IL21R

Summary

IL21R (interleukin 21 receptor, HGNC:6006) is a protein-coding gene on chromosome 16p12.1, encoding Interleukin-21 receptor (Q9HBE5). This is a receptor for interleukin-21.

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.

Source: NCBI Gene 50615 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 429 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 18
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_181078

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6006
Approved symbol	IL21R
Name	interleukin 21 receptor
Location	16p12.1
Locus type	gene with protein product
Status	Approved
Aliases	CD360
Ensembl gene	ENSG00000103522
Ensembl biotype	protein_coding
OMIM	605383
Entrez	50615

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000337929, ENST00000395754, ENST00000561953, ENST00000564089, ENST00000564583, ENST00000697146, ENST00000871346, ENST00000871347, ENST00000944544, ENST00000944545

RefSeq mRNA: 3 — MANE Select: NM_181078 NM_021798, NM_181078, NM_181079

CCDS: CCDS10630

Canonical transcript exons

ENST00000337929 — 9 exons

Exon	Start	End
ENSE00000681662	27437488	27437687
ENSE00000681697	27445177	27445276
ENSE00000830171	27442962	27443116
ENSE00000830172	27434347	27434449
ENSE00000830173	27430056	27430120
ENSE00001181108	27448534	27452042
ENSE00002616618	27402174	27402618
ENSE00003468670	27446007	27446088
ENSE00003693167	27444542	27444719

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 87.47.

FANTOM5 (CAGE): breadth broad, TPM avg 15.8094 / max 849.4845, expressed in 882 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153330	5.3593	394
153331	4.4693	384
153336	2.6376	431
153334	2.0782	315
153332	0.5608	210
153335	0.2756	98
207819	0.1420	68
207818	0.1343	76
153337	0.0974	31
153333	0.0549	22

Top tissues by expression

271 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	87.47	gold quality
lymph node	UBERON:0000029	83.94	gold quality
blood	UBERON:0000178	80.24	gold quality
vermiform appendix	UBERON:0001154	79.23	gold quality
epithelium of nasopharynx	UBERON:0001951	77.30	gold quality
caecum	UBERON:0001153	75.95	gold quality
tonsil	UBERON:0002372	73.19	gold quality
spleen	UBERON:0002106	71.94	gold quality
bone marrow	UBERON:0002371	71.87	gold quality
bone marrow cell	CL:0002092	71.82	silver quality
superficial temporal artery	UBERON:0001614	71.54	gold quality
right lung	UBERON:0002167	71.54	gold quality
leukocyte	CL:0000738	71.37	gold quality
monocyte	CL:0000576	70.06	gold quality
mononuclear cell	CL:0000842	69.99	gold quality
left testis	UBERON:0004533	69.57	gold quality
thymus	UBERON:0002370	69.24	silver quality
right testis	UBERON:0004534	69.09	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	68.33	gold quality
testis	UBERON:0000473	67.81	gold quality
trabecular bone tissue	UBERON:0002483	67.38	silver quality
lower lobe of lung	UBERON:0008949	67.31	silver quality
upper lobe of left lung	UBERON:0008952	67.04	gold quality
upper lobe of lung	UBERON:0008948	67.02	gold quality
buccal mucosa cell	CL:0002336	66.49	gold quality
tibia	UBERON:0000979	65.22	gold quality
endothelial cell	CL:0000115	65.03	silver quality
superior surface of tongue	UBERON:0007371	64.91	gold quality
lung	UBERON:0002048	63.62	gold quality
rectum	UBERON:0001052	63.36	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JUN, SP1, SSRP1

miRNA regulators (miRDB)

60 targeting IL21R, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4667-3P	99.26	65.45	1608

