IFNAR2

Summary

IFNAR2 (interferon alpha and beta receptor subunit 2, HGNC:5433) is a protein-coding gene on chromosome 21q22.11, encoding Interferon alpha/beta receptor 2 (P48551). Together with IFNAR1, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa).

The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for interferons alpha and beta. Binding and activation of the receptor stimulates Janus protein kinases, which in turn phosphorylate several proteins, including STAT1 and STAT2. The protein belongs to the type II cytokine receptor family. Mutations in this gene are associated with Immunodeficiency 45.

Source: NCBI Gene 3455 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 45 (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 324 total — 11 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_001289125

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5433
Approved symbol	IFNAR2
Name	interferon alpha and beta receptor subunit 2
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000159110
Ensembl biotype	protein_coding
OMIM	602376
Entrez	3455

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000342101, ENST00000342136, ENST00000382238, ENST00000382264, ENST00000404220, ENST00000413881, ENST00000417007, ENST00000420068, ENST00000443073, ENST00000447980, ENST00000682044, ENST00000683941, ENST00000700427, ENST00000700429, ENST00000869362, ENST00000869363, ENST00000869364, ENST00000869365, ENST00000954794

RefSeq mRNA: 8 — MANE Select: NM_001289125 NM_000874, NM_001289125, NM_001289126, NM_001289128, NM_001385054, NM_001385055, NM_207584, NM_207585

CCDS: CCDS13621, CCDS13622, CCDS74782

Canonical transcript exons

ENST00000342136 — 9 exons

Exon	Start	End
ENSE00001366893	33241840	33241977
ENSE00001384199	33229938	33230216
ENSE00001733110	33246718	33246890
ENSE00003460001	33262793	33265664
ENSE00003535341	33243673	33243714
ENSE00003542940	33252662	33252830
ENSE00003620483	33244951	33245074
ENSE00003650647	33260597	33260727
ENSE00003787406	33248709	33248854

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 94.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.9542 / max 327.4116, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188839	27.6823	1812
188838	0.5852	368
188841	0.5183	232
188840	0.1685	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	94.92	gold quality
monocyte	CL:0000576	94.91	gold quality
leukocyte	CL:0000738	94.21	gold quality
oocyte	CL:0000023	94.17	gold quality
mononuclear cell	CL:0000842	94.13	gold quality
granulocyte	CL:0000094	93.32	gold quality
trabecular bone tissue	UBERON:0002483	93.19	gold quality
pylorus	UBERON:0001166	92.97	gold quality
cartilage tissue	UBERON:0002418	92.72	gold quality
lymph node	UBERON:0000029	92.36	gold quality
islet of Langerhans	UBERON:0000006	92.06	gold quality
spleen	UBERON:0002106	92.04	gold quality
superficial temporal artery	UBERON:0001614	91.85	gold quality
cardia of stomach	UBERON:0001162	91.76	gold quality
secondary oocyte	CL:0000655	91.72	gold quality
caecum	UBERON:0001153	91.55	gold quality
tendon of biceps brachii	UBERON:0008188	91.53	gold quality
buccal mucosa cell	CL:0002336	91.50	gold quality
vermiform appendix	UBERON:0001154	91.36	gold quality
bone marrow	UBERON:0002371	90.41	gold quality
bone marrow cell	CL:0002092	90.35	gold quality
dorsal root ganglion	UBERON:0000044	90.08	gold quality
cauda epididymis	UBERON:0004360	90.01	gold quality
gall bladder	UBERON:0002110	89.84	gold quality
epithelium of nasopharynx	UBERON:0001951	89.77	gold quality
thymus	UBERON:0002370	89.75	gold quality
sural nerve	UBERON:0015488	89.51	gold quality
bronchial epithelial cell	CL:0002328	89.06	gold quality
pericardium	UBERON:0002407	89.01	gold quality
trigeminal ganglion	UBERON:0001675	88.81	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	45.15
E-HCAD-1	yes	38.19
E-MTAB-8410	yes	30.27
E-ANND-3	yes	20.70
E-HCAD-11	yes	19.00
E-CURD-88	yes	14.15
E-MTAB-6678	yes	4.44
E-MTAB-7303	no	222.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

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)
• STAT3 activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c (PMID:12105218)
• Expression and signaling activity of interferon alpha/beta receptors modulates dendritic cell (DC) responsiveness during terminal maturation and differentiation of monocyte-derived DCs. (PMID:12218119)
• Subunit 2 of the interferon alpha receptor (IFNaR2) is bound more avidly to Stat2 than is phosphorylated IFNaR1. (PMID:12220192)
• IFNAR1 and IFNAR2 levels reveal that the KAS-6/1 cell line overexpresses IFNAR1 relative to other myeloma cell lines that are growth arrested by IFN-alpha. (PMID:14647450)
• Administration as a complex with sIFNAR-2 may provide a method of enhancing the delivery and effectiveness of type I interferons in Burkitt lymphoma in scid mice. (PMID:14980076)
• IFNaR2, a subunit of the type I IFN receptor, is proteolytically cleaved in a regulated manner. (PMID:15286706)
• Dynamics of the IFNAR2 extracellular domain binding site reveal highly flexible loop segments and a malleable binding surface interacting with the IFN ligand supported by a more rigid scaffold which stabilizes the binding site conformation. (PMID:15287740)
• A dynamic model for the IFN-alpha/receptor complex predicts that IFNAR2 and IFNAR1 are probably anchored in close proximity on the cell surface and that upon IFN binding, the complex assumes a closed form, resulting in activation of intracellular kinases. (PMID:15449939)
• IFNaR2 intracellular domain transcriptional modulation is dependent upon the carboxyl-terminal transactivation domain of Stat2. (PMID:15717316)
• Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines. (PMID:16054712)
• Oveexpression of IFNAR2 is associated with hepatocellular carcinoma (PMID:16106266)
• Hepatic IFNAR2c mRNA expression appears to correlate inversely with the fibrosis stage and age in hepatitis C infection. (PMID:16518956)
• Monocyte-derived dendritic cells can modulate their sensitivity to two IFN subtypes by differential regulation of the IFNAR subunits. (PMID:16624932)
• IFNAR2 cytoplasmic domain serves to link STAT4 to the IFNAR as a pre-assembled complex that facilitates cytokine-driven STAT4 activation. (PMID:17095088)
• Data describe the species specificity of IFN-alphas, the residues in murine IFN-alpha4 that preclude strong affinity interactions with human IFNAR1 and 2, and residues in human IFN-alpha8 that resemble a receptor interactive domain in murine IFN-alpha4. (PMID:17517919)
• binding of IFN-alpha8 rather than binding of IFN-alpha2 to IFNAR-2 leads to activation and subsequent antiproliferative activity despite the same antiviral activity in renal cell carcinoma (PMID:17572016)
• The intensity and distribution of IFNAR-2 may predict the response to therapy with IFN-alpha and IFN-beta in pancreatic cancer. (PMID:17667505)
• High IFNAR2 is associated with renal cell carcinoma metastasis (PMID:17697365)
• Results demonstrated that FNAR2-extracellular domain interact differentially with two individual IFN-alphas, suggesting the mutual interaction between multiple IFN-alpha subtypes during the competition for binding to the receptor. (PMID:18027911)
• 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)
• The Stat3-activating Tyk2 V678F mutant does not up-regulate signaling through the type I interferon receptor but confers ligand hypersensitivity to a homodimeric receptor (PMID:18456658)
• the stability of the ternary interferon-receptor complex rather than the affinity to the individual subunits dictates differential biological activities (PMID:18801736)
• Findings show that interferon-alpha/beta receptor (IFNAR)-2 isoforms are important regulators of the responsiveness to endogenous and systemically administered interferon beta (IFNbeta). (PMID:18971450)
