT2 could lessen the efficacy of type I IFN immunotherapy. (PMID:20068068)
• STAT2 may interact with IRF-9 in a STAT1-independent manner. The complex STAT2/IRF-9 is the key factor mediating the expression of RIG-G gene regulated by IFN-alpha. (PMID:20403236)
• These data indicate for the first time a mechanism involving STAT1/2 upregulation under the transcriptional control of INF-alpha signaling after knockdown of miR-221/222 cluster in U251 glioma cells. (PMID:20428775)
• STAT2 and IRF-1 comppete at binding interferon-stimulated response elements (ISREs) located on the retinoic acid-induced gene G (RIG-G) promoter in RIG-G. (PMID:20533260)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	stat2	ENSDARG00000031647
mus_musculus	Stat2	ENSMUSG00000040033
rattus_norvegicus	Stat2	ENSRNOG00000031081
drosophila_melanogaster	Stat92E	FBGN0016917
caenorhabditis_elegans		WBGENE00010251
caenorhabditis_elegans		WBGENE00013111

Paralogs (6): STAT1 (ENSG00000115415), STAT5A (ENSG00000126561), STAT4 (ENSG00000138378), STAT6 (ENSG00000166888), STAT3 (ENSG00000168610), STAT5B (ENSG00000173757)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103039) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased level of surface class I molecules	1
abnormal T cell differentiation	1
abnormal level of surface class II molecules	1
decreased CD8-positive, alpha-beta T cell number	1
decreased single-positive T cell number	1
decreased plasmacytoid dendritic cell number	1
decreased dendritic cell number	1
decreased central memory CD8-positive, alpha-beta T cell number	1
increased susceptibility to Riboviria infection	1
increased susceptibility to Picornaviridae infection induced morbidity/mortality	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
Sus scrofa	Q19S50	99.7%	Diamond
Bos taurus	P61635	99.4%	Diamond
Gallus gallus	Q6DV79	97.5%	Diamond
Xenopus laevis	Q7ZXK3	96.1%	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
APOF	protein-coding	319
IL23A	protein-coding	51561
PAN2	protein-coding	9924
TIMELESS	protein-coding	8914
CNPY2	protein-coding	10330
CNPY2-AS1	ncRNA	112268098
CS	protein-coding	1431

Protein

Protein identifiers

Signal transducer and activator of transcription 2 — P52630 (reviewed: P52630)

Alternative names: p113

All UniProt accessions (10): P52630, A0A494C0B5, A0A494C164, A0A494C1L3, A0A8V8TLG8, A0A8V8TLJ4, B4DHE0, B4DLC8, G3V319, R9QE65

UniProt curated annotations — full annotation on UniProt →

Function. Signal transducer and activator of transcription that mediates signaling by type I interferons (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with IRF9/ISGF3G 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 interferon stimulated genes, which drive the cell in an antiviral state. In addition, also has a negative feedback regulatory role in the type I interferon signaling by recruiting USP18 to the type I IFN receptor subunit IFNAR2 thereby mitigating the response to type I IFNs. Acts as a regulator of mitochondrial fission by modulating the phosphorylation of DNM1L at ‘Ser-616’ and ‘Ser-637’ which activate and inactivate the GTPase activity of DNM1L respectively.