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• IL-21R is associated with the activated phenotype of rheumatoid arthritis synovial fibroblasts independently of the major proinflammatory cytokines IL-1beta and TNFalpha, but not with the destruction of articular cartilage and bone. (PMID:15146416)
• The up-regulation of IL-21R in keratinocytes indicates that its expression pattern is not only altered but it appears to be independent of key cytokines that are operant in systemic scleosis. (PMID:15751077)
• TCR-induced IL-21R expression is driven by TCR-mediated augmentation of Sp1 protein levels and may partly depend on the dephosphorylation of Sp1 (PMID:16260592)
• surface IL-21 receptor is expressed at variable levels by chronic lymphocytic leukemia B cells (PMID:16391014)
• IL-21 differentially regulates IL-4-induced IgE production, via its growth- and differentiation-promoting capacities on isotype- committed B cells, & via its ability to induce IFNg production; the outcome depends on the presence of a IL-21R polymorphism. (PMID:17015683)
• IL-21R is overexpressed in the inflamed synovial membrane and in peripheral blood or synovial fluid leukocytes of RA patients. Thus, blockade of IL-21R signalling pathway may have a therapeutic potential in acute RA patients. (PMID:17032244)
• Data suggest a contribution of IL21 and IL21R to genetic susceptibility to type 1 diabetes and possible involvement of IL-21 and its receptor system in the disease pathogenesis. (PMID:17462506)
• Follicular lymphoma cells showed exceptionally high IL-21R expression. IL-21 induced apoptosis in follicular lymphoma cells expressing high levels of IL-21 receptor. (PMID:17624663)
• These results suggest an important role for IL-21R in the mobilization of skin dendritic cells to draining lymph nodes and the subsequent allergic response to epicutaneously introduced antigen. (PMID:19075398)
• analyzed the transcriptional differences between B-cell subsets by gene expression profiling, and identified 15 genes significantly correlated to survival/proliferation. Among them, IL-21R and TCL1 were highly expressed in naive B cells. (PMID:19230867)
• Increased IL-21R is associated with inflammatory bowel disease. (PMID:19322899)
• Tax1 transactivates the interleukin-21 (IL-21) and its receptor (IL-21R) genes in human T-cells. (PMID:19617351)
• A polymorphism within IL21R confers risk for systemic lupus erythematosus. (PMID:19644854)
• parathyroid hormone (PTH) and interleukin 21 receptor (IL21R), achieved consistent association results for bone mineral density in both discovery and replication samples. (PMID:19874204)
• This report provides the first evidence that WSB-2 is a regulator of IL-21R expression and IL-21-induced signal transduction. (PMID:20059963)
• IL-21R is expressed in follicular lymphoma cells from early diagnosed, untreated patients. It mediates apoptosis. It is heterogenously expressed by human FL cell lines bearing the t(14;18) translocation. (PMID:20193734)
• These findings suggest role(s) for IL-21 in both the acute and chronic stages of multiple sclerosis via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons. (PMID:21281812)
• IL21R and vezatin were also cleaved in apoptotic HeLa cells with the cleavage sites Asp344, Asp655 and Asp53. (PMID:21524651)
• Data suggest that the association of 2009 H1N1 vaccine-induced Ab responses with IL-21/IL-21R upregulation and with development of memory B cells and plasmablasts has implications for future research in vaccine design. (PMID:21531891)
• For risk-factor studies, anti-citrullinated peptide antibody-positive (CCP)-negative rheumatoid arthritis patients can be studied as one group via measurement of their IL-21 and IL-21 receptor levels. (PMID:22032620)
• Crystal structure of IL-21 binding to IL-21R reveals that the WSXWS motif of IL-21R is C-mannosylated at the first tryptophan. (PMID:22235133)
• Abundant expression of interleukin-21 receptor in follicular lymphoma cells is associated with more aggressive disease. (PMID:23098230)
• IL-21R gene polymorphisms and serum IL-21 levels predict virological response to interferon-based therapy in Asian chronic hepatitis C patients. (PMID:23296193)
• Data suggest that IL21 rs2221903 and IL21R rs3093301 polymorphisms may, independently or interactively, affect the susceptibility to and/or persistence of HBV infection potentially through altering IL-21 and IgE production. (PMID:23354321)
• Human monocyte-like THP-1 cells express two IL-21 receptor components, CD132 (gammac) and IL-21Ralpha, on their cell surface, as assessed by flow cytometry. (PMID:23396946)
• human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis (PMID:23440042)
• The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. (PMID:23830147)
• Human neutrophils in peripheral blood express functional IL-21 receptors. (PMID:24728504)
• IL-21R on B cells is upregulated in allergic rhinitis patients when compared to controls. IL-21/IL-21R may be involved in the regulation of allergic reactions through the inhibition of IgE. (PMID:25007029)
• interleukin-21 receptor deficiency is associated with Severe Combined Immunodeficiency. (PMID:25398835)
• IL-21/IL-21R could act as potential biomarkers presenting early systemic sclerosis skin lesions severity. (PMID:25500255)
• expression of IL-21 and IL-21R were up-regulated in autoimmune thyroid disease and may be involved in the pathogenesis of the disease through augmenting aberrant immune cascade (PMID:25647271)
• STAT3 signaling downstream of IL-23R and IL-21R has a role in controlling human mucosal-associated invariant T cells and NKT cell numbers (PMID:25941256)
• Report increased levels of IL-21R in the skeletal muscle endothelial cells of patients with peripheral arterial disease compared to control individuals. (PMID:26705256)
• bone marrow monocytes from multiple myeloma patients show distinct features compared to those from patients with indolent monoclonal gammopathies, supporting the role of IL21R over-expression by bone marrow CD14(+) cells in enhanced osteoclast formation. (PMID:28057743)
• The number of IL-2-dependent FoxP3(+) regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). (PMID:28303891)
• Results showed the upregulation of IL-21R in gastric cancer (GC) associated with tumor size and lymphatic metastasis and acted as an independent prognostic factor of a poor survival and recurrence in GC. IL-21R functioned as an oncogenic factor and alleviated the suppressive effects of miR-125a in GC cells. (PMID:30387833)
• in IL-21R (rs3093390C/T) gene polymorphism, allele frequency of T is statistically different in the hepatitis B virus spontaneous clearance group compared to chronic hepatitis B virus infection cases (PMID:30639626)
• IL-21R rs2285452 AA genotype increases the risk of hepatitis B-related hepatocellular carcinoma in Chinese patients. (PMID:30758075)
• The IL21/IL21R axis reduced the growth and invasion of NSCLC cells via inhibiting Wnt/betacatenin signaling and PDL1 expression. The present results may provide a novel molecular target for NSCLC diagnosis and therapy. (PMID:31573051)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il21r	ENSMUSG00000030745
rattus_norvegicus	Il21r	ENSRNOG00000015773