• Defective monocyte responses to IFNalpha/beta may play an important role in the pathogenesis of HIV-1 infection, and decreased IFNalpha/betaR expression may serve as a novel marker of disease progression. (PMID:19299650)
• Results suggest that zinc, especially polaprezinc, enhances the expression of type 1 interferon 2 receptor in U937 cells, thereby inducing production of the anti-viral protein 2’-5’OAS. (PMID:19362011)
• Ep-CAM is a potentially useful marker for resistance to INFalpha/5-FU therapy, especially in IFNAR2-positive cases. (PMID:19401692)
• The IFNAR2-8SS genotype was associated with HBeAg negative patients; IFNAR2-8F allele was associated with the risk to high viral loads; the IFNAR2-8FF genotype predisposed to higher MxA gene induction and correlated with sustained IFN response. (PMID:19714778)
• IFNAR1 (interferon-alpha receptor 1) (G/C in SNP18417) and IFNAR1 (interferon-alpha receptor 2) (G/T in SNP 11876) polymorphisms jointly, but not individually, may confer susceptibility to Behcets disease in a Turkish population (PMID:19796549)
• A low number of receptors suffices for antiviral response and is thus a robust feature common to all cells. Conversely, a high number of receptors is required for antiproliferative activity, which allows for fine-tuning on a single-cell level. (PMID:21690295)
• IFNAR2 overexpression was observed in various histological types of lung cancer, and appears to be associated with lung cancers that behave aggressively. (PMID:22236545)
• Results suggest that oxidative stress play an important role in the regulation of type I interferon receptors IFNAR1 and IFNAR2 in chronic hepatitis B virus (HBV) infection. (PMID:23663046)
• The effects of two functional polymorphisms, type I interferon receptor 2 gene (IFNAR2)-F8S and interleukin-10 receptor subunit beta gene (IL10RB)-K47E, on chronic hepatitis B virus (HBV) infection, were investigated. (PMID:23745570)
• Therefore, this study associated, for the first time, in a large panel of pancreatic cancer cell lines the effects of IFN-alpha/-beta with the expression of type-I IFN receptors. (PMID:24460759)
• A very small percentage of the pancreatic tumors showed strong expression of the IFNAR-2c. (PMID:25072284)
• The expression of IFNAR1, IFNgammaR1 and ribovarin transporters were significantly impaired in chronic liver disease and cirrhotic livers. (PMID:25265476)
• Dimerization of IFNAR1 and IFNAR2 and the limiting role of IFNAR1 binding affinity in complex assembly is modulated by USP18. (PMID:26008745)
• Lack of expression of functional IFNAR2 does not seem to be the major cause of interferon resistance in hepatitis C virus patients receiving standard interferon therapy. (PMID:26176069)
• Data suggest IFNA2 (interferon, alpha 2) binding to extracellular domain of IFNAR1 or IFNAR2 promotes proximity between intracellular domains; signaling depends on duration of activation/affinity of binding rather than specific conformational changes. (PMID:26679999)
• the level of IFNAR1, IFNAR2, and CCR5 mRNA expression was found to be significantly lower in the responders than nonresponders.Our results highlighted the significance of IFNAR and CCR5 genes in multiple sclerosis risk and the response to IFN-b therapy. (PMID:27346865)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	il22ra2	ENSDARG00000039439
danio_rerio	ifngr2	ENSDARG00000067795
danio_rerio	ifngr1l	ENSDARG00000074488
danio_rerio	ifngr1	ENSDARG00000074771
danio_rerio	crfb16	ENSDARG00000075181
danio_rerio	ifnlr1	ENSDARG00000087131
danio_rerio	crfb15	ENSDARG00000099342
danio_rerio	il10ra	ENSDARG00000100383
mus_musculus	Ifnar2	ENSMUSG00000022971
rattus_norvegicus	Ifnar2	ENSRNOG00000045668

