IFNAR1

Summary

IFNAR1 (interferon alpha and beta receptor subunit 1, HGNC:5432) is a protein-coding gene on chromosome 21q22.11, encoding Interferon alpha/beta receptor 1 (P17181). Together with IFNAR2, 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 and functions as an antiviral factor.

Source: NCBI Gene 3454 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 106, susceptibility to viral infections (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 368 total — 16 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes
• MANE Select transcript: NM_000629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5432
Approved symbol	IFNAR1
Name	interferon alpha and beta receptor subunit 1
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	IFRC
Ensembl gene	ENSG00000142166
Ensembl biotype	protein_coding
OMIM	107450
Entrez	3454

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 16 protein_coding, 12 nonsense_mediated_decay, 5 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000270139, ENST00000442071, ENST00000651609, ENST00000652450, ENST00000652513, ENST00000652601, ENST00000652654, ENST00000700045, ENST00000700046, ENST00000700080, ENST00000700084, ENST00000700085, ENST00000700086, ENST00000700087, ENST00000700099, ENST00000700301, ENST00000703514, ENST00000703515, ENST00000703516, ENST00000703556, ENST00000703557, ENST00000703561, ENST00000703562, ENST00000703563, ENST00000703564, ENST00000703565, ENST00000703776, ENST00000703778, ENST00000703779, ENST00000873009, ENST00000873010, ENST00000873011, ENST00000873012, ENST00000970405, ENST00000970409, ENST00000970411

RefSeq mRNA: 8 — MANE Select: NM_000629 NM_000629, NM_001384498, NM_001384499, NM_001384500, NM_001384501, NM_001384502, NM_001384503, NM_001384504

CCDS: CCDS13624, CCDS93088, CCDS93089, CCDS93090

Canonical transcript exons

ENST00000270139 — 11 exons

Exon	Start	End
ENSE00000952626	33343268	33343422
ENSE00000952627	33343535	33343676
ENSE00000952628	33345246	33345360
ENSE00000952629	33349091	33349290
ENSE00000952630	33349389	33349543
ENSE00000952632	33353638	33353783
ENSE00001043348	33352758	33352908
ENSE00003978662	33324970	33325131
ENSE00003978783	33335524	33335647
ENSE00003978784	33340999	33341174
ENSE00003978785	33355316	33359864

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 95.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.6654 / max 881.5075, expressed in 1811 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188848	35.4957	1809
188849	1.1697	698

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.36	gold quality
mononuclear cell	CL:0000842	94.48	gold quality
leukocyte	CL:0000738	94.29	gold quality
rectum	UBERON:0001052	92.89	gold quality
gall bladder	UBERON:0002110	92.87	gold quality
ventricular zone	UBERON:0003053	92.35	gold quality
islet of Langerhans	UBERON:0000006	91.95	gold quality
endothelial cell	CL:0000115	91.46	gold quality
calcaneal tendon	UBERON:0003701	91.06	gold quality
blood	UBERON:0000178	91.05	gold quality
colonic epithelium	UBERON:0000397	91.02	gold quality
stromal cell of endometrium	CL:0002255	90.59	gold quality
ganglionic eminence	UBERON:0004023	90.52	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.48	gold quality
cortical plate	UBERON:0005343	90.23	gold quality
body of pancreas	UBERON:0001150	89.45	gold quality
adrenal tissue	UBERON:0018303	89.44	gold quality
germinal epithelium of ovary	UBERON:0001304	89.34	gold quality
omental fat pad	UBERON:0010414	89.26	gold quality
peritoneum	UBERON:0002358	89.21	gold quality
right lobe of liver	UBERON:0001114	89.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.03	gold quality
pancreas	UBERON:0001264	88.95	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.72	gold quality
right lung	UBERON:0002167	88.44	gold quality
descending thoracic aorta	UBERON:0002345	88.35	gold quality
right coronary artery	UBERON:0001625	88.29	gold quality
left coronary artery	UBERON:0001626	88.21	gold quality
minor salivary gland	UBERON:0001830	88.09	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.14
E-MTAB-10042	yes	4.23
E-MTAB-6379	no	1764.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, HBP1, IRF3, IRF6, NFKB, PARP1, STAT3

miRNA regulators (miRDB)

143 targeting IFNAR1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4778-3P	99.93	70.40	1818

Literature-anchored findings (GeneRIF, showing 40)

• Only the tyrosine-phosphorylated form of interferon alpha receptor subunit 1 binds to Stat2. (PMID:12220192)
• Data show that Tyk2 tyrosine kinase is essential for stable cell surface expression of IFNAR1. (PMID:12554654)
• Measles virus suppresses interferon-alpha signaling pathway: association of viral accessory proteins, C and V, with interferon-alpha receptor complex (PMID:12620806)
• An association has been demonstrated between two IFNAR1 polymorphisms and cerebral malaria. (PMID:12761564)
• IFNAR1 interacts with the Homolog of Slimb (HOS) F-box protein in a phosphorylation-dependent manner, and that this interaction is promoted by interferon alpha (PMID:14532120)
• 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)
• phosphorylation and ubiquitin acceptor sites are required for ubiquitination and degradation of IFNAR1 (PMID:15337770)
• A dynamic model for the IFN-alpha/receptor complex predicts that IFNAR1 and IFNAR2 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)
• The IFNAR1 subunit of the type I IFN receptor complex contains a functional nuclear localization sequence. (PMID:15589821)
• analysis of the roles of the four Ig-like sub-domains (SDs) of the extracellular domain of ifnar1 (ifnar1-EC) for ligand recognition and receptor assembling (PMID:15946680)
• The promoter GT repeat dinucleotide microsatellite polymorphism of the IFNAR1 gene may represent a risk factor for the development of depressive symptoms during IFN-alpha therapy for hepatitis C and other conditions. (PMID:15990456)
• Data describe the mapping of the complete binding region of IFNAR1 on IFNalpha2 using a panel of 21 single alanine mutant proteins. (PMID:16171819)
• Monocyte-derived dendritic cells can modulate their sensitivity to two IFN subtypes through a differential regulation of the IFNAR subunits. (PMID:16624932)
• Human type I interferon receptor binding site on human interferon-alpha2 by cross saturation and an NMR-based model of the complex. (PMID:17001036)
• Polymorphisms of IFNAR1 promoter may affect, at least in part, the outcomes of HBV infection. (PMID:17125879)
• constructed a phage display library by randomizing three positions on IFNalpha2 previously shown to confer weak binding to IFNAR1 (PMID:17310065)
• 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)
• The intensity and distribution of IFNAR-1 may predict the response to therapy with IFN-alpha and IFN-beta in pancreatic cancer. (PMID:17667505)
• This study suggests that when combination therapy with high dose IFN-alpha and ribavirin is administered, HCV genotypes and age rather than the IFNAR1 polymorphisms are the predictors of a sustained response. (PMID:17823081)
• report that in response to type 1 interferon (IFNalpha), IFNalpha type 1 receptors recruit cytoplasmic CREB-binding protein (CBP). (PMID:17923090)
• Ubiquitination of IFNAR1 promotes its interaction with the adaptin complex that is required for the robust internalization of IFNAR1, implicating cooperation between site-specific ubiquitination and the linear endocytic motif in regulating this process. (PMID:18056411)
• We discuss the signaling events that might lead to ubiquitination and degradation of IFNAR1 via ligand-dependent and independent pathways and their potential physiologic significance. (PMID:18166147)
• An IFNAR1/retinoic acid-inducible gene I (RIG-I)-dependent pathway mediates SOCS1 and SOCS3 up-regulation in influenza A virus-infected bronchial epithelial cells. (PMID:18250407)
• place TRAF2 directly in the signaling pathway transduced through the IFNAR1 subunit of the IFN receptor (PMID:18362156)
• Tyk2 contributes to both the regulation of total IFNAR1 levels as well as the regulation of the cell surface density of this receptor chain. (PMID:18474601)
• a major bottleneck was observed during POLIOVIRUS transit to the brain in PVR mice, but was absent in PVR-IFNAR-/- mice, suggesting that the interferon response was a determinant of the peripheral site-to-brain bottleneck (PMID:18535656)
• In conclusion, IFNAR1 19158C/G polymorphism is primarily associated with susceptibility to chronic HBV infection. (PMID:18761606)
• the stability of the ternary interferon-receptor complex rather than the affinity to the individual subunits dictates differential biological activities (PMID:18801736)
• Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists. (PMID:18937499)
• two variants of the IFNAR1 gene are associated with the clinical presentation of hepatitis B virus infection (PMID:19103527)
• CD11c-Cre+/- ifnar1(fl/fl) transgenic mice respond with vigorous IFN-alpha production to mouse hepatitis virus infection, suggesting that lack of IFNAR on plasmacytoid dendritic cells has no significant impact on the early type I IFN response. (PMID:19124753)
• The expression of interferon-alpha receptor in liver tissues in patients with chronic hepatitis B correlates well with the pathological grading and alanine aminotransferase level. (PMID:19220955)
• 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)
• Upon HBV infection, decreased binding affinity of HMGB1 to the IFNAR1 promoter -3T variant is aggravated by the suppressed PARP-1 expression caused by HBV, resulting in a further attenuated IFNAR1 expression. (PMID:19501422)
• Palmitoylation of interferon-alpha (IFN-alpha) receptor subunit IFNAR1 is required for the activation of Stat1 and Stat2 by IFN-alpha. (PMID:19561067)
• 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)
• Results suggest a role for mammalian and parasite casein kinase 1alpha in regulating IFNAR1 stability and type I IFN signaling. (PMID:19805514)
• These results suggest that a combination of serum soluble interferon-alpha/beta receptor and high-sensitivity-CRP thresholds may be more reliable diagnostic parameter for gastrointestinal and hepatobiliary-pancreatic cancer. (PMID:19879773)
• Both ligand-dependent and -independent pathways converge on phosphorylation of Ser(535) within the IFNAR1 degron leading to recruitment of beta-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation (PMID:19948722)
• Down-regulation of type I interferon receptor sensitizes bladder cancer cells to vesicular stomatitis virus-induced cell death. (PMID:19957332)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	il10rb	ENSDARG00000078042
mus_musculus	Ifnar1	ENSMUSG00000022967
rattus_norvegicus	Ifnar1	ENSRNOG00000028594