Paralogs (7): IL4R (ENSG00000077238), CSF2RB (ENSG00000100368), IL2RB (ENSG00000100385), MPL (ENSG00000117400), IL9R (ENSG00000124334), IL7R (ENSG00000168685), EPOR (ENSG00000187266)

Protein

Protein identifiers

Interleukin-21 receptor — Q9HBE5 (reviewed: Q9HBE5)

Alternative names: Novel interleukin receptor

All UniProt accessions (2): Q9HBE5, A0A8V8TL34

UniProt curated annotations — full annotation on UniProt →

Function. This is a receptor for interleukin-21.

Subunit / interactions. Heterodimer with the common gamma subunit. Associates with JAK1.

Subcellular location. Membrane.

Tissue specificity. Selectively expressed in lymphoid tissues. Most highly expressed in thymus and spleen.

Post-translational modifications. C-mannosylated at Trp-214 in the WSXWS motif, the sugar chain makes extensive hydrogen bonds with Asn-73 sugar, and bridges the two fibronectin domains transforming the V-shaped receptor into an A-frame.

Disease relevance. Immunodeficiency 56 (IMD56) [MIM:615207] An autosomal recessive primary immunodeficiency characterized by B- and T-cell defects and variable dysfunction of NK cells. Patients tend to have normal numbers of lymphocytes, but show defective class-switched B-cells, low IgG, defective antibody response, and defective T-cell responses to certain antigens. The disease is caused by variants affecting the gene represented in this entry. Chromosomal aberrations involving IL21R is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;16)(q27;p11), with BCL6.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Similarity. Belongs to the type I cytokine receptor family. Type 4 subfamily.