Paralogs (11): IL20RA (ENSG00000016402), IFNGR1 (ENSG00000027697), IL10RA (ENSG00000110324), F3 (ENSG00000117525), IFNAR1 (ENSG00000142166), IL22RA1 (ENSG00000142677), IFNGR2 (ENSG00000159128), IL22RA2 (ENSG00000164485), IL20RB (ENSG00000174564), IFNLR1 (ENSG00000185436), IL10RB (ENSG00000243646)

Protein

Protein identifiers

Interferon alpha/beta receptor 2 — P48551 (reviewed: P48551)

Alternative names: Interferon alpha binding protein, Type I interferon receptor 2

All UniProt accessions (7): P48551, A0A804HLE8, C9JCU0, C9JM33, C9K067, F8WDE1, H7C176

UniProt curated annotations — full annotation on UniProt →

Function. Together with IFNAR1, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa). Type I interferon binding activates the JAK-STAT signaling cascade, resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response. Mechanistically, type I interferon-binding brings the IFNAR1 and IFNAR2 subunits into close proximity with one another, driving their associated Janus kinases (JAKs) (TYK2 bound to IFNAR1 and JAK1 bound to IFNAR2) to cross-phosphorylate one another. The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors (STAT1, STAT2 and STAT). STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes. Potent inhibitor of type I IFN receptor activity.

Subunit / interactions. Heterodimer with IFNAR1; forming the receptor for type I interferon. Interacts with JAK1. Interacts with the transcriptional factors STAT1 and STAT2. Interacts with USP18; indirectly via STAT2, it negatively regulates the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and therefore type I interferon signaling.

Subcellular location. Cell membrane Cell membrane Secreted.

Tissue specificity. Isoform 3 is detected in the urine (at protein level). Expressed in blood cells. Expressed in lymphoblastoid and fibrosarcoma cell lines.

Post-translational modifications. Phosphorylated on tyrosine residues upon interferon binding. Phosphorylation at Tyr-337 or Tyr-512 are sufficient to mediate interferon dependent activation of STAT1, STAT2 and STAT3 leading to antiproliferative effects on many different cell types. Glycosylated.

Disease relevance. Immunodeficiency 45 (IMD45) [MIM:616669] An autosomal recessive disorder characterized by increased susceptibility to viral infection due to impaired antiviral immunity, resulting in infection-associated encephalopathy. Affected individuals are at risk for developing fatal encephalitis after routine measles/mumps/rubella (MMR) vaccination. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in IFNAR2 influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].

Miscellaneous. Soluble receptor.

Similarity. Belongs to the type II cytokine receptor family.

Isoforms (3)

UniProt ID	Names	Canonical?
P48551-1	1, Long form beta, IFNaR2-2, IFNaR2-1b	yes
P48551-2	2, Short form beta, IFNaR2-1, IFNaR2-1a
P48551-3	3, IFNaR2-3, IFNaR2-2a, P40

RefSeq proteins (8): NP_000865, NP_001276054, NP_001276055, NP_001276057, NP_001371983, NP_001371984, NP_997467, NP_997468 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015373	Interferon/interleukin_rcp_dom	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050650

Pfam: PF01108, PF09294

UniProt features (70 total): strand 17, sequence variant 15, mutagenesis site 7, glycosylation site 5, modified residue 4, splice variant 4, disulfide bond 3, region of interest 3, helix 3, topological domain 2, compositionally biased region 2, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
3S9D	X-RAY DIFFRACTION	2
3S8W	X-RAY DIFFRACTION	2.6
3SE4	X-RAY DIFFRACTION	3.5
3SE3	X-RAY DIFFRACTION	4
1N6U	SOLUTION NMR
1N6V	SOLUTION NMR
2HYM	SOLUTION NMR
2KZ1	SOLUTION NMR
2LAG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48551-F1	64.86	0.28

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 (4): 337, 400, 467, 512

Disulfide bonds (3): 39–122, 85–93, 207–227

Glycosylation sites (5): 58, 87, 116, 188, 192

Mutagenesis-validated functional residues (7):