Paralogs (11): IL20RA (ENSG00000016402), IFNGR1 (ENSG00000027697), IL10RA (ENSG00000110324), F3 (ENSG00000117525), IL22RA1 (ENSG00000142677), IFNAR2 (ENSG00000159110), IFNGR2 (ENSG00000159128), IL22RA2 (ENSG00000164485), IL20RB (ENSG00000174564), IFNLR1 (ENSG00000185436), IL10RB (ENSG00000243646)

Protein

Protein identifiers

Interferon alpha/beta receptor 1 — P17181 (reviewed: P17181)

Alternative names: Cytokine receptor class-II member 1, Cytokine receptor family 2 member 1, Type I interferon receptor 1

All UniProt accessions (14): P17181, A0A494BZU5, A0A494C0E2, A0A494C0K3, A0A494C0P2, A0A8V8TQJ9, A0A8V8TQK8, A0A994J3P7, A0A994J479, A0A994J4B0, A0A994J6F6, A0A994J6F9, A0A994J6V0, C9J114

UniProt curated annotations — full annotation on UniProt →

Function. Together with IFNAR2, 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. STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes. Can also act independently of IFNAR2: form an active IFNB1 receptor by itself and activate a signaling cascade that does not involve activation of the JAK-STAT pathway.

Subunit / interactions. Heterodimer with IFNAR2; forming the receptor for type I interferon. Interacts with TYK2. Interacts with STAT1 and STAT2; the interaction requires its phosphorylation at Tyr-466. Interacts (serine-phosphorylated form) with FBXW11, the substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Interacts with SHMT2; this promotes interaction with ABRAXAS2 and the BRISC complex. Interacts with TRIM10; this interaction prevents association between IFNAR1 and TYK2.