RefSeq proteins (3): NP_068570, NP_851564, NP_851565 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003531	Hempt_rcpt_S_F1_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily

UniProt features (49 total): strand 17, glycosylation site 6, sequence variant 5, helix 5, disulfide bond 3, short sequence motif 2, topological domain 2, domain 2, region of interest 2, signal peptide 1, chain 1, sequence conflict 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6PLH	X-RAY DIFFRACTION	1.6
7KQ7	X-RAY DIFFRACTION	2.2
9E2T	X-RAY DIFFRACTION	2.28
4NZD	X-RAY DIFFRACTION	2.75
3TGX	X-RAY DIFFRACTION	2.8
8ENT	X-RAY DIFFRACTION	2.83

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBE5-F1	65.44	0.34

Antibody-complex structures (SAbDab): 2 — 6PLH, 7KQ7

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 20–109, 25–35, 65–81

Glycosylation sites (6): 73, 97, 104, 125, 135, 214

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9020958	Interleukin-21 signaling

MSigDB gene sets: 269 (showing top): REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOCC_CELL_SURFACE, TGACCTY_ERR1_Q2, GAURNIER_PSMD4_TARGETS, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, COUP_01, PATIL_LIVER_CANCER, GOBP_B_CELL_MEDIATED_IMMUNITY, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, GOBP_ADAPTIVE_IMMUNE_RESPONSE

GO Biological Process (3): cytokine-mediated signaling pathway (GO:0019221), natural killer cell activation (GO:0030101), interleukin-21-mediated signaling pathway (GO:0038114)

GO Molecular Function (4): interleukin-21 receptor activity (GO:0001532), transmembrane signaling receptor activity (GO:0004888), cytokine receptor activity (GO:0004896), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-2 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	2
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
lymphocyte activation	1
cellular response to interleukin-21	1
cytokine receptor activity	1
interleukin-21 binding	1
interleukin-21-mediated signaling pathway	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
cytokine binding	1
immune receptor activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1585 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL21R	IL21	Q9HBE4	993
IL21R	IL2RG	P31785	952
IL21R	IL4	P05112	940
IL21R	IL7	P13232	869
IL21R	IL15	P40933	836
IL21R	IL2	P01585	829
IL21R	STAT3	P40763	816
IL21R	CXCR5	P32302	800
IL21R	CD19	P15391	798
IL21R	IL2RA	P01589	796
IL21R	IL6	P05231	793
IL21R	IL9	P15248	792
IL21R	CD4	P01730	776
IL21R	BCL6	P41182	775
IL21R	JAK1	P23458	768

IntAct

4 interactions, top by confidence:

A	B	Type	Score
AQP1	IL21R	psi-mi:“MI:0915”(physical association)	0.560
AQP1	IL21R	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): AQP1 (Two-hybrid), IL21R (Affinity Capture-Western), IL21R (Affinity Capture-MS), PIK3R1 (Positive Genetic), LCK (Negative Genetic), WSB2 (Affinity Capture-Western), IL21R (Affinity Capture-Western)

ESM2 similar proteins: A2APT9, A5PJC7, B0BN44, O94989, O95153, P14753, P19235, P25118, P36941, P40238, Q01114, Q07303, Q13671, Q2KL21, Q3U4N7, Q3UYR4, Q400G9, Q49LS3, Q5F267, Q5FWH6, Q5GH66, Q5JXC2, Q5R866, Q6UX68, Q6ZVH7, Q7TNF8, Q7Z3H0, Q80VJ8, Q80W87, Q8BG26, Q8BX43, Q8C310, Q8CII8, Q8MII8, Q8N386, Q8NBR0, Q8TE82, Q8WZ75, Q921Q7, Q93038

Diamond homologs: Q9HBE5, Q9JHX3, Q2KL21

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
IL21R	up-regulates	STAT3
IL21	up-regulates	IL21R	binding
IL21R	up-regulates	JAK1	binding
IL21R	up-regulates	JAK3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

429 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	199
Likely benign	174
Benign	22

