IL21

Summary

IL21 (interleukin 21, HGNC:6005) is a protein-coding gene on chromosome 4q27, encoding Interleukin-21 (Q9HBE4). Cytokine with immunoregulatory activity.

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.

Source: NCBI Gene 59067 — RefSeq curated summary.

At a glance

• Gene–disease (curated): IL21-related infantile inflammatory bowel disease (Supportive, GenCC)
• GWAS associations: 51
• Clinical variants (ClinVar): 120 total — 1 pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• MANE Select transcript: NM_021803

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6005
Approved symbol	IL21
Name	interleukin 21
Location	4q27
Locus type	gene with protein product
Status	Approved
Aliases	Za11, IL-21
Ensembl gene	ENSG00000138684
Ensembl biotype	protein_coding
OMIM	605384
Entrez	59067

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000611104, ENST00000647784, ENST00000648588

RefSeq mRNA: 2 — MANE Select: NM_021803 NM_001207006, NM_021803

CCDS: CCDS3727, CCDS75189

Canonical transcript exons

ENST00000648588 — 5 exons

Exon	Start	End
ENSE00000935270	122620701	122620736
ENSE00000935271	122615682	122615837
ENSE00000935272	122612851	122612928
ENSE00003722561	122620844	122621066
ENSE00003832256	122610108	122612760

Expression profiles

Bgee: expression breadth broad, 26 present calls, max score 78.24.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.24	silver quality
olfactory bulb	UBERON:0002264	75.89	gold quality
type B pancreatic cell	CL:0000169	73.65	gold quality
male germ cell	CL:0000015	69.28	gold quality
diaphragm	UBERON:0001103	69.26	gold quality
sperm	CL:0000019	68.56	gold quality
lymph node	UBERON:0000029	67.84	gold quality
vermiform appendix	UBERON:0001154	60.97	gold quality
tibialis anterior	UBERON:0001385	60.45	silver quality
upper arm skin	UBERON:0004263	60.35	gold quality
tongue squamous epithelium	UBERON:0006919	60.23	gold quality
caecum	UBERON:0001153	58.49	gold quality
pancreatic ductal cell	CL:0002079	57.72	silver quality
thymus	UBERON:0002370	55.00	gold quality
ileal mucosa	UBERON:0000331	54.82	silver quality
buccal mucosa cell	CL:0002336	54.76	silver quality
vena cava	UBERON:0004087	54.66	gold quality
epithelial cell of pancreas	CL:0000083	54.34	gold quality
epithelium of mammary gland	UBERON:0003244	53.32	gold quality
cerebellar vermis	UBERON:0004720	53.27	gold quality
mammary duct	UBERON:0001765	53.16	gold quality
deltoid	UBERON:0001476	52.87	gold quality
mucosa of urinary bladder	UBERON:0001259	51.36	gold quality
pigmented layer of retina	UBERON:0001782	50.88	gold quality
blood vessel layer	UBERON:0004797	50.47	gold quality
tonsil	UBERON:0002372	50.28	gold quality
quadriceps femoris	UBERON:0001377	49.79	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.64	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.26
E-HCAD-29	no	5195.85

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
BCL6	Activation
PAX5	Activation

Upstream regulators (CollecTRI, top): AHR, AP1, BATF, BCL6, BMAL2, EOMES, ETV5, HAND1, HAND2, IKZF1, IRF4, JUN, JUND, MAF, NFATC1, NFATC2, NFKB1, NFKB2, NFKB, REL, RELB, RORA, RORC, SSRP1, STAT1, STAT2, STAT3, STAT4, STAT5A, TBX21, THAP9

Literature-anchored findings (GeneRIF, showing 40)