Subunit / interactions. Heterodimer with STAT1 upon IFN-alpha/beta induced phosphorylation. The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9; interacts with IRF9 in the cytoplasm. Interacts with CRSP2 and CRSP6. Can form a homodimer upon IFN-alpha induced phosphorylation. Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at ‘Tyr-466’. Interacts with IFNAR2; the interaction is direct. Interacts with ARL2BP. Interacts with E3 ubiquitin ligase DCST1; the interaction results in STAT2 ubiquitin-mediated proteasomal degradation. Interacts with USP18; the interaction is direct and allows the recruitment of USP18 to IFNAR2. (Microbial infection) Interacts with vaccinia virus protein C6. (Microbial infection) Interacts with Simian virus 5 protein V. (Microbial infection) Interacts with Rabies virus phosphoprotein. (Microbial infection) Interacts with Human cytomegalovirus/HHV-5 protein UL123; this interaction promotes viral growth. (Microbial infection) Interacts with Dengue virus NS5; this interaction inhibits the phosphorylation of STAT2, and, when all viral proteins are present (polyprotein), targets STAT2 for degradation. (Microbial infection) Interacts with Zika virus NS5; this interaction targets STAT2 for degradation. (Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction promotes viral growth and counteracts the antiviral interferon response. (Microbial infection) Interacts with heartland virus NSs; this interaction blocks the nuclear translocation and activation of STAT2. (Microbial infection) Interacts with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction leads to STAT2 sequestration into viral inclusion bodies and inhibition of STAT2 phosphorylation thereby suppressing type I IFN-induced nuclear translocation of the transcription factor. (Microbial infection) Interacts with Epstein Barr virus (EBV) tegument protein BGLF2; this interaction leads to STAT2 degradation. (Microbial infection) Interacts with measles V protein; this interaction is involved in the inhibition of the host type I interferon signaling pathway.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Tyrosine phosphorylated in response to IFN-alpha. Phosphorylation at Ser-287 negatively regulates the transcriptional response. ‘Lys-48’-linked ubiquitination by DCST1 leads to STAT2 proteasomal degradation. (Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22.

Disease relevance. Immunodeficiency 44 (IMD44) [MIM:616636] An autosomal recessive disorder characterized by increased susceptibility to viral infection, resulting in some patients in encephalopathy and infection-associated neurologic decompensation. The disease is caused by variants affecting the gene represented in this entry. Pseudo-TORCH syndrome 3 (PTORCH3) [MIM:618886] An autosomal recessive disorder characterized by developmental delay with acute episodes of fever and multisystemic organ involvement, including coagulopathy, elevated liver enzymes, and proteinuria, often associated with thrombotic microangiopathy. Brain imaging shows progressive intracranial calcifications, white matter abnormalities, and sometimes cerebral or cerebellar atrophy. Disease onset is in the neonatal period, and death in early childhood is common. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to competing acceptor splice site.

Similarity. Belongs to the transcription factor STAT family.

Isoforms (2)

UniProt ID	Names	Canonical?
P52630-3	1	yes
P52630-4	2

RefSeq proteins (7): NP_001372039, NP_001372040, NP_001372042, NP_001372043, NP_001372044, NP_005410, NP_938146 (=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
IPR022756	STAT2_C	Domain
IPR035854	STAT2_SH2	Domain
IPR036535	STAT_N_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR048988	STAT_linker	Domain

Pfam: PF00017, PF01017, PF02864, PF02865, PF12188, PF21354

UniProt features (86 total): helix 34, strand 20, sequence variant 10, modified residue 6, mutagenesis site 5, turn 4, region of interest 3, chain 1, domain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
6UX2	Crystal structure of ZIKV RdRp in complex with STAT2	X-RAY DIFFRACTION	3.01
9ZFO	Cryo-EM Structure of Human STAT2-USP18-ISG15 Complex	ELECTRON MICROSCOPY	3.05
8T12	Cryo-EM structure of DENV2 NS5 in complex with human STAT2 with the N-terminal domain of …	ELECTRON MICROSCOPY	3.34
8T13	Cryo-EM structure of DENV2 NS5 in complex with human STAT2 with the N-terminal domain of …	ELECTRON MICROSCOPY	3.45
6WCZ	CryoEM structure of full-length ZIKV NS5-hSTAT2 complex	ELECTRON MICROSCOPY	4
2KA4	NMR structure of the CBP-TAZ1/STAT2-TAD complex	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52630-F1	78.45	0.49

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Immunoglobulin fold, Disease related genes, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; mid piece; plasma membrane; principal piece

Antibody reliability (HPA): IH approved · 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 (6)

Type	Positions
Phosphothreonine	800, 294
Phosphoserine	283, 287, 753
Phosphotyrosine	690

Mutagenesis-validated functional residues (5)

Position	Phenotype
374	prevents the nuclear import; when associated with a-375.
375	prevents the nuclear import; when associated with a-374.
409	prevents the nuclear import; when associated with a-415.
415	prevents the nuclear import; when associated with a-409.
690	reduces phosphorylation of stat1 in response to ifn-alpha.