Subcellular location. Cell membrane. Late endosome. Lysosome.

Tissue specificity. IFN receptors are present in all tissues and even on the surface of most IFN-resistant cells. Isoform 1, isoform 2 and isoform 3 are expressed in the IFN-alpha sensitive myeloma cell line U266B1. Isoform 2 and isoform 3 are expressed in the IFN-alpha resistant myeloma cell line U266R. Isoform 1 is not expressed in IFN-alpha resistant myeloma cell line U266R.

Post-translational modifications. Ubiquitinated, leading to its internalization and degradation. Polyubiquitinated via ‘Lys-48’-linked and ‘Lys-63’-linked ubiquitin chains, leading to receptor internalization and lysosomal degradation. The ‘Lys-63’-linked ubiquitin chains are cleaved off by the BRISC complex. Phosphorylated on tyrosine residues in response to interferon-binding: phosphorylation by TYK2 tyrosine kinase creates docking sites for STAT proteins. Phosphorylated on serine residues in response to interferon binding; this promotes interaction with FBXW11 and ubiquitination. Palmitoylation at Cys-463 is required for the activation of STAT1 and STAT2.

Disease relevance. Immunodeficiency 106, susceptibility to viral infections (IMD106) [MIM:619935] An autosomal recessive immunologic disorder characterized by increased susceptibility to viral infections beginning in infancy or early childhood. IMD106 affected individuals may demonstrate adverse reactions to vaccination with live attenuated viral vaccines, most notably measles, mumps and rubella (MMR) and yellow fever vaccines. A subset of IMD106 patients develop severe reactions, including excessive hyperinflammatory response, encephalopathy, acute respiratory distress syndrome, and multiorgan failure. IMD106 may also predispose to severe respiratory infection with SARS-CoV-2. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. Incomplete sequence. Incomplete sequence.

Similarity. Belongs to the type II cytokine receptor family.

Isoforms (4)

UniProt ID	Names	Canonical?
P17181-1	1	yes
P17181-2	2, Sol-1, Soluble form 1
P17181-3	3, Sol-2, Soluble form 2
P17181-4	4

RefSeq proteins (8): NP_000620, NP_001371427, NP_001371428, NP_001371429, NP_001371430, NP_001371431, NP_001371432, NP_001371433 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015373	Interferon/interleukin_rcp_dom	Domain
IPR016669	Interferon_alpha/beta_rcpt-1	Family
IPR036116	FN3_sf	Homologous_superfamily
IPR050650

Pfam: PF01108, PF09294

UniProt features (102 total): strand 20, sequence variant 20, glycosylation site 12, mutagenesis site 9, splice variant 5, sequence conflict 5, helix 5, modified residue 4, disulfide bond 4, domain 4, cross-link 3, region of interest 2, topological domain 2, turn 2, signal peptide 1, chain 1, compositionally biased region 1, lipid moiety-binding region 1, transmembrane region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3S98	X-RAY DIFFRACTION	1.9
4PO6	X-RAY DIFFRACTION	1.99
8Y31	X-RAY DIFFRACTION	2.68
3SE4	X-RAY DIFFRACTION	3.5
3SE3	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17181-F1	78.71	0.48

Antibody-complex structures (SAbDab): 1 — 8Y31

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 (8): 466, 481, 495, 535, 463, 501, 525, 526

Disulfide bonds (4): 79–87, 199–220, 283–291, 403–426

Glycosylation sites (12): 50, 58, 81, 88, 110, 172, 254, 313, 314, 376, 416, 433

Mutagenesis-validated functional residues (9):

Position	Phenotype
466	impairs internalization in response to interferon.
491–492	impairs interaction with tyk2.
496–497	impairs interaction with tyk2.
500	impairs interaction with tyk2.
501	mildly reduces ubiquitination. nearly abolishes ubiquitination and subsequent degradation; when associated with 525-r-r-
525–526	reduces ubiquitination. nearly abolishes ubiquitination and subsequent degradation; when associated with r-501.
535	abolishes interaction with fbxw11 and decreases ubiquitination.
535	abolishes phosphorylation at this site and interaction with shmt2.
539	abolishes interaction with fbxw11 and decreases ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