• IL-21 rapidly induces mRNA synthesis for IFN-gamma, T-bet, IL-2 receptor alpha, IL-12 receptor beta 2, IL-18 receptor, and myeloid differentiation factor 88, the genes that are important in activating innate immunity and Th1 response in NK and T cells. (PMID:12244150)
• Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain. (PMID:12504082)
• Synergistic interactions between IL-21, IL-15, and IL-18 play an important role in NK and T cell functions by enhancing IFN-gamma gene expression; IL-21 activates STAT DNA binding to IFN-gamma regulatory elements. (PMID:12759422)
• identify a dichotomous action of IL21 and IL15 on dendritic cells, establishing IL-21 as inhibitory cytokine on DC activation and IL-15 as potent stimulator of DC function (PMID:12893770)
• In addition to promoting growth and differentiation of committed B cells, IL-21 is a specific switch factor for the production of IgG1 and IgG3. (PMID:15100251)
• Study of IL-21-transgenic mice establishes new roles for IL-21 in the differentiation of B cells into postswitch and plasma cells, in inducing Blimp-1 and Bcl-6 expression, and in development of autoimmune disease. (PMID:15494482)
• Data show that the proximal promoter of IL-21 controls its Th-cell-subset-specific expression through the action of NFATc2 and T-bet. (PMID:15684054)
• Our findings indicate that IL-21 may influence the production of both human IgE and IgG4, and thus contribute to the regulation of atopic reactions (PMID:15919378)
• IL-21 prevents down-modulation of CD28 and enhances interferon-gamma production in naive CD8+ T cells that undergo IL-15- mediated homeostatic proliferation. (PMID:16002671)
• A positive regulatory role is demonstrated for IL-21 in augmenting the induction of a primary antigen-specific human cytotoxic T cell (CTL) response (PMID:16081794)
• In this review, IL-21 has pleiotropic actions, from augmenting the proliferation of T cells and driving the differentiation of B cells into memory cells and terminally differentiated plasma cells to augmenting the activity of natural killer cells. (PMID:16138102)
• When B cells were stimulated thru the BCR, IL21 induced minimal proliferation, IgD down-modulation, and small numbers of plasma cells. After CD40 engagement, IL21 induced extensive proliferation, class switch recombination, & plasma cell differentiation (PMID:16339522)
• the peak of IL-21 mRNA production in both the HSV-2 and LCMV-challenged mice coincides with the onset of the adaptive immune response. Thus, our data suggest a role for IL-21 in the early stages of adaptive immune response against virus infections. (PMID:16406655)
• IL-21 is able to channel natural killer (NK) and CD8+ T cell function by altering the expression pattern of activation/costimulatory receptors. (PMID:16424177)
• IL-21, a cytokine produced by activated T cells, can directly inhibit the activation and cytokine production of myeloid dendritic cells, providing a negative feedback loop between DCs and T lymphocytes. (PMID:16551679)
• 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-21 is a powerful growth factor for naive B cells; Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. (PMID:17015709)
• the link between IL-21-induced JAK/STAT signaling, c-Myc regulation, and differentiation of human B cells (PMID:17142735)
• IL-21 expression by in PBMCs reduced IgE production by B cells. (PMID:17178921)
• intestinal epithelial cells are a target of IL-21 and that IL-21 is involved in the cross-talk between epithelial and immune cells in the gut (PMID:17241869)
• IL-21 is overexpressed in Hp-infected gastric mucosa where it could contribute to increased epithelial gelatinase production. (PMID:17442980)
• 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)
• IL-21 has a physiological role in immunity, infection, and cancer [review] (PMID:17509926)
• Genetic variation in a linkage disequilibrium block encompassing the KIAA1109-TENR-IL2-IL21 genes predisposes to celiac disease. (PMID:17558408)
• analysis and engineering of conformers of interleukin-21 (PMID:17565991)
• IL-21 induced apoptosis in follicular lymphoma cells expressing high levels of IL-21 receptor. (PMID:17624663)
• occurrence of an unusual TG 3’ splice site in intron 3 (PMID:17672918)
• there are some different regulatory mechanisms to produce IL-21 or IL-21iso in transcriptional and secretory steps. (PMID:17673207)
• IL-21 produced from CD4(+) memory T cells may have a supportive role in the maintenance of CD4(+) T cell subsets. (PMID:17698559)
• REVIEW:IL-21 is highly produced by activated CD4+ lymphocytes in the inflamed gut of patients with Crohn’s disease, where it contributes to sustaining the ongoing Th1 inflammation (PMID:17712836)
• IL-21 may play an important role in enhancing the host immune response of Sezary syndrome patients through the increased cytolytic activity of T and NK cells (PMID:17713571)
• findings indicate that IL-21 polymorphism is a candidate association with SLE. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets (PMID:17720724)
• can stimulate proliferation and cytokine secretion by antigen-specific rhesus monkey CD8+ T cells; IL-21 drives these cells to apoptosis by down-regulation of Bcl-2. (PMID:17785794)
• In summary, IL-21 enhances IgE production at low densities through stimulating cell division and plasma cell differentiation and this activity is reduced upon BCR cross-linking. (PMID:17888893)
• mechanism for IL-21-mediated expansion of antigen-specific CTLs that involves suppression of Foxp3-expressing cells and reversal of inhibition to tumor-associated antigen-specific cytotoxic T cell generation in (PMID:17921346)
• IL-15 but not IL-21 caused an increased phosphorylation of Shc and ERK1/2. (PMID:17938255)
• These data are the first to document that B cell activation, expansion, and PC differentiation induced by direct interaction of B cells with activated T cells requires IL-21 (PMID:17947662)
• The levels of serum BAFF and IL-21 level are increased in the patients with SLE. (PMID:17988587)
• IL-21 produced by TFH cells during the primary as well as the subsequent responses to T cell-dependent Ag makes a major contribution to eliciting and maintaining long-lived humoral immunity. (PMID:18056361)
• In addition to its proapoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced antibody-dependent cellular cytotoxicity against rituximab-coated CLL cells (PMID:18182577)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il21	ENSMUSG00000027718
rattus_norvegicus	Il21	ENSRNOG00000017376