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1332701	NM_181078.3(IL21R):c.842dup (p.Tyr281Ter)	Pathogenic
2053574	NM_181078.3(IL21R):c.468T>A (p.Tyr156Ter)	Pathogenic
2105229	NM_181078.3(IL21R):c.27dup (p.Leu10fs)	Pathogenic
42199	NM_181078.3(IL21R):c.241_246del (p.Cys81_His82del)	Pathogenic
42200	NM_181078.3(IL21R):c.602G>T (p.Arg201Leu)	Pathogenic
4293560	NM_181078.3(IL21R):c.503_507+3del	Pathogenic
1687495	NM_181078.3(IL21R):c.946del (p.Val316fs)	Likely pathogenic
1900828	NM_181078.3(IL21R):c.686-2A>G	Likely pathogenic
3362656	NM_181078.3(IL21R):c.637del (p.Thr213fs)	Likely pathogenic
3693887	NM_181078.3(IL21R):c.507+1G>A	Likely pathogenic
973584	NM_181078.3(IL21R):c.352+1G>C	Likely pathogenic

SpliceAI

1642 predictions. Top by Δscore:

Variant	Effect	Δscore
16:27430116:GGGAG:G	donor_gain	1.0000
16:27430117:GGAGG:G	donor_gain	1.0000
16:27434449:GGT:G	donor_loss	1.0000
16:27434450:G:GG	donor_gain	1.0000
16:27434450:GTAA:G	donor_loss	1.0000
16:27434451:T:A	donor_loss	1.0000
16:27437683:GAGCA:G	donor_gain	1.0000
16:27437684:AGCA:A	donor_gain	1.0000
16:27437685:GCA:G	donor_gain	1.0000
16:27437685:GCAG:G	donor_gain	1.0000
16:27437686:CA:C	donor_gain	1.0000
16:27437687:AGT:A	donor_loss	1.0000
16:27437688:G:GG	donor_gain	1.0000
16:27437689:T:A	donor_loss	1.0000
16:27437690:GAGTA:G	donor_loss	1.0000
16:27437691:AGTAT:A	donor_loss	1.0000
16:27442945:T:A	acceptor_gain	1.0000
16:27442960:A:G	acceptor_gain	1.0000
16:27443092:G:GT	donor_gain	1.0000
16:27443093:A:T	donor_gain	1.0000
16:27443123:A:T	donor_gain	1.0000
16:27444534:A:AG	acceptor_gain	1.0000
16:27444540:A:AG	acceptor_gain	1.0000
16:27444541:G:GG	acceptor_gain	1.0000
16:27444716:GAGG:G	donor_gain	1.0000
16:27444718:GG:G	donor_gain	1.0000
16:27444719:GG:G	donor_gain	1.0000
16:27445175:A:AG	acceptor_gain	1.0000
16:27445176:G:GT	acceptor_gain	1.0000
16:27445176:GA:G	acceptor_gain	1.0000

AlphaMissense

3488 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:27443021:T:A	W138R	0.996
16:27443021:T:C	W138R	0.996
16:27444603:T:C	F190S	0.996
16:27444677:A:C	S215R	0.995
16:27444679:T:A	S215R	0.995
16:27444679:T:G	S215R	0.995
16:27444685:G:C	W217C	0.995
16:27444685:G:T	W217C	0.995
16:27444683:T:A	W217R	0.994
16:27444683:T:C	W217R	0.994
16:27444686:A:C	S218R	0.994
16:27444688:T:A	S218R	0.994
16:27444688:T:G	S218R	0.994
16:27443023:G:C	W138C	0.993
16:27443023:G:T	W138C	0.993
16:27434370:T:A	C25S	0.990
16:27434371:G:C	C25S	0.990
16:27444636:G:C	R201P	0.990
16:27444678:G:T	S215I	0.990
16:27434400:T:A	C35S	0.989
16:27434400:T:C	C35R	0.989
16:27434401:G:C	C35S	0.989
16:27443082:T:C	L158P	0.989
16:27444676:G:C	W214C	0.989
16:27444676:G:T	W214C	0.989
16:27434401:G:A	C35Y	0.988
16:27437576:T:A	C81S	0.988
16:27437577:G:C	C81S	0.988
16:27437576:T:C	C81R	0.987
16:27434370:T:C	C25R	0.986