Position	Phenotype
269	does not inhibit stat1, stat2 and stat3 activation by ifn. inhibits stat1, stat2 and stat3 activation by ifn; when assoc
306	does not inhibit stat1, stat2 and stat3 activation by ifn. inhibits stat1, stat2 and stat3 activation by ifn; when assoc
316	does not inhibit stat1, stat2 and stat3 activation by ifn. inhibits stat1, stat2 and stat3 activation by ifn; when assoc
318	does not inhibit stat1, stat2 and stat3 activation by ifn. inhibits stat1, stat2 and stat3 activation by ifn; when assoc
337	does not inhibit stat1, stat2 and stat3 activation by ifn. inhibits stat1, stat2 and stat3 activation by ifn; when assoc
411	does not inhibit stat1, stat2 and stat3 activation by ifn. inhibits stat1, stat2 and stat3 activation by ifn; when assoc
512	does not inhibit stat1, stat2 and stat3 activation by ifn. inhibits stat1, stat2 and stat3 activation by ifn; when assoc

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
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

MSigDB gene sets: 259 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_CELLULAR_RESPONSE_TO_VIRUS, PID_TELOMERASE_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOLDRATH_IMMUNE_MEMORY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_RESPONSE_TO_INTERFERON_BETA, GOBP_RESPONSE_TO_INTERFERON_ALPHA, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_DEFENSE_RESPONSE_TO_VIRUS, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP

GO Biological Process (12): cell surface receptor signaling pathway (GO:0007166), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), response to virus (GO:0009615), response to interferon-alpha (GO:0035455), response to interferon-beta (GO:0035456), cellular response to interferon-beta (GO:0035458), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337), cellular response to virus (GO:0098586), regulation of transcription by RNA polymerase II (GO:0006357), regulation of receptor signaling pathway via JAK-STAT (GO:0046425), positive regulation of protein localization to nucleus (GO:1900182)

GO Molecular Function (6): type I interferon receptor activity (GO:0004905), JAK pathway signal transduction adaptor activity (GO:0008269), protein kinase binding (GO:0019901), cytokine binding (GO:0019955), type I interferon binding (GO:0019962), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Interferon Signaling	1
Interferon alpha/beta signaling	1
SARS-CoV Infections	1
SARS-CoV-2-host interactions	1
RSV-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to cytokine	2
response to virus	2
cellular anatomical structure	2
signal transduction	1
cell surface receptor signaling pathway via STAT	1
response to other organism	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
defense response	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via STAT	1
protein localization to nucleus	1
regulation of protein localization to nucleus	1
positive regulation of protein localization	1
interferon receptor activity	1
type I interferon binding	1
type I interferon-mediated signaling pathway	1
signaling adaptor activity	1
regulation of receptor signaling pathway via JAK-STAT	1
kinase binding	1
protein binding	1
interferon binding	1
binding	1
membrane	1
cell periphery	1
protein-containing complex	1

Protein interactions and networks

STRING

2058 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFNAR2	IFNAR1	P17181	999
IFNAR2	IFNB1	P01574	998
IFNAR2	IFNA13	P01562	997
IFNAR2	JAK1	P23458	997
IFNAR2	USP18	Q9UMW8	996
IFNAR2	TYK2	P29597	995
IFNAR2	IFNA2	P01563	991
IFNAR2	STAT1	P42224	957
IFNAR2	IFNE	Q86WN2	955
IFNAR2	IFNK	Q9P0W0	920
IFNAR2	IFNGR1	P15260	918
IFNAR2	IL10RB	Q08334	899
IFNAR2	STAT2	P52630	889
IFNAR2	IFNGR2	P38484	883
IFNAR2	IFNG	P01579	862

IntAct

38 interactions, top by confidence:

