IFNAR2

protein-coding

interferon alpha and beta receptor subunit 2, the group of Interferon receptors

Gene summary

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. [provided by RefSeq, Jul 2020]

Previous symbols:

IFNABR

MANE transcript

NM_001289125.3

Inheritance

ClinVar variants

P:13U:146B:111

Top phenotype

Immunodeficiency 45

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr21:33,205,282-33,265,675

External References & Databases

Ensembl (ENSG00000159110)

Transcript & Mutation Effects

hg38 • Region Span ~60.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 45LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014727

Submitter: Ambry Genetics

immunodeficiency 45STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014727

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 45STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014727

Submitter: PanelApp Australia

immunodeficiency 45DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014727

Submitter: ClinGen

*IFNAR2* was first reported in relation to **autosomal recessive (AR) IFNAR2-related immunodeficiency (previously referred to as immunodeficiency 45)** in 2015 (Duncan et al., PMID: 26424569). *IFNAR2* encodes one of the two chains of the receptor of type I interferons. IFNAR2-related immunodeficiency is characterized by patients who present with severe adverse reactions (e.g. meningoencephalitis, hemophagocytic lymphohistiocytosis) to live attenuated viral vaccines and life-threatening respiratory infections with COVID-19 or influenza. Laboratory studies have shown affected individuals have an impaired response to alpha-interferon, impaired type I interferon signatures after stimulation, and heightened vulnerability to multiple viruses *in vitro*. Of note, this gene has also been implicated in susceptibility to Hepatitis B virus (OMIM:610424). This will be assessed separately as it appears that *IFNAR2* variants associated with susceptibility to HBV are gain of function. **6 variants** (1 missense, 1 nonsense, 1 splice donor, and 3 indel leading to a premature stopgain, 4 of which were found in homozygous state, remaining 2 were in compound heterozygous state) that have been reported in **5 probands in 5 publications** (PMIDs: 33544838, 39436454, 35442417, 33193576, 26424569) are included in this curation. None of the parents or siblings who were heterozygous carriers showed any clinical phenotype. More evidence is available in the literature, but the maximum score for genetic evidence (**12 pts.**) has been reached. The mechanism of pathogenicity **is reported to be loss of function**. This gene-disease relationship is also supported by **rescue of patient cells, *in vitro* functional assays, and mouse models** (PMIDs: 35442417, 26424569, 26424569, 26424569, 30473701). A null mouse model recapitulates disease with increased morbidity and mortality in response to influenza A infection (PMID: 30473701). Additionally, patient dermal fibroblasts were unable to develop an antiviral state in response to exogenous IFN-α with no expression of antiviral gene products. These cells also showed complete failure of tyrosine phosphorylation of JAK1, TYK2, or STAT1/2 in patient cells exposed to IFN-α or IFN-β, a finding recapitulated in another paper with whole blood cells from the patient (PMIDs: 26424569, 33193576). Rescue of patient fibroblasts with *IFNAR2* restored STAT1 phosphorylation in response to IFNβ stimulation (PMID: 35442417). In summary, there is definitive evidence supporting the relationship between *IFNAR2* and **autosomal recessive IFNAR2-related immunodeficiency**. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the **ClinGen SCID-CID GCEP** on the meeting date **March 19, 2026 (SOP Version 12)**.

Clinical Genomic Database (CGD)

Immunodeficiency 45AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have immunodeficiency, and related adverse reactions to vaccinations have been reported such that awareness may help prevent morbidity

Refs: 26424569

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IFNAR2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 283

not specifiedTotal: 94

IFNAR2-related disorderTotal: 10

Immunodeficiency 45Total: 10

IFNAR2-related disordersTotal: 3

Susceptibility to severe COVID-19Total: 2

Associated with severe COVID-19 diseaseTotal: 2

Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infectionTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001289125.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				90 clinvar	5 clinvar	95
missense		1 clinvar	142 clinvar	15 clinvar	1 clinvar	159
nonsense	3 clinvar					3
start loss						0
frameshift	4 clinvar	2 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)		3 clinvar	3 clinvar			6
Total	7	6	146	105	6	270

Highest pathogenic variant AF is 0.000031601372

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001289125.3	RefSeq	NP_001276054.1	8	MANE Select
ENST00000342136.9	Ensembl	ENSP00000343957.5	8	MANE Select
NM_000874.5	RefSeq	NP_000865.2	8	Standard
NM_001289126.2	RefSeq	NP_001276055.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
Influenza A - Homo sapiens (human)
Necroptosis - Homo sapiens (human)

Biological Process

cell surface receptor signaling pathway
JAK-STAT cascade
response to virus
cytokine-mediated signaling pathway
response to interferon-alpha

Molecular Function

cytokine receptor activity
type I interferon receptor activity
protein binding
protein kinase binding

Cellular Component

extracellular region
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342136
Coding exons: 8
Length: 35775
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.258	265	277	0.956	0.0000141	3411
Missense (PolyPhen)		86	105.39	0.81604		1325
Synonymous	0.135	110	112	0.984	0.00000668	967
Loss of Function	1.22	10	15.1	0.662	7.16e-7	204

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00055	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Associates with IFNAR1 to form the type I interferon receptor. Receptor for interferons alpha and beta. Involved in IFN-mediated STAT1, STAT2 and STAT3 activation (PubMed:26424569). Isoform 1 and isoform 2 are directly involved in signal transduction due to their association with the TYR kinase, JAK1 (PubMed:8181059, PubMed:7665574, PubMed:7759950). Isoform 3 is a potent inhibitor of type I IFN receptor activity (PubMed:7759950). {ECO:0000269|PubMed:10049744, ECO:0000269|PubMed:11682488, ECO:0000269|PubMed:12105218, ECO:0000269|PubMed:26424569, ECO:0000269|PubMed:7665574, ECO:0000269|PubMed:7759950, ECO:0000269|PubMed:8181059}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:26424569}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.318

Intolerance Scores

LoFtool: 0.915
RVIS EVS: 0.16
RVIS percentile EVS: 64.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.836

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium