IL4R

Chr 16

interleukin 4 receptor

Also known as: CD124, IL-4RA, IL4RA

NCBI Gene: 3566 ENSG00000077238 UniProt: P24394 OMIM: 147781

The IL4R protein is the alpha chain of the interleukin-4 receptor that binds IL-4 and IL-13 to regulate IgE production and promote Th2 cell differentiation through the JAK-STAT6 pathway. Mutations are associated with atopy manifesting as allergic rhinitis, asthma, eczema, or sinusitis, with autosomal recessive inheritance patterns reported for severe forms. The gene shows low constraint to loss-of-function variation, suggesting tolerance to reduced protein levels.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes the alpha chain of the interleukin-4 receptor, a type I transmembrane protein that can bind interleukin 4 and interleukin 13 to regulate IgE production. The encoded protein also can bind interleukin 4 to promote differentiation of Th2 cells. A soluble form of the encoded protein can be produced by proteolysis of the membrane-bound protein, and this soluble form can inhibit IL4-mediated cell proliferation and IL5 upregulation by T-cells. Allelic variations in this gene have been associated with atopy, a condition that can manifest itself as allergic rhinitis, sinusitus, asthma, or eczema. Polymorphisms in this gene are also associated with resistance to human immunodeficiency virus type-1 infection. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.83

Clinical Summary— IL4R

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.11

OE 0.48 (0.29–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.77Z-score

OE missense 0.90 (0.83–0.98)

428 obs / 475.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.29–0.83)

0≤0.351.4

Missense OE?0.90 (0.83–0.98)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 9 / 18.9Missense obs/exp: 428 / 475.2Syn Z: 0.24

This gene — mechanism propensity

0.7228th %ile

GOF

0.78top 25%

LOF

0.3066th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFHere, we describe novel somatic IL4R mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functiona1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References