16 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
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1643685	Disease
R-HSA-168256	Immune System
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): cell surface receptor signaling pathway via JAK-STAT (GO:0007259), response to virus (GO:0009615), response to lipopolysaccharide (GO:0032496), cellular response to interferon-alpha (GO:0035457), cellular response to interferon-beta (GO:0035458), type I interferon-mediated signaling pathway (GO:0060337), cellular response to virus (GO:0098586), positive regulation of cellular respiration (GO:1901857), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of metabolic process (GO:0009893), cytokine-mediated signaling pathway (GO:0019221), 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), cytokine binding (GO:0019955), type I interferon binding (GO:0019962), interferon receptor activity (GO:0004904), protein binding (GO:0005515)

GO Cellular Component (6): lysosome (GO:0005764), late endosome (GO:0005770), plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
SARS-CoV Infections	2
Viral Infection Pathways	2
Interferon Signaling	1
Interferon alpha/beta signaling	1
SARS-CoV-2-host interactions	1
RSV-host interactions	1
Immune System	1
Disease	1
Cytokine Signaling in Immune system	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 response to cytokine stimulus	3
interferon binding	2
cell surface receptor signaling pathway via STAT	1
response to other organism	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
response to interferon-alpha	1
response to interferon-beta	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
response to virus	1
positive regulation of metabolic process	1
regulation of cellular respiration	1
cellular respiration	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
metabolic process	1
regulation of metabolic process	1
positive regulation of cellular process	1
cell surface receptor signaling pathway	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
protein binding	1
cytokine receptor activity	1
binding	1
lytic vacuole	1
endosome	1
membrane	1
cell periphery	1
protein-containing complex	1
endomembrane system	1

Protein interactions and networks

STRING

2164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFNAR1	IFNA13	P01562	999
IFNAR1	IFNB1	P01574	999
IFNAR1	IFNAR2	P48551	999
IFNAR1	JAK1	P23458	998
IFNAR1	IFNA2	P01563	997
IFNAR1	TYK2	P29597	997
IFNAR1	STAT1	P42224	982
IFNAR1	IFNE	Q86WN2	977
IFNAR1	SOCS1	O15524	970
IFNAR1	IFNK	Q9P0W0	970
IFNAR1	IFNLR1	Q8IU57	966
IFNAR1	STAT2	P52630	949
IFNAR1	IFNA17	P01571	948
IFNAR1	AXL	P30530	921
IFNAR1	IFNG	P01579	899

IntAct

35 interactions, top by confidence:

A	B	Type	Score
STAT2	IFNAR1	psi-mi:“MI:0914”(association)	0.760
FBXW11	IFNAR1	psi-mi:“MI:0407”(direct interaction)	0.720
IFNAR1	FBXW11	psi-mi:“MI:0915”(physical association)	0.720
FBXW11	IFNAR1	psi-mi:“MI:0915”(physical association)	0.720
IFNAR1	LAPTM4B	psi-mi:“MI:0915”(physical association)	0.560
TYK2	IFNAR1	psi-mi:“MI:0915”(physical association)	0.560
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
STAT1	IFNAR1	psi-mi:“MI:0915”(physical association)	0.500
IFNAR1	STAT1	psi-mi:“MI:0914”(association)	0.500
IFNW1	IFNAR1	psi-mi:“MI:0407”(direct interaction)	0.440
IFNAR1	EP300	psi-mi:“MI:0915”(physical association)	0.400
IFNA2	IFNAR1	psi-mi:“MI:0915”(physical association)	0.400
IFNB1	IFNAR1	psi-mi:“MI:0915”(physical association)	0.400
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
COPB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
CTLA4	TMEM120B	psi-mi:“MI:0914”(association)	0.350
BTRC	ACOT7	psi-mi:“MI:0914”(association)	0.350
IFNAR1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
IFNAR1	TGFBR2	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (101): IFNAR1 (Reconstituted Complex), IFNAR2 (Co-localization), IFNAR1 (Affinity Capture-MS), IFNAR1 (Affinity Capture-MS), IFNAR1 (Affinity Capture-MS), IFNAR1 (Affinity Capture-RNA), IFNAR1 (Affinity Capture-Western), USP7 (Affinity Capture-Western), IFNAR1 (Reconstituted Complex), SHMT2 (Affinity Capture-Western), IFNAR1 (Co-localization), IFNAR1 (Co-localization), IFNAR2 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), SHMT1 (Affinity Capture-MS)