dbSNP variants (sampled 300 via entrez): RS1000078072 (16:27442844 T>C,G), RS1000126083 (16:27447556 G>A), RS1000168232 (16:27403137 C>A,T), RS1000217446 (16:27410091 T>G), RS1000259540 (16:27449212 C>A,T), RS1000307611 (16:27410801 C>G,T), RS1000336677 (16:27420311 T>G), RS1000441837 (16:27443240 C>T), RS1000485275 (16:27405257 T>C), RS1000485884 (16:27431809 A>G), RS1000587730 (16:27409555 G>T), RS1000680642 (16:27441611 C>G), RS1000704317 (16:27442420 G>A), RS1000730129 (16:27425221 T>G), RS1000770148 (16:27404266 A>G,T)

Disease associations

OMIM: gene MIM:605383 | disease phenotypes: MIM:615207, MIM:147050, MIM:614162

GenCC curated gene-disease

Disease	Classification	Inheritance
cryptosporidiosis-chronic cholangitis-liver disease syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency disease	Definitive	AR

Mondo (3): cryptosporidiosis-chronic cholangitis-liver disease syndrome (MONDO:0014082), IgE responsiveness, atopic (MONDO:0007817), autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (MONDO:0013599)

Orphanet (2): Combined immunodeficiency due to IL21R deficiency (Orphanet:357329), STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome (Orphanet:391487)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001508	Failure to thrive
HP:0002028	Chronic diarrhea
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0003139	Panhypogammaglobulinemia
HP:0004798	Recurrent infection of the gastrointestinal tract
HP:0006532	Recurrent pneumonia
HP:0011108	Recurrent sinusitis
HP:0011463	Childhood onset
HP:0020102	Pneumocystis jirovecii pneumonia
HP:0030151	Cholangitis
HP:0200124	Chronic hepatitis due to cryptosporidium infection

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000515_2	Bone mineral density	2.000000e-06
GCST002083_31	Self-reported allergy	3.000000e-07
GCST002717_2	Serum IgE levels	2.000000e-06
GCST003129_4	Primary biliary cholangitis	2.000000e-07
GCST004009_6	Leprosy	6.000000e-07
GCST004302_15	Primary biliary cholangitis	4.000000e-16
GCST004863_73	Mosquito bite size	8.000000e-06
GCST007995_47	Asthma (childhood onset)	6.000000e-13
GCST009798_29	Asthma	3.000000e-08
GCST009798_58	Asthma	3.000000e-09
GCST009798_64	Asthma	4.000000e-17
GCST009798_67	Asthma	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008378	mosquito bite reaction size measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564133	Ige Responsiveness, Atopic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3093390	IL21R		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — IL-2 receptor family

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression, decreases methylation	4
bisphenol A	decreases methylation, affects cotreatment, increases methylation	2
sodium arsenite	increases expression	2
bisphenol S	decreases methylation, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
bisphenol F	decreases methylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
caffeic acid	decreases expression, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
4-methoxycinnamate methyl ester	decreases expression, increases reaction	1
Fulvestrant	increases methylation, affects cotreatment	1
Benzene	increases expression	1
Dexamethasone	decreases expression	1
Drugs, Chinese Herbal	decreases expression, increases reaction	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Methotrexate	decreases expression	1
N-Nitrosopyrrolidine	increases expression	1
Nickel	increases expression	1
Silicon Dioxide	increases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1
Thapsigargin	decreases expression, increases reaction	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1GE	Abcam Raji IL21R KO	Cancer cell line	Male
CVCL_IU39	YM	Cancer cell line	Male

Clinical trials (associated diseases)