A	B	Type	Score
IFNAR2	STAT2	psi-mi:“MI:0915”(physical association)	0.690
IFNAR2	IRF9	psi-mi:“MI:0914”(association)	0.620
IRF9	IFNAR2	psi-mi:“MI:0915”(physical association)	0.620
IFNAR2	IRF9	psi-mi:“MI:0915”(physical association)	0.620
IFNAR2	JAK1	psi-mi:“MI:0915”(physical association)	0.590
JAK1	IFNAR2	psi-mi:“MI:0915”(physical association)	0.590
CREBBP	IFNAR2	psi-mi:“MI:0915”(physical association)	0.580
IFNAR2	CREBBP	psi-mi:“MI:0915”(physical association)	0.580
IFNAR2	RACK1	psi-mi:“MI:0915”(physical association)	0.580
RACK1	IFNAR2	psi-mi:“MI:0915”(physical association)	0.580
IFNAR2	IFNA2	psi-mi:“MI:0407”(direct interaction)	0.540
IFNAR2	STAT1	psi-mi:“MI:0914”(association)	0.500
IFNAR2	STAT1	psi-mi:“MI:0915”(physical association)	0.500
IFNAR2	PDLIM1	psi-mi:“MI:0914”(association)	0.500
IFNAR2	PDLIM1	psi-mi:“MI:0915”(physical association)	0.500
IFNAR2	IFNAR2	psi-mi:“MI:0407”(direct interaction)	0.440
IFNW1	IFNAR1	psi-mi:“MI:0407”(direct interaction)	0.440
IFNAR2	EP300	psi-mi:“MI:0915”(physical association)	0.400
IFNA2	IFNAR1	psi-mi:“MI:0915”(physical association)	0.400
USP18	IFNAR2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (63): GRAP2 (Affinity Capture-MS), IFNAR2 (Co-localization), USP18 (Affinity Capture-Western), GRAP2 (Affinity Capture-MS), IFNAR2 (Affinity Capture-MS), IFNAR2 (Affinity Capture-Western), USP18 (Affinity Capture-Western), STAT2 (Affinity Capture-Western), USP18 (Co-localization), STAT2 (Co-localization), IFNAR2 (Affinity Capture-RNA), IFNA2 (Reconstituted Complex), IFNA2 (Co-purification), STAT1 (Reconstituted Complex), STAT2 (Reconstituted Complex)

ESM2 similar proteins: A0MSX9, A5HJM1, C8AW46, C8AW47, K9JA28, O02671, O35664, O46561, O70458, P05710, P14787, P15260, P15261, P16297, P16471, P16871, P16872, P16882, P26896, P48356, P48357, P48551, P97378, Q08501, Q13651, Q28172, Q28235, Q38IC7, Q38J85, Q3SYS8, Q4W815, Q5VWK5, Q61727, Q62959, Q63257, Q65Z14, Q6JTA8, Q6PHB0, Q80VH0, Q80XZ4

Diamond homologs: O35664, P48551, Q95141, Q95207

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
IFNA1	up-regulates	IFNAR2	binding
IFNB1	up-regulates	IFNAR2	binding
IFNW1	up-regulates	IFNAR2	binding
IRF9	“up-regulates activity”	IFNAR2	binding
CREBBP	“up-regulates activity”	IFNAR2	acetylation
IFNAR2	“form complex”	IFNAR	binding
IFNA1	“up-regulates activity”	IFNAR2	binding
IFNB1	“up-regulates activity”	IFNAR2	binding
G8RGG88B68	“up-regulates activity”	IFNAR2	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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	6	263.5×	3e-12
Evasion by RSV of host interferon responses	6	195.8×	1e-11
Interferon alpha/beta signaling	6	91.4×	1e-09
Interferon Signaling	5	60.1×	3e-07
SARS-CoV-2-host interactions	5	59.5×	3e-07
SARS-CoV-2 activates/modulates innate and adaptive immune responses	6	53.5×	2e-08
SARS-CoV-2 Infection	5	40.2×	2e-06
SARS-CoV Infections	5	27.7×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
type I interferon-mediated signaling pathway	6	158.7×	2e-10
defense response to virus	5	26.7×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	4
Uncertain significance	145
Likely benign	126
Benign	17

