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): 599 total — 31 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes
• Transcription factor: yes — 58 downstream targets (CollecTRI)
• MANE Select transcript: NM_005419

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: 50 — 24 retained_intron, 13 protein_coding, 9 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

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

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.

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

300 total, 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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

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)

85 targeting STAT2, 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-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

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

5 orthologs

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

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

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 (84 total): helix 32, 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.

PDB	Method	Resolution (Å)
6UX2	X-RAY DIFFRACTION	3.01
9ZFO	ELECTRON MICROSCOPY	3.05
8T12	ELECTRON MICROSCOPY	3.34
8T13	ELECTRON MICROSCOPY	3.45
6WCZ	ELECTRON MICROSCOPY	4
2KA4	SOLUTION NMR

Predicted structure (AlphaFold)

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

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): 800, 283, 287, 294, 690, 753

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

19 pathways

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

MSigDB gene sets: 0 (showing top):

GO Biological Process (13): regulation of protein phosphorylation (GO:0001932), 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 (10): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), ISGF3 complex (GO:0070721), RNA polymerase II transcription regulator complex (GO:0090575), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228)

Reactome top-level categories

Rollup of top-14 pathways:

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

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
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
sperm flagellum	2
protein phosphorylation	1
regulation of protein modification process	1
regulation of phosphorylation	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 interactions and networks

STRING

2452 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAT2	IRF9	Q00978	999
STAT2	STAT1	P42224	985
STAT2	TYK2	P29597	965
STAT2	JAK1	P23458	956
STAT2	IFNAR1	P17181	949
STAT2	IFNA13	P01562	922
STAT2	IRF7	Q92985	922
STAT2	IRF1	P10914	909
STAT2	HDAC1	Q13547	905
STAT2	NMI	Q13287	902
STAT2	IFNB1	P01574	889
STAT2	IFNAR2	P48551	889
STAT2	ISG15	P05161	875
STAT2	STAT6	P42226	873
STAT2	JAK2	O60674	871

IntAct

124 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	STAT2	psi-mi:“MI:0915”(physical association)	0.930
STAT1	STAT3	psi-mi:“MI:0914”(association)	0.910
STAT2	IRF9	psi-mi:“MI:0915”(physical association)	0.880
IRF9	STAT2	psi-mi:“MI:0915”(physical association)	0.880
N	STAT2	psi-mi:“MI:0915”(physical association)	0.760
N	STAT2	psi-mi:“MI:0403”(colocalization)	0.760
STAT2	N	psi-mi:“MI:0915”(physical association)	0.760
STAT2	N	psi-mi:“MI:0914”(association)	0.760
STAT2	IFNAR1	psi-mi:“MI:0914”(association)	0.760

BioGRID (194): STAT2 (Reconstituted Complex), STAT2 (Two-hybrid), STAT2 (Affinity Capture-MS), STAT2 (Two-hybrid), STAT2 (Affinity Capture-MS), STAT2 (Affinity Capture-MS), STAT2 (PCA), STAT2 (Affinity Capture-Western), STAT2 (Reconstituted Complex), STAT2 (Proximity Label-MS), STAT2 (Affinity Capture-MS), STAT2 (Affinity Capture-MS), ZNF692 (Affinity Capture-MS), TACC1 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LIF8, A0JN92, A1Z198, A6H603, B1ARD6, B1ARD8, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E1BPN0, G1SRW8, O02799, P0C7P3, P52630, Q08AF3, Q0GKD5, Q0P3U3, Q149M9, Q1LXZ7, Q1LZ50, Q2LKU9, Q2LKV5, Q2LKW6, Q32KW9, Q5I0J8, Q5NCI0, Q5RCZ8, Q5RFJ8, Q5SY16, Q5U311, Q60766, Q63035, Q68D06, Q6AYC2, Q6AYF9, Q6IEE8, Q6NXR0, Q7Z7L1

