IL21R

Chr 16AR

interleukin 21 receptor

Also known as: CD360, IMD56, NILR

NCBI Gene: 50615 ENSG00000103522 UniProt: Q9HBE5 OMIM: 605383

The IL21R protein is a cytokine receptor that forms a complex with the common gamma-chain to transduce IL-21 signaling, which is essential for T cell, B cell, and natural killer cell proliferation and differentiation. Mutations cause autosomal recessive immunodeficiency 56, a primary immunodeficiency affecting adaptive immune responses. This gene is highly constrained against loss-of-function variants (pLI = 0.998, LOEUF = 0.205), indicating that complete loss of IL21R function is likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismARLOEUF 0.201 OMIM phenotype

Clinical Summary— IL21R

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Gene-Disease Validity (ClinGen)

immunodeficiency disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — 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

LoF intolerant — likely haploinsufficient

LoF Constraint

0.20LOEUF

pLI 0.998

Z-score 4.26

OE 0.04 (0.01–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

0.75Z-score

OE missense 0.88 (0.80–0.97)

272 obs / 309.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.04 (0.01–0.20)

0≤0.351.4

Missense OE0.88 (0.80–0.97)

0≤0.61.4

Synonymous OE0.90

0≤1.21.6

LoF obs/exp: 1 / 23.1Missense obs/exp: 272 / 309.1Syn Z: 0.92

0.5280th %ile

GOF

0.6541th %ile

LOF

0.57top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.20

GOFprediction 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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.