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 19; 12 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

19 pathways:

ID	Pathway	Evidence
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses ⚕	curated
R-HSA-9833109	Evasion by RSV of host interferon responses ⚕	curated
R-HSA-9679191	Potential therapeutics for SARS ⚕	curated
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses ⚕	curated
R-HSA-909733	Interferon alpha/beta signaling	curated
R-HSA-8854691	Interleukin-20 family signaling	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9833110	RSV-host interactions ⚕	—
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway ⚕	—
R-HSA-9679506	SARS-CoV Infections ⚕	—
R-HSA-9694516	SARS-CoV-2 Infection ⚕	—
R-HSA-9705683	SARS-CoV-2-host interactions ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168256	Immune System	—
R-HSA-913531	Interferon Signaling	—
R-HSA-912694	Regulation of IFNA/IFNB signaling	electronic
R-HSA-449147	Signaling by Interleukins	—

MSigDB gene sets: 0 (showing top):

GO Biological Process (14): regulation of protein phosphorylation (GO:0001932), 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), regulation of cell population proliferation (GO:0042127), response to peptide hormone (GO:0043434), positive regulation of transcription by RNA polymerase II (GO:0045944), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), regulation of mitochondrial fission (GO:0090140), regulation of DNA-templated transcription (GO:0006355), signal transduction (GO:0007165)

GO Molecular Function (7): 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), ubiquitin-like protein ligase binding (GO:0044389), 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), ISGF3 complex (GO:0070721), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

14 top-level categories:

Category	Pathways
SARS-CoV Infections	2
Cytokine Signaling in Immune system	2
Viral Infection Pathways	2
Signaling by Interleukins	1
Interferon Signaling	1
Interferon alpha/beta signaling	1
SARS-CoV-2-host interactions	1
RSV-host interactions	1
Dengue Virus-Host Interactions	1
Immune System	1
Disease	1
SARS-CoV-2 Infection	1
Infectious disease	1
Respiratory Syncytial Virus Infection Pathway	1

GO top-level categories

53 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
protein phosphorylation	1
regulation of protein modification process	1
regulation of phosphorylation	1
gene expression	1
RNA biosynthetic process	1
response to stress	1
cell surface receptor signaling pathway via STAT	1
cell population proliferation	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
positive regulation of DNA-templated transcription	1
defense response	1
response to virus	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
mitochondrial fission	1
regulation of mitochondrion organization	1
regulation of anatomical structure morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	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
enzyme binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
RNA polymerase II transcription regulator complex	1
transcription regulator complex	1
nuclear protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 14 of 28 annotations. The rest are phylogenetic / computational / electronic (IEA).

14 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor signaling pathway via JAK-STAT	BP	direct assay
defense response to virus	BP	mutant phenotype
negative regulation of type I interferon-mediated signaling pathway	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	direct assay
regulation of mitochondrial fission	BP	mutant phenotype
regulation of protein phosphorylation	BP	mutant phenotype
regulation of transcription by RNA polymerase II	BP	direct assay
type I interferon-mediated signaling pathway	BP	mutant phenotype
cytosol	CC	direct assay
nucleus	CC	direct assay
DNA-binding transcription factor activity	MF	direct assay
DNA-binding transcription factor activity, RNA polymerase II-specific	MF	direct assay
identical protein binding	MF	physical interaction
ubiquitin-like protein ligase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,200 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAT2	IRF9	Q00978	945
STAT2	TYK2	P29597	915
STAT2	IFNAR1	P17181	899
STAT2	JAK1	P23458	899
STAT2	IFNA13	P01562	868
STAT2	STAT1	P42224	868
STAT2	IFNB1	P01574	843
STAT2	IFNG	P01579	795
STAT2	JAK2	O60674	793
STAT2	IRF3	Q14653	792
STAT2	IRF7	Q92985	773
STAT2	ISG15	P05161	757
STAT2	IFNAR2	P48551	753
STAT2	IFNA2	P01563	744
STAT2	IRF1	P10914	736