ESM2 similar proteins: K7NA32, K7NAJ3, O09030, O70458, O70535, P14753, P16310, P17181, P19235, P21183, P22272, P22273, P24055, P26955, P31785, P33896, P34902, P40190, P40223, P40321, P42701, P42702, P42703, P78552, Q00560, Q04790, Q07303, Q28589, Q5XNR9, Q60837, Q65Z14, Q6PHB0, Q6UXL0, Q764M8, Q7TNI4, Q80XF5, Q8K5B1, Q8MJS1, Q8NI17, Q95118

Diamond homologs: P17181, P33896, Q04790, Q28589, Q764M8, Q08334

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
IFNB1	up-regulates	IFNAR1	binding
IFNW1	up-regulates	IFNAR1	binding
TYK2	“up-regulates activity”	IFNAR1	phosphorylation
IFNAR1	“form complex”	IFNAR	binding
IFNAR1	“up-regulates activity”	PI3K	phosphorylation
IFNA1	up-regulates	IFNAR1	binding
IFNB1	“up-regulates activity”	IFNAR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 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	99.8×	3e-07
Evasion by RSV of host interferon responses	5	74.2×	4e-07
Interferon alpha/beta signaling	6	41.5×	4e-07
SARS-CoV-2 activates/modulates innate and adaptive immune responses	6	24.3×	7e-06

GO biological processes:

GO term	Partners	Fold	FDR
type I interferon-mediated signaling pathway	6	79.4×	3e-08
defense response to virus	5	13.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	9
Uncertain significance	154
Likely benign	131
Benign	17

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1404509	NM_000629.3(IFNAR1):c.506del (p.Ile169fs)	Pathogenic
1437264	NM_000629.3(IFNAR1):c.1156G>T (p.Glu386Ter)	Pathogenic
1452864	NM_000629.3(IFNAR1):c.934G>T (p.Gly312Ter)	Pathogenic
1501733	NM_000629.3(IFNAR1):c.360del (p.Phe120fs)	Pathogenic
1911154	NM_000629.3(IFNAR1):c.831G>A (p.Trp277Ter)	Pathogenic
2006398	NM_000629.3(IFNAR1):c.291T>A (p.Tyr97Ter)	Pathogenic
2025845	NM_000629.3(IFNAR1):c.252dup (p.Thr85fs)	Pathogenic
2050663	NM_000629.3(IFNAR1):c.27del (p.Thr10fs)	Pathogenic
2417374	NM_000629.3(IFNAR1):c.1241del (p.Lys414fs)	Pathogenic
2423334	NC_000021.8:g.(?34713285)(34713500_?)del	Pathogenic
2431416	NC_000021.9:g.(33336874_33344911)del	Pathogenic
2712324	NM_000629.3(IFNAR1):c.1165del (p.Thr389fs)	Pathogenic
2767189	NM_000629.3(IFNAR1):c.227dup (p.Leu76fs)	Pathogenic
2991649	NM_000629.3(IFNAR1):c.100C>T (p.Gln34Ter)	Pathogenic
2996847	NM_000629.3(IFNAR1):c.1130_1134del (p.Thr377fs)	Pathogenic
4768306	NM_000629.3(IFNAR1):c.263_267del (p.Asn88fs)	Pathogenic
1481917	NM_000629.3(IFNAR1):c.200+2del	Likely pathogenic
1498680	NM_000629.3(IFNAR1):c.377-2A>G	Likely pathogenic
1514288	NM_000629.3(IFNAR1):c.1294+1G>A	Likely pathogenic
1930164	NM_000629.3(IFNAR1):c.1143+1G>A	Likely pathogenic
1971552	NM_000629.3(IFNAR1):c.988+2_988+6del	Likely pathogenic
1972985	NM_000629.3(IFNAR1):c.531+2T>G	Likely pathogenic
2581563	NM_000629.3(IFNAR1):c.1356del (p.Phe452fs)	Likely pathogenic
2992362	NM_000629.3(IFNAR1):c.789-2A>G	Likely pathogenic
3248178	NC_000021.8:g.(?34720267)(34721595_?)del	Likely pathogenic

