IL21

Chr 4AR

interleukin 21

Also known as: CVID11, IL-21, Za11

NCBI Gene: 59067 ENSG00000138684 UniProt: Q9HBE4 OMIM: 605384

This gene encodes interleukin-21, a cytokine that regulates both innate and adaptive immune responses by inducing differentiation, proliferation and activity of B cells, T cells, natural killer cells, and macrophages, and is critical for antibody production and T follicular helper cell formation. Mutations cause autosomal recessive common variable immunodeficiency-11, affecting the immune system's ability to produce effective antibody responses. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.643), suggesting some tolerance for reduced function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the common-gamma chain family of cytokines with immunoregulatory activity. The encoded protein plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. Dysregulation of this gene plays a role in multiple immune-mediated diseases including lupus, psoriasis and chronic inflammatory diseases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Immunodeficiency, common variable, 11MIM #615767

Clinical highlights

Gene–disease validity (ClinGen)

Limited · IL21-related infantile inflammatory bowel disease · AR · ClinGen 2026

not for standalone diagnostic reporting

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

0.64

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.64LOEUF

pLI 0.625

Z-score 2.18

OE 0.14 (0.05–0.64)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.54Z-score

OE missense 0.53 (0.41–0.68)

44 obs / 83.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.05–0.64)

0≤0.351.4

Missense OE?0.53 (0.41–0.68)

0≤0.61.4

Synonymous OE?0.39

0≤1.21.6

LoF obs/exp: 1 / 7.4Missense obs/exp: 44 / 83.6Syn Z: 2.56

Background carrier burden — how many people carry a rare variant somewhere in IL21?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 770

145 rare PASS variants

Rare truncating (LoF)

1 in 19,000

13 rare PASS variants

Rare synonymous (reference)

1 in 2,400

44 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IL21. 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 900	1 in 11,000
South Asian	~43k	1 in 640	≈ 1 in 22,000
Remaining (unassigned)	~30k	1 in 820	≈ 1 in 30,000
European (Finnish)	~27k	1 in 3,800	none seen
Admixed American	~22k	1 in 620	none seen
African / African American	~21k	1 in 460	none seen
East Asian	~20k	1 in 1,000	none seen
Ashkenazi Jewish	~13k	1 in 620	none seen
Middle Eastern	~2,884	≈ 1 in 940	none seen

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): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