IntAct

Human interaction partners of STAT2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

21 partners by confidence:

Partner	Interaction type	MIscore	Records
STAT1	physical association	0.930	15
IRF9	physical association	0.880	4
N	physical association	0.760	7
IFNAR1	association	0.760	4
IFNAR2	physical association	0.690	3
TYK2	physical association	0.640	2
EGFR	physical association	0.550	2
INPPL1	association	0.530	3
U90	physical association	0.520	2
DOK4	physical association	0.490	2
DCST1	physical association	0.400	1
HSP90AB1	physical association	0.400	1
SPICE1	physical association	0.400	1
STAT3	physical association	0.400	1
USP18	physical association	0.400	1
ALK	physical association	0.370	1
FNTA	physical association	0.370	1
GAA	physical association	0.370	1
IWS1	physical association	0.370	1
INTS6	association	0.350	1
TNIK	physical association	0.000	1

BioGRID (196 interactions; top human partners by supporting records): STAT1 (Affinity Capture-MS; 17 records), IRF9 (Affinity Capture-MS; 10 records), USP18 (Two-hybrid; 10 records), IFNAR2 (Affinity Capture-Western; 9 records), CREBBP (Affinity Capture-MS; 7 records), IFNAR1 (Reconstituted Complex; 5 records), FBXW7 (Two-hybrid; 4 records), DCST1 (Affinity Capture-Western; 3 records), EP300 (Reconstituted Complex; 3 records), LIPT1 (Affinity Capture-MS; 3 records), SMARCA4 (Affinity Capture-Western; 3 records), DPP9 (Affinity Capture-MS; 2 records), EGFR (Two-hybrid; 2 records), EP400 (Affinity Capture-MS; 2 records), EPHB4 (Proximity Label-MS; 2 records)

SIGNOR signaling

showing 13 of 18 signaling interactions:

A	Effect	B	Mechanism
IRF9	“up-regulates activity”	STAT2	binding
CREBBP	“up-regulates activity”	STAT2	acetylation
STAT2	“up-regulates activity”	STAT1	binding
ZNF804A	“up-regulates activity”	STAT2	binding
GSK3A	“down-regulates quantity by destabilization”	STAT2	phosphorylation
GSK3B	“down-regulates quantity by destabilization”	STAT2	phosphorylation
SCF-FBW7	“down-regulates quantity by destabilization”	STAT2	ubiquitination
DCST1	“down-regulates quantity by destabilization”	STAT2	ubiquitination
DCST1	“down-regulates activity”	STAT2	ubiquitination
TYK2	“up-regulates activity”	STAT2	phosphorylation
JAK1	“up-regulates activity”	STAT2	phosphorylation
STAT2	“form complex”	“ISGF3 complex”	binding
PTPRG	“up-regulates activity”	STAT2	dephosphorylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
ISGF3 complex	3	IRF9, STAT1, STAT2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 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
Regulation of IFNA/IFNB signaling	5	129.2×	5e-08
Interferon alpha/beta signaling	5	44.8×	6e-06
Potential therapeutics for SARS	5	33.6×	2e-05
SARS-CoV-2 activates/modulates innate and adaptive immune responses	5	26.2×	3e-05
Cytokine Signaling in Immune system	5	12.0×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor signaling pathway via JAK-STAT	5	76.5×	1e-06

Disease & clinical

Genetic variants

Variant evidence for STAT2: 613 ClinVar records (31 pathogenic / likely pathogenic); 15 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	28
Likely pathogenic	3
Uncertain significance	247
Likely benign	273
Benign	7