SpliceAI

2001 predictions. Top by Δscore:

Variant	Effect	Δscore
21:33325129:CAGG:C	donor_loss	1.0000
21:33325130:AG:A	donor_loss	1.0000
21:33325131:GG:G	donor_loss	1.0000
21:33325132:GT:G	donor_loss	1.0000
21:33325133:T:A	donor_loss	1.0000
21:33335518:TTATA:T	acceptor_loss	1.0000
21:33335519:TATAG:T	acceptor_loss	1.0000
21:33335520:ATAGG:A	acceptor_loss	1.0000
21:33335521:TAG:T	acceptor_loss	1.0000
21:33335522:A:T	acceptor_loss	1.0000
21:33335618:G:GT	donor_gain	1.0000
21:33335619:A:T	donor_gain	1.0000
21:33335644:AAAAG:A	donor_loss	1.0000
21:33335645:AAA:A	donor_gain	1.0000
21:33335646:AA:A	donor_gain	1.0000
21:33335646:AAG:A	donor_loss	1.0000
21:33335647:AG:A	donor_loss	1.0000
21:33335648:G:GG	donor_gain	1.0000
21:33335648:GT:G	donor_loss	1.0000
21:33335649:T:A	donor_loss	1.0000
21:33343346:A:G	donor_gain	1.0000
21:33343352:T:G	donor_gain	1.0000
21:33345361:G:GG	donor_gain	1.0000
21:33355538:GAC:G	donor_gain	1.0000
21:33355564:TGTC:T	donor_gain	1.0000
21:33335522:A:AG	acceptor_gain	0.9900
21:33335522:AGGT:A	acceptor_gain	0.9900
21:33335523:G:GC	acceptor_gain	0.9900
21:33335523:GGT:G	acceptor_gain	0.9900
21:33335523:GGTG:G	acceptor_gain	0.9900

AlphaMissense

3705 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:33345314:T:A	W248R	0.992
21:33345314:T:C	W248R	0.992
21:33345316:G:C	W248C	0.991
21:33345316:G:T	W248C	0.991
21:33349133:G:C	W277C	0.986
21:33349133:G:T	W277C	0.986
21:33349219:G:C	R306P	0.986
21:33341106:G:C	R103P	0.978
21:33352890:T:A	C426S	0.977
21:33352891:G:C	C426S	0.977
21:33352821:T:A	C403S	0.975
21:33352822:G:C	C403S	0.975
21:33345341:T:C	F257L	0.971
21:33345343:T:A	F257L	0.971
21:33345343:T:G	F257L	0.971
21:33349131:T:A	W277R	0.971
21:33349131:T:C	W277R	0.971
21:33343359:G:C	W156C	0.970
21:33343359:G:T	W156C	0.970
21:33343312:G:C	A141P	0.968
21:33349173:T:A	C291S	0.968
21:33349174:G:C	C291S	0.968
21:33343602:T:C	L200P	0.967
21:33352869:A:C	S419R	0.966
21:33352871:T:A	S419R	0.966
21:33352871:T:G	S419R	0.966
21:33335592:T:A	W49R	0.965
21:33335592:T:C	W49R	0.965
21:33349173:T:C	C291R	0.965
21:33352821:T:C	C403R	0.961

dbSNP variants (sampled 300 via entrez): RS1000003233 (21:33354117 T>G), RS1000009204 (21:33354569 A>G), RS1000173348 (21:33333591 A>G,T), RS1000180942 (21:33328228 A>G), RS1000200998 (21:33343210 G>A), RS1000246226 (21:33324020 A>G,T), RS1000300721 (21:33348025 G>T), RS1000312493 (21:33323920 G>A,T), RS1000423208 (21:33340351 A>G), RS1000471618 (21:33330718 C>T), RS1000541630 (21:33330097 T>G), RS1000597572 (21:33336940 G>A), RS1000652789 (21:33337358 A>G), RS1000781831 (21:33342933 T>C), RS1000794677 (21:33341789 C>G,T)