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1509792	NM_001289125.3(IFNAR2):c.117C>A (p.Cys39Ter)	Pathogenic
1929034	NM_001289125.3(IFNAR2):c.136C>T (p.Arg46Ter)	Pathogenic
218160	NM_001289125.3(IFNAR2):c.311del (p.Glu104fs)	Pathogenic
2427781	NC_000021.8:g.(?34614228)(34635805_?)del	Pathogenic
2427782	NC_000021.8:g.(?34614228)(34614302_?)del	Pathogenic
2847928	NM_001289125.3(IFNAR2):c.503_504del (p.Leu168fs)	Pathogenic
2867111	NM_001289125.3(IFNAR2):c.626_627del (p.Ser209fs)	Pathogenic
2878128	NM_001289125.3(IFNAR2):c.394del (p.Met132fs)	Pathogenic
3248218	NC_000021.8:g.(?34620994)(34621179_?)del	Pathogenic
4762846	NM_001289125.3(IFNAR2):c.131C>G (p.Ser44Ter)	Pathogenic
976791	NM_207585.3(IFNAR2):c.555_559del (p.Ile185fs)	Pathogenic
1479817	NM_001289125.3(IFNAR2):c.221+2T>C	Likely pathogenic
2184999	NM_001289125.3(IFNAR2):c.395-1G>A	Likely pathogenic
3068469	NM_001289125.3(IFNAR2):c.158_160del (p.Ser53del)	Likely pathogenic
4693433	NM_001289125.3(IFNAR2):c.56-1G>A	Likely pathogenic

SpliceAI

1667 predictions. Top by Δscore:

Variant	Effect	Δscore
21:33244949:A:AG	acceptor_gain	1.0000
21:33244950:G:GG	acceptor_gain	1.0000
21:33246714:A:AG	acceptor_gain	1.0000
21:33246715:A:G	acceptor_gain	1.0000
21:33246716:A:G	acceptor_gain	1.0000
21:33246717:G:GT	acceptor_gain	1.0000
21:33246717:GT:G	acceptor_gain	1.0000
21:33246717:GTA:G	acceptor_gain	1.0000
21:33246717:GTAA:G	acceptor_gain	1.0000
21:33246717:GTAAA:G	acceptor_gain	1.0000
21:33246886:AGACA:A	donor_gain	1.0000
21:33246887:GACA:G	donor_gain	1.0000
21:33246887:GACAG:G	donor_gain	1.0000
21:33246888:ACA:A	donor_gain	1.0000
21:33246888:ACAG:A	donor_loss	1.0000
21:33246889:CA:C	donor_gain	1.0000
21:33246889:CAG:C	donor_loss	1.0000
21:33246890:AGTGA:A	donor_loss	1.0000
21:33246891:G:GG	donor_gain	1.0000
21:33246891:GTGA:G	donor_loss	1.0000
21:33246892:TGA:T	donor_loss	1.0000
21:33246893:GAG:G	donor_loss	1.0000
21:33248702:T:A	acceptor_gain	1.0000
21:33248705:A:AG	acceptor_gain	1.0000
21:33248705:ACAGT:A	acceptor_gain	1.0000
21:33248706:C:G	acceptor_gain	1.0000
21:33248707:A:AG	acceptor_gain	1.0000
21:33248707:AGT:A	acceptor_gain	1.0000
21:33248708:G:GA	acceptor_gain	1.0000
21:33248708:G:GC	acceptor_gain	1.0000

AlphaMissense

3420 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:33245013:T:A	W54R	0.994
21:33245013:T:C	W54R	0.994
21:33245015:G:C	W54C	0.992
21:33245015:G:T	W54C	0.992
21:33246773:T:A	C93S	0.992
21:33246774:G:C	C93S	0.992
21:33246773:T:C	C93R	0.990
21:33263232:T:C	L427S	0.989
21:33246774:G:A	C93Y	0.988
21:33246749:T:A	C85S	0.986
21:33246750:G:C	C85S	0.986
21:33246791:T:A	W99R	0.986
21:33246791:T:C	W99R	0.986
21:33246749:T:C	C85R	0.984
21:33246793:G:C	W99C	0.984
21:33246793:G:T	W99C	0.984
21:33248763:T:A	V150E	0.983
21:33252750:T:A	V210D	0.983
21:33248729:T:C	F139L	0.982
21:33248731:T:A	F139L	0.982
21:33248731:T:G	F139L	0.982
21:33246775:T:G	C93W	0.981
21:33246780:T:C	L95P	0.981
21:33252746:T:C	S209P	0.981
21:33252800:T:A	C227S	0.980
21:33252801:G:C	C227S	0.980
21:33246751:T:G	C85W	0.979
21:33246774:G:T	C93F	0.979
21:33246750:G:A	C85Y	0.978
21:33252800:T:C	C227R	0.974

dbSNP variants (sampled 300 via entrez): RS1000001509 (21:33247760 A>G), RS1000251675 (21:33265172 T>C), RS1000380275 (21:33241600 A>G), RS1000403142 (21:33251526 A>G), RS1000666388 (21:33253158 G>A), RS1000683323 (21:33253481 T>A), RS1000709363 (21:33235591 C>G,T), RS1000966318 (21:33246552 G>A,T), RS1000987012 (21:33231091 G>T), RS1001042650 (21:33230877 G>C), RS1001158250 (21:33260012 G>A), RS1001265574 (21:33228573 G>A), RS1001317407 (21:33235483 C>G), RS1001335486 (21:33229812 G>A), RS1001364947 (21:33235581 C>A,G)

Disease associations

OMIM: gene MIM:602376 | disease phenotypes: MIM:616669, MIM:610424, MIM:616636

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 45	Strong	Autosomal recessive

Mondo (3): immunodeficiency 45 (MONDO:0014727), hepatitis B virus, susceptibility to (MONDO:0012488), primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (MONDO:0014715)

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

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0020088	Post-vaccination measles

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001729_26	Crohn’s disease	2.000000e-16
GCST006484_18	Type 2 diabetes	6.000000e-07
GCST006916_13	Attention deficit hyperactivity disorder	6.000000e-06
GCST006916_14	Attention deficit hyperactivity disorder	1.000000e-06
GCST009254_11	Cerebellum white matter volume	1.000000e-06
GCST012399_3	COVID-19	3.000000e-06
GCST90002381_260	Eosinophil count	2.000000e-10
GCST90002382_538	Eosinophil percentage of white cells	5.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008320	white matter volume measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364170 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Interferon receptor family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
(+)-JQ1 compound	decreases expression, increases expression	2
Arsenic	affects expression, affects methylation	2
Benzo(a)pyrene	increases methylation, increases expression	2
Fluorouracil	increases expression	2
Nickel	increases expression	2
FR900359	increases phosphorylation	1
PAM2-CSK4	affects reaction, increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
K 7174	increases expression	1
FSL-1 lipoprotein, synthetic	affects reaction, increases expression	1
abrine	increases expression	1
Pam(3)CSK(4) peptide	affects reaction, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Panobinostat	affects expression, affects cotreatment	1
Glyphosate	decreases expression	1
Allergens	affects cotreatment, increases expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Biological Factors	increases expression	1
Caffeine	increases phosphorylation	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	affects cotreatment, affects expression	1
Copper	affects binding, increases expression	1
Curcumin	increases expression, increases reaction, decreases reaction	1
Methotrexate	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AL	THP1-Dual KO-IFNAR2	Cancer cell line	Male
CVCL_F1Q8	HyCyte Hep-G2 KO-hIFNAR2	Cancer cell line	Male
CVCL_SS25	HAP1 IFNAR2 (-) 1	Cancer cell line	Male
CVCL_SS26	HAP1 IFNAR2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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