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 31 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
4386842	NM_005419.4(STAT2):c.633+2T>C	Pathogenic	criteria provided, single submitter	2
872172	NM_005419.4(STAT2):c.1045_1046insCA (p.Arg349fs)	Pathogenic	criteria provided, single submitter	1
872173	NM_005419.4(STAT2):c.948del (p.Phe316fs)	Pathogenic	criteria provided, single submitter	1
966700	NM_005419.4(STAT2):c.1791del (p.Leu599fs)	Pathogenic	criteria provided, single submitter	1
1360363	NM_005419.4(STAT2):c.676dup (p.Thr226fs)	Pathogenic	criteria provided, single submitter	1
1451222	NM_005419.4(STAT2):c.667C>T (p.Arg223Ter)	Pathogenic	criteria provided, single submitter	1
1451841	NM_005419.4(STAT2):c.124C>T (p.Gln42Ter)	Pathogenic	criteria provided, single submitter	1
1452515	NM_005419.4(STAT2):c.1580del (p.Gln527fs)	Pathogenic	criteria provided, single submitter	1
1453231	NM_005419.4(STAT2):c.1528C>T (p.Arg510Ter)	Pathogenic	criteria provided, single submitter	1
1453440	NM_005419.4(STAT2):c.1826del (p.Gly609fs)	Pathogenic	criteria provided, single submitter	1
1455233	NM_005419.4(STAT2):c.1852C>T (p.Gln618Ter)	Pathogenic	criteria provided, single submitter	1
2137378	NM_005419.4(STAT2):c.1576G>A (p.Gly526Arg)	Pathogenic	criteria provided, single submitter	1
2190527	NM_005419.4(STAT2):c.403G>T (p.Glu135Ter)	Pathogenic	criteria provided, single submitter	1
2728515	NM_005419.4(STAT2):c.1728_1734dup (p.Gly579fs)	Pathogenic	criteria provided, single submitter	1
2753872	NM_005419.4(STAT2):c.1658del (p.Phe553fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore STAT2’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; 35 predictions of 1,986):

Position(s)	Effect	Δscore	Sites
12:56344145–56344146	acceptor_gain	1.0000	2
12:56346440–56346441	donor_loss	1.0000	5
12:56346956–56346957	acceptor_loss	1.0000	5
12:56348527–56348528	donor_loss	1.0000	4
12:56350211	acceptor_gain	1.0000
12:56350325	donor_gain	1.0000
12:56354615–56354616	acceptor_loss	1.0000	6
12:56354725	donor_gain	1.0000
12:56355352–56355353	acceptor_loss	1.0000	6
12:56356130–56356131	donor_loss	1.0000	4

AlphaMissense

986 missense substitutions predicted likely pathogenic (of 5,555 scored), across 318 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
F580	8	0.967	0.996
F598	8	0.948	0.995
F602	8	0.940	0.994
F674	8	0.889	0.965
F541	8	0.879	0.982
S603	8	0.872	0.989
H429	8	0.847	0.969
F553	8	0.828	0.956
D558	8	0.730	0.873
W572	7	0.954	0.987
W614	7	0.949	0.988
W44	7	0.941	0.987
F504	7	0.939	0.981
W554	7	0.936	0.992
F340	7	0.920	0.985
W556	7	0.920	0.982
W471	7	0.917	0.989
W538	7	0.917	0.970
F376	7	0.916	0.981
E115	7	0.905	0.964

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.6e-06

Disease associations

OMIM: gene MIM:600556 | disease phenotypes: MIM:616636, MIM:618886

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection	Strong	Autosomal recessive	4
pseudo-TORCH syndrome 3	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Hypotonic infant	amber
Leukodystrophy, childhood onset	amber
Likely inborn error of metabolism	amber
Paediatric disorders	amber
Undiagnosed metabolic disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (2): primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (MONDO:0014715), pseudo-TORCH syndrome 3 (MONDO:0030044)

Orphanet (1): Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (Orphanet:431166)

