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

The protein encoded by this gene is a cytokine receptor for interleukin 21 (IL21). It belongs to the type I cytokine receptors, and has been shown to form a heterodimeric receptor complex with the common gamma-chain, a receptor subunit also shared by the receptors for interleukin 2, 4, 7, 9, and 15. This receptor transduces the growth promoting signal of IL21, and is important for the proliferation and differentiation of T cells, B cells, and natural killer (NK) cells. The ligand binding of this receptor leads to the activation of multiple downstream signaling molecules, including JAK1, JAK3, STAT1, and STAT3. Knockout studies of a similar gene in mouse suggest a role for this gene in regulating immunoglobulin production. Three alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 87 VUS of 194 total submissions

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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 OE?0.04 (0.01–0.20)

0≤0.351.4

Missense OE?0.88 (0.80–0.97)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

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

This gene — mechanism propensity

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.

LOF100% of P/LP variants are LoF · LOEUF 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.

ClinVar Variant Classifications

194 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS87

Likely Benign82

Benign17

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	2	0	0	0	2
VUS	1	83	2	1	87
Likely Benign	0	0	31	51	82
Benign	0	0	15	2	17
Conflicting	—				3
Total	6	83	48	54	194

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

5 pathogenic / likely-pathogenic (of 6) ClinVar copy-number / structural variants overlap IL21R — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →