IL21R

Chr 16AR

interleukin 21 receptor

Also known as: CD360, IMD56, NILR

NCBI Gene: 50615ENSG00000103522UniProt: Q9HBE5

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]

Primary Disease Associations & Inheritance

Immunodeficiency 56MIM #615207
AR
492
ClinVar variants
44
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— IL21R
⚡
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.
📋
ClinVar Variants
44 Pathogenic / Likely Pathogenic· 222 VUS of 492 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.75Z-score
OE missense 0.88 (0.80–0.97)
272 obs / 309.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.80–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 1 / 23.1Missense obs/exp: 272 / 309.1Syn Z: 0.92

ClinVar Variant Classifications

492 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic8
VUS222
Likely Benign184
Benign22
Conflicting11
36
Pathogenic
8
Likely Pathogenic
222
VUS
184
Likely Benign
22
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
33
0
36
Likely Pathogenic
5
0
3
0
8
VUS
1
203
16
2
222
Likely Benign
0
6
61
117
184
Benign
0
1
16
5
22
Conflicting
—11
Total8211129124483

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

View in ClinVar →

Protein Context — Lollipop Plot

IL21R · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Immunodeficiency 56

MIM #615207

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA(+) B cells.
Xie Y et al.·Mol Cancer
2024
When to suspect inborn errors of immunity in Epstein-Barr virus-related lymphoproliferative disorders.
Sacco KA et al.·Clin Microbiol Infect
2023Review
IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome-wide association study.
Guo Y et al.·J Bone Miner Res
2010Meta-analysis
IL21R hypomethylation as a biomarker for distinguishing benign and malignant breast tumours.
Zang Z et al.·Epigenetics
2024
Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells.
Yang R et al.·Sci Immunol
2022Case report
Construction of molecular subgroups of ulcerative colitis.
Ma JL et al.·Eur Rev Med Pharmacol Sci
2023
The effects of air and transportation noise pollution-related altered blood gene expression, DNA methylation, and protein abundance levels on gastrointestinal diseases risk.
Zhan ZQ et al.·Sci Total Environ
2024
Role of IL-21 signaling pathway in transplant-related biology.
Shi X et al.·Transplant Rev (Orlando)
2016Review
Interleukin-21 in immune and allergic diseases.
Sarra M et al.·Inflamm Allergy Drug Targets
2012Review
ChIP-seq analysis found IL21R, a target gene of GTF2I-the susceptibility gene for primary biliary cholangitis in Chinese Han.
Wu Z et al.·Hepatol Int
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rejection; Transplant, Liver

Transcriptomics as an Aid in the Histological Diagnosis of Acute Rejection After Liver Transplantation

RECRUITING
NCT06734013Phase NAIRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2024-10-17
Molecular diagnostic

External Resources

Links to major genomics databases and tools