HPO phenotypes

34 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001321	Cerebellar hypoplasia
HP:0001342	Cerebral hemorrhage
HP:0001522	Death in infancy
HP:0001622	Premature birth
HP:0001640	Cardiomegaly
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0001905	Congenital thrombocytopenia
HP:0001919	Acute kidney injury
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002093	Respiratory insufficiency
HP:0002104	Apnea
HP:0002151	Increased circulating lactate concentration
HP:0002500	Abnormal cerebral white matter morphology
HP:0002514	Cerebral calcification
HP:0002720	Decreased circulating IgA concentration
HP:0002840	Lymphadenitis
HP:0002850	Decreased circulating IgM concentration
HP:0003281	Increased circulating ferritin concentration
HP:0003593	Infantile onset
HP:0011463	Childhood onset
HP:0020088	Post-vaccination measles
HP:0031691	Severe viral infection
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0033106	Elevated circulating D-dimer concentration
HP:0040204	Elevated CSF neopterin level
HP:0410242	Abnormal circulating IgG concentration

GWAS associations

15 associations:

Study	Trait	p-value
GCST010002_69	Refractive error	6e-174
GCST005527_15	Psoriasis	5e-17
GCST003268_3	Psoriasis vulgaris	4e-15
GCST000817_156	Height	1e-13
GCST002740_34	Inflammatory skin disease	2e-12
GCST002874_53	Psoriasis	5e-12
GCST002702_66	Height	9e-12
GCST006976_64	Macular thickness	1e-11
GCST002874_52	Psoriasis	1e-10
GCST002738_2	Psoriasis	6e-10
GCST000322_6	Psoriasis	1e-9
GCST90002389_415	Lymphocyte percentage of white cells	1e-9
GCST001885_1	Height	3e-9
GCST002115_16	Axial length	4e-7
GCST003270_11	Psoriatic arthritis	5e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0005318	axial length measurement
EFO:1001494	psoriasis vulgaris
EFO:0007993	lymphocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523239 (SINGLE PROTEIN), CHEMBL4523699 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, increases phosphorylation, decreases methylation	4
Arsenic	affects expression, increases expression, increases abundance	3
ruxolitinib	affects localization, decreases reaction, increases phosphorylation, increases expression	2
(+)-JQ1 compound	decreases expression, increases expression	2
Benzo(a)pyrene	affects expression, decreases expression	2
Lipopolysaccharides	increases expression, affects response to substance	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	affects reaction, increases expression	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
TAK-243	increases sumoylation	1
6-hydroxy-3-O-methylkaempferol 6-O-glucopyranoside	increases phosphorylation, increases reaction	1
bufotalin	decreases expression	1
alpha phellandrene	increases expression	1
3,4-dihydroxyphenylethanol	affects cotreatment, decreases expression	1
kaempferol	affects cotreatment, decreases expression	1
geraniol	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
7,7’-dimethoxy-(4,4’-bi-1,3-benzodioxole)-5,5’-dicarboxylic acid dimethyl ester	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
arsenic disulfide	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
hexabromocyclododecane	increases phosphorylation	1

ChEMBL screening assays

24 unique, capped per target: 24 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4362119	Binding	Effect on STAT2 at Y689 phosphorylation level in human NCI-H1975 incubated for 12 hrs by human phosphokinase proteome profiler array relative to control	Structure-guided development of purine amide, hydroxamate, and amidoxime for the inhibition of non-small cell lung cancer. — *Eur J Med Chem*

Cellosaurus cell lines

15 cell lines: 12 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1HT	Abcam A-549 STAT2 KO 2	Cancer cell line	Male
CVCL_B2HJ	Abcam HeLa STAT2 KO	Cancer cell line	Female
CVCL_B2QB	Abcam A-549 STAT2 KO 1	Cancer cell line	Male
CVCL_B2QC	Abcam A-549 STAT2 KO 3	Cancer cell line	Male
CVCL_C2UY	Huh-7.5 STAT2 KO #1	Cancer cell line	Male
CVCL_C2UZ	Huh-7.5 STAT2 KO #2	Cancer cell line	Male
CVCL_D8BK	Ubigene A-549 STAT2 KO	Cancer cell line	Male
CVCL_D8WE	Ubigene HCT 116 STAT2 KO	Cancer cell line	Male
CVCL_D9T7	Ubigene HEK293 STAT2 KO	Transformed cell line	Female
CVCL_E0Q3	Ubigene HeLa STAT2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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