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…

Primary Disease Associations & Inheritance

Immunodeficiency 56MIM #615207

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · immunodeficiency disease · AR · ClinGen 2022

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in IL21R?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

637 rare PASS variants

Rare truncating (LoF)

1 in 6,100

56 rare PASS variants

Rare synonymous (reference)

1 in 140

302 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IL21R. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 5,700
South Asian	~43k	1 in 93	1 in 6,100
Remaining (unassigned)	~30k	1 in 68	≈ 1 in 14,000
European (Finnish)	~27k	1 in 440	1 in 2,500
Admixed American	~22k	1 in 96	≈ 1 in 19,000
African / African American	~21k	1 in 62	≈ 1 in 21,000
East Asian	~20k	1 in 94	1 in 2,300
Ashkenazi Jewish	~13k	1 in 440	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 85	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 6 marginal. Genomes: all 8.? see exons ↓