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

SIGNOR signaling

18 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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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	40.7×	2e-05
Antimicrobial mechanism of IFN-stimulated genes	5	18.2×	5e-04
Interferon Signaling	8	17.8×	7e-06
Interferon alpha/beta signaling	6	16.9×	2e-04
ISG15 antiviral mechanism	5	13.9×	1e-03
Potential therapeutics for SARS	6	12.7×	5e-04
SARS-CoV-2 activates/modulates innate and adaptive immune responses	7	11.6×	2e-04
Cytokine Signaling in Immune system	11	8.3×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor signaling pathway via JAK-STAT	5	19.9×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	3
Uncertain significance	242
Likely benign	268
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028887	NM_005419.4(STAT2):c.820C>T (p.Gln274Ter)	Pathogenic
1360363	NM_005419.4(STAT2):c.676dup (p.Thr226fs)	Pathogenic
1451222	NM_005419.4(STAT2):c.667C>T (p.Arg223Ter)	Pathogenic
1451841	NM_005419.4(STAT2):c.124C>T (p.Gln42Ter)	Pathogenic
1452515	NM_005419.4(STAT2):c.1580del (p.Gln527fs)	Pathogenic
1453231	NM_005419.4(STAT2):c.1528C>T (p.Arg510Ter)	Pathogenic
1453440	NM_005419.4(STAT2):c.1826del (p.Gly609fs)	Pathogenic
1455233	NM_005419.4(STAT2):c.1852C>T (p.Gln618Ter)	Pathogenic
1457429	NM_005419.4(STAT2):c.1467dup (p.Lys490fs)	Pathogenic
2137378	NM_005419.4(STAT2):c.1576G>A (p.Gly526Arg)	Pathogenic
218140	NM_005419.4(STAT2):c.381+5G>C	Pathogenic
218141	NM_005419.4(STAT2):c.1836C>A (p.Cys612Ter)	Pathogenic
2190527	NM_005419.4(STAT2):c.403G>T (p.Glu135Ter)	Pathogenic
2728515	NM_005419.4(STAT2):c.1728_1734dup (p.Gly579fs)	Pathogenic
2753872	NM_005419.4(STAT2):c.1658del (p.Phe553fs)	Pathogenic
2787614	NM_005419.4(STAT2):c.1630C>T (p.Arg544Ter)	Pathogenic
2791440	NM_005419.4(STAT2):c.2266del (p.Glu756fs)	Pathogenic
2798041	NM_005419.4(STAT2):c.778del (p.Thr260fs)	Pathogenic
2831685	NM_005419.4(STAT2):c.1180C>T (p.Gln394Ter)	Pathogenic
2832802	NM_005419.4(STAT2):c.2197del (p.Leu733fs)	Pathogenic
3605839	NM_005419.4(STAT2):c.94C>T (p.Arg32Ter)	Pathogenic
4386842	NM_005419.4(STAT2):c.633+2T>C	Pathogenic
4722763	NM_005419.4(STAT2):c.171_172insT (p.Met58fs)	Pathogenic
4748275	NM_005419.4(STAT2):c.1467del (p.Lys490fs)	Pathogenic
4765527	NM_005419.4(STAT2):c.1027C>T (p.Arg343Ter)	Pathogenic
578415	NM_005419.4(STAT2):c.1999C>T (p.Arg667Ter)	Pathogenic
663294	NM_005419.4(STAT2):c.1209+1del	Pathogenic
872172	NM_005419.4(STAT2):c.1045_1046insCA (p.Arg349fs)	Pathogenic
872173	NM_005419.4(STAT2):c.948del (p.Phe316fs)	Pathogenic
966700	NM_005419.4(STAT2):c.1791del (p.Leu599fs)	Pathogenic

SpliceAI

3512 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56343387:T:TA	donor_gain	1.0000
12:56344145:C:CT	acceptor_gain	1.0000
12:56344145:C:T	acceptor_gain	1.0000
12:56344146:A:T	acceptor_gain	1.0000
12:56346436:TCCCA:T	donor_loss	1.0000
12:56346437:CCCAC:C	donor_loss	1.0000
12:56346438:CCA:C	donor_loss	1.0000
12:56346439:CACCT:C	donor_loss	1.0000
12:56346440:AC:A	donor_loss	1.0000
12:56346441:C:A	donor_loss	1.0000
12:56346824:T:TA	donor_gain	1.0000
12:56346871:A:AC	donor_gain	1.0000
12:56346872:C:CC	donor_gain	1.0000
12:56346951:TGCGT:T	acceptor_gain	1.0000
12:56346953:CGT:C	acceptor_gain	1.0000
12:56346954:GT:G	acceptor_gain	1.0000
12:56346954:GTCT:G	acceptor_loss	1.0000
12:56346955:TCT:T	acceptor_loss	1.0000
12:56346956:C:CC	acceptor_gain	1.0000
12:56346956:C:T	acceptor_loss	1.0000
12:56346957:T:A	acceptor_loss	1.0000
12:56348524:CTTAC:C	donor_loss	1.0000
12:56348525:TTA:T	donor_loss	1.0000
12:56348526:TACCC:T	donor_loss	1.0000
12:56348527:A:AC	donor_gain	1.0000
12:56348527:AC:A	donor_gain	1.0000
12:56348528:C:CC	donor_gain	1.0000
12:56348528:CC:C	donor_gain	1.0000
12:56348528:CCCAT:C	donor_gain	1.0000
12:56348620:CTCG:C	acceptor_gain	1.0000

AlphaMissense

5555 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56346940:A:C	F580L	0.996
12:56346940:A:T	F580L	0.996
12:56346942:A:G	F580L	0.996
12:56346886:A:C	F598L	0.995
12:56346886:A:T	F598L	0.995
12:56346888:A:G	F598L	0.995
12:56346941:A:G	F580S	0.995
12:56346874:G:C	F602L	0.994
12:56346874:G:T	F602L	0.994
12:56346876:A:G	F602L	0.994
12:56346875:A:G	F602S	0.992
12:56348593:A:G	W554R	0.992
12:56348593:A:T	W554R	0.992
12:56346851:A:T	I610N	0.989
12:56346871:A:C	S603R	0.989
12:56346871:A:T	S603R	0.989
12:56346873:T:G	S603R	0.989
12:56349192:A:G	W471R	0.989
12:56349192:A:T	W471R	0.989
12:56346840:A:G	W614R	0.988
12:56346840:A:T	W614R	0.988
12:56346887:A:G	F598S	0.988
12:56346851:A:C	I610S	0.987
12:56348539:A:G	W572R	0.987
12:56348539:A:T	W572R	0.987
12:56356442:A:G	W44R	0.987
12:56356442:A:T	W44R	0.987
12:56351112:G:C	F340L	0.985
12:56351112:G:T	F340L	0.985
12:56351114:A:G	F340L	0.985

dbSNP variants (sampled 300 via entrez): RS1000258306 (12:56347225 G>A,T), RS1000265616 (12:56354530 C>A,T), RS1000315746 (12:56354958 G>A), RS1000558694 (12:56341129 G>A,C), RS1001058737 (12:56358266 G>A,T), RS1001178418 (12:56356796 C>T), RS1001228611 (12:56362101 A>G), RS1001608340 (12:56361604 T>C), RS1001619806 (12:56361975 G>A,C), RS1001820443 (12:56353763 T>C,G), RS1001877742 (12:56342163 G>A), RS1002124178 (12:56353400 T>C,G), RS1002212963 (12:56347668 A>G), RS1002304918 (12:56359049 C>T), RS1002637941 (12:56358808 A>G)

Disease associations

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

GenCC curated gene-disease

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

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 total (30 of 34 shown, 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 total IgM
HP:0003281	Increased circulating ferritin concentration
HP:0003593	Infantile onset
HP:0011463	Childhood onset
HP:0020088	Post-vaccination measles
HP:0031691	Severe viral infection

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000322_6	Psoriasis	1.000000e-09
GCST000817_73	Height	1.000000e-13
GCST001885_1	Height	3.000000e-09
GCST002115_16	Axial length	4.000000e-07
GCST002702_66	Height	9.000000e-12
GCST002738_2	Psoriasis	6.000000e-10
GCST002740_45	Inflammatory skin disease	2.000000e-12
GCST002874_52	Psoriasis	1.000000e-10
GCST002874_53	Psoriasis	5.000000e-12
GCST003268_19	Psoriasis vulgaris	4.000000e-15
GCST003270_10	Psoriatic arthritis	5.000000e-06
GCST005527_15	Psoriasis	5.000000e-17
GCST006976_114	Macular thickness	1.000000e-11
GCST010002_217	Refractive error	6.000000e-174
GCST90002389_464	Lymphocyte percentage of white cells	1.000000e-09

EFO canonical traits (3, from GWAS)

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 (VIP=true, CPIC=false)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression, increases phosphorylation	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 expression, increases abundance	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)

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