Disease associations

OMIM: gene MIM:107450 | disease phenotypes: MIM:619935, MIM:614889

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 106, susceptibility to viral infections	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 106, susceptibility to viral infections	Definitive	AR

Mondo (2): immunodeficiency 106, susceptibility to viral infections (MONDO:0030970), immunodeficiency 28 (MONDO:0013953)

Orphanet (2): Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency (Orphanet:319547), Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency (Orphanet:319574)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0020088	Post-vaccination measles
HP:0034310	Post-vaccination yellow fever

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001729_26	Crohn’s disease	2.000000e-16
GCST002874_36	Psoriasis	5.000000e-06
GCST002874_38	Psoriasis	7.000000e-06
GCST006585_2623	Blood protein levels	3.000000e-32

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1887 (SINGLE PROTEIN), CHEMBL2364170 (PROTEIN COMPLEX)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1012335	IFNAR1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Interferon receptor family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
anifrolumab	Binding	10.0	pKd
IFN-β	Agonist	7.8	pKd

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.40	Kd	4000	nM	CHEMBL1617534

PubChem BioAssay actives

1 with measured affinity, of 50 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine	1141059: Binding affinity to IFNAR (unknown origin) assessed as inhibition of interaction with IFN-alpha	kd	4.0000	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
7,7’-dimethoxy-(4,4’-bi-1,3-benzodioxole)-5,5’-dicarboxylic acid dimethyl ester	affects expression	1
ICG 001	increases expression	1
Acetaminophen	decreases expression	1
Glyphosate	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Amantadine	affects expression	1
Benzo(a)pyrene	decreases expression	1
Biological Factors	increases expression	1
Cannabidiol	affects expression	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Curcumin	increases expression, increases reaction	1
Doxorubicin	decreases expression	1
Fluorouracil	increases expression	1
Nickel	decreases expression	1
Nicotine	decreases expression	1
Quercetin	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1
Zinc	decreases expression	1
2-Naphthylamine	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Genistein	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 5 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3107493	Binding	Inhibition of IFNAR in human Daudi cells assessed as reduction of STAT-DNA binding at 200 uM by EMSA	Small molecule mimetics of an interferon-α receptor interacting domain. — Bioorg Med Chem
CHEMBL977008	Functional	Antagonist activity at IFNAR in human Daudi cells assessed as inhibition of IFN-inducible Stat1 tyrosine phosphorylation by SDS-PAGE	De novo design of nonpeptidic compounds targeting the interactions between interferon-alpha and its cognate cell surface receptor. — J Med Chem

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8HV	Abcam HCT 116 IFNAR1 KO	Cancer cell line	Male
CVCL_B9K5	Abcam A-549 IFNAR1 KO	Cancer cell line	Male
CVCL_B9VL	Abcam HeLa IFNAR1 KO	Cancer cell line	Female
CVCL_D2FQ	Abcam MCF-7 IFNAR1 KO	Cancer cell line	Female
CVCL_D7RP	Ubigene A-549 IFNAR1 KO	Cancer cell line	Male
CVCL_D8MS	Ubigene HCT 116 IFNAR1 KO	Cancer cell line	Male
CVCL_D9GN	Ubigene HEK293 IFNAR1 KO	Transformed cell line	Female
CVCL_E0EL	Ubigene HeLa IFNAR1 KO	Cancer cell line	Female
CVCL_SS23	HAP1 IFNAR1 (-) 1	Cancer cell line	Male
CVCL_SS24	HAP1 IFNAR1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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