27 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00414141	PHASE3	COMPLETED	Efficacy and Safety/Tolerability of Grass MATA MPL
NCT00423787	PHASE3	COMPLETED	Efficacy and Safety/Tolerability of Ragweed MATA MPL
NCT00104377	PHASE2	COMPLETED	Induction of Immunogenicity With Different Doses of Grass MATA in Subjects Allergic to Grass and Rye Pollen
NCT00110786	PHASE2	COMPLETED	Investigation of Efficacy and Safety of Ragweed MATAMPL, Pollinex-R and Placebo in Patients With Ragweed Allergy
NCT00113750	PHASE2	COMPLETED	Induction of Immunogenicity With Different Doses of TreeMATA in Subjects Allergic to Tree Pollen
NCT00118612	PHASE2	COMPLETED	Different Doses of Tyrosine Adsorbed Tree Pollen Allergoid With Monophosphoryl Lipid A (MPL) in Patients Sensitized to Tree Pollen
NCT00118625	PHASE2	COMPLETED	Assessment of the Contribution of Monophosphoryl Lipid A (MPL) to a Tree Pollen Allergy Vaccine
NCT00133146	PHASE2	COMPLETED	Assessment of the Contribution of Monophosphoryl Lipid A (MPL) to a Grass Pollen Allergy Vaccine
NCT00133159	PHASE2	COMPLETED	Different Doses of Tyrosine Adsorbed Grass Pollen Allergoid With Monophosphoryl Lipid A (MPL) in Patients Sensitized to Grass Pollen
NCT00258635	PHASE2	COMPLETED	Investigation of Safety+Efficacy of Different Doses of RagweedMATAMPL;Assessment of Residual Allergenicity Using Skin Prick Test
NCT00325338	PHASE2	COMPLETED	Follow-up Investigation of Efficacy of Ragweed MATAMPL,and Placebo in Patients With Ragweed-induced Seasonal Allergic Rhinitis
NCT00387478	PHASE2	TERMINATED	Investigation of Efficacy and Safety of Tree MATAMPL,Tree MATA, and Placebo in Patients With Birch-Induced Seasonal Allergic Rhinitis
NCT00461097	PHASE2	COMPLETED	Oral Immunotherapy for Childhood Egg Allergy
NCT00104390	PHASE1	COMPLETED	Assessment of Residual Allergenicity of Grass/Rye Pollen Allergoid Using Skin Prick Testing
NCT00107705	PHASE1	COMPLETED	Assessment of Residual Allergenicity of Tree (Birch, Hazel, and Alder) Pollen Allergoid Using Skin Prick Testing
NCT00109759	PHASE1	WITHDRAWN	Evaluation of Safety and Tolerability of Tyrosine Adsorbed Ragweed Pollen Allergoid With MPL (Monophosphoryl Lipid A)
NCT00116285	PHASE1	COMPLETED	Assessment of Residual Allergenicity of Ragweed Pollen Allergoid With Monophosphoryl Lipid A (MPL) Using Skin Prick Testing
NCT00241410	PHASE1	COMPLETED	Safety, Immunological Effect and Efficacy of the Combined Application of MPL and Grass Pollen Allergen
NCT00850668	PHASE1	COMPLETED	Peanut Allergy Vaccine Study in Healthy and Peanut-allergic Adults
NCT00580606	PHASE1/PHASE2	COMPLETED	A Randomized, Double-Blind Placebo-Controlled Peanut Sublingual Immunotherapy Trial
NCT01084174	PHASE1/PHASE2	COMPLETED	A Randomized, Double-Blind, Placebo-Controlled Pilot Study of Sublingual/Oral Immunotherapy for the Treatment of Peanut Allergy
NCT05003804	PHASE1/PHASE2	COMPLETED	Allergic Disease Onset Prevention Study
NCT01407640	Not specified	COMPLETED	Diagnosis and Physiopathology of Insulin Allergy
NCT02561390	Not specified	COMPLETED	Comparison Between spIgE and Skin Prick Test of Local and Imported Aeroallergens
NCT02561429	Not specified	COMPLETED	Comparison of Difference Histamine Concentration (1, 5 and 10 mg/ml) for Skin Prick Test Positive Control
NCT02733926	Not specified	UNKNOWN	Effect of Vegetation in Kindergartens on the Immune Response of Children
NCT06065137	Not specified	COMPLETED	Standardised Drug Provocation Testing in Perioperative Hypersensitivity