Protein

Protein identifiers

Interleukin-21 — Q9HBE4 (reviewed: Q9HBE4)

Alternative names: Za11

All UniProt accessions (2): Q9HBE4, A0A224B028

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine with immunoregulatory activity. May promote the transition between innate and adaptive immunity. Induces the production of IgG(1) and IgG(3) in B-cells. Implicated in the generation and maintenance of T follicular helper (Tfh) cells and the formation of germinal-centers. Together with IL6, control the early generation of Tfh cells and are critical for an effective antibody response to acute viral infection. May play a role in proliferation and maturation of natural killer (NK) cells in synergy with IL15. May regulate proliferation of mature B- and T-cells in response to activating stimuli. In synergy with IL15 and IL18 stimulates interferon gamma production in T-cells and NK cells. During T-cell mediated immune response may inhibit dendritic cells (DC) activation and maturation.

Subcellular location. Secreted.

Tissue specificity. Expressed in activated CD4-positive T-cells but not in CD8-positive T-cells, B-cells, or monocytes.

Disease relevance. Immunodeficiency, common variable, 11 (CVID11) [MIM:615767] A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the IL-15/IL-21 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HBE4-1	1	yes
Q9HBE4-2	2, IL-21iso

RefSeq proteins (2): NP_001193935, NP_068575* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003443	IL-15/IL-21_fam	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily

Pfam: PF02372

UniProt features (18 total): helix 7, strand 2, disulfide bond 2, signal peptide 1, chain 1, turn 1, region of interest 1, glycosylation site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3TGX	X-RAY DIFFRACTION	2.8
8ENT	X-RAY DIFFRACTION	2.83
2OQP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBE4-F1	83.92	0.58

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 (2): 71–122, 78–125

Glycosylation sites (1): 97

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9020958	Interleukin-21 signaling

MSigDB gene sets: 319 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_NATURAL_KILLER_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_B_CELL_PROLIFERATION, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY

GO Biological Process (28): natural killer cell differentiation (GO:0001779), positive regulation of cytokine production (GO:0001819), germinal center B cell differentiation (GO:0002314), positive regulation of immunoglobulin production (GO:0002639), positive regulation of natural killer cell cytokine production (GO:0002729), signal transduction (GO:0007165), tyrosine phosphorylation of STAT protein (GO:0007260), positive regulation of cell population proliferation (GO:0008284), positive regulation of B cell proliferation (GO:0030890), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-17 production (GO:0032740), positive regulation of natural killer cell differentiation (GO:0032825), positive regulation of tissue remodeling (GO:0034105), positive regulation of T cell proliferation (GO:0042102), natural killer cell mediated cytotoxicity (GO:0042267), positive regulation of tyrosine phosphorylation of STAT protein (GO:0042531), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), cell maturation (GO:0048469), positive regulation of inflammatory response (GO:0050729), defense response to virus (GO:0051607), T follicular helper cell differentiation (GO:0061470), cellular response to virus (GO:0098586), immune response (GO:0006955), response to virus (GO:0009615), cell development (GO:0048468), positive regulation of lymphocyte activation (GO:0051251), defense response to other organism (GO:0098542)

GO Molecular Function (4): cytokine activity (GO:0005125), cytokine receptor binding (GO:0005126), interleukin-2 receptor binding (GO:0005134), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

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
positive regulation of cytokine production	3
positive regulation of multicellular organismal process	2
positive regulation of natural killer cell mediated immunity	2
positive regulation of lymphocyte proliferation	2
lymphocyte differentiation	1
natural killer cell activation	1
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
mature B cell differentiation involved in immune response	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
natural killer cell cytokine production	1
positive regulation of cytokine production involved in immune response	1
regulation of natural killer cell cytokine production	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway via JAK-STAT	1
peptidyl-tyrosine phosphorylation	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of B cell activation	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-17 production	1
regulation of interleukin-17 production	1
natural killer cell differentiation	1
positive regulation of natural killer cell activation	1
regulation of natural killer cell differentiation	1
positive regulation of lymphocyte differentiation	1
regulation of tissue remodeling	1

Protein interactions and networks

STRING

1066 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL21	IL21R	Q9HBE5	993
IL21	BCL6	P41182	815
IL21	CD4	P01730	715
IL21	IFNG	P01579	705
IL21	CXCR5	P32302	691
IL21	PRDM1	O75626	687
IL21	IL4	P05112	676
IL21	CD40LG	P29965	670
IL21	CD19	P15391	664
IL21	CD27	P26842	661
IL21	IL2	P01585	652
IL21	ICOS	Q9Y6W8	651
IL21	IL17A	Q16552	641
IL21	IL15	P40933	630
IL21	CD38	P28907	627

IntAct

6 interactions, top by confidence:

A	B	Type	Score
ASPH	IL21	psi-mi:“MI:0915”(physical association)	0.560
PARP2	IL21	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
DGKA	IL21	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (8): IL21 (Affinity Capture-Western), DGKA (Co-localization), ALDH1A1 (Affinity Capture-MS), IL21 (Synthetic Lethality), ASPH (Two-hybrid), S100P (Reconstituted Complex), S100A6 (Reconstituted Complex), IL21 (Biochemical Activity)

ESM2 similar proteins: A3QPB9, H2N2P1, O02699, O62757, O77515, O77762, P04401, P05112, P05113, P07750, P20096, P30367, P30368, P42202, P46652, P46685, P47966, P48093, P51492, P51744, P52173, P55030, P79155, P79339, Q04745, Q08125, Q28586, Q2PE74, Q3S4V6, Q588F8, Q588G0, Q60440, Q62575, Q6L7I9, Q76LU5, Q76LU6, Q7YS71, Q865W5, Q865X3, Q865X5

Diamond homologs: A3QPB9, Q6L7I9, Q76LU5, Q76LU6, Q80XG2, Q9ES17, Q9HBE4

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
IL21	up-regulates	IL2RG	binding
IL21	up-regulates	IL21R	binding
IL21	“up-regulates quantity by expression”	BCL6	“transcriptional regulation”
IL21	“up-regulates quantity by expression”	PAX5	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	68
Likely benign	43
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
127140	NM_021803.4(IL21):c.146T>C (p.Leu49Pro)	Pathogenic

SpliceAI

310 predictions. Top by Δscore:

Variant	Effect	Δscore
4:122615680:A:AC	donor_gain	1.0000
4:122615681:C:CT	donor_gain	1.0000
4:122615681:CT:C	donor_gain	1.0000
4:122615681:CTA:C	donor_gain	1.0000
4:122615681:CTAG:C	donor_gain	1.0000
4:122615681:CTAGT:C	donor_gain	1.0000
4:122615703:C:CA	donor_gain	1.0000
4:122615834:TTGT:T	acceptor_gain	1.0000
4:122615838:C:CC	acceptor_gain	1.0000
4:122620696:CTTAC:C	donor_loss	1.0000
4:122620697:TTACC:T	donor_loss	1.0000
4:122620698:TA:T	donor_loss	1.0000
4:122620838:TCTTA:T	donor_loss	1.0000
4:122620839:CTTAC:C	donor_loss	1.0000
4:122620841:TA:T	donor_loss	1.0000
4:122612924:CATGT:C	acceptor_gain	0.9900
4:122612926:TGT:T	acceptor_gain	0.9900
4:122612929:C:CC	acceptor_gain	0.9900
4:122615676:TCTTA:T	donor_loss	0.9900
4:122615677:CTTA:C	donor_loss	0.9900
4:122615678:TTA:T	donor_loss	0.9900
4:122615679:TACT:T	donor_loss	0.9900
4:122615680:AC:A	donor_loss	0.9900
4:122615681:C:CA	donor_loss	0.9900
4:122615833:TTTGT:T	acceptor_gain	0.9900
4:122615834:TTGTC:T	acceptor_loss	0.9900
4:122615835:TGT:T	acceptor_gain	0.9900
4:122615836:GT:G	acceptor_gain	0.9900
4:122615836:GTC:G	acceptor_loss	0.9900
4:122615837:TC:T	acceptor_loss	0.9900

AlphaMissense

1072 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:122612881:G:C	F136L	0.992
4:122612881:G:T	F136L	0.992
4:122612883:A:G	F136L	0.992
4:122615806:A:C	F79C	0.987
4:122615805:A:C	F79L	0.985
4:122615805:A:T	F79L	0.985
4:122615807:A:G	F79L	0.985
4:122612882:A:C	F136C	0.982
4:122612882:A:G	F136S	0.979
4:122615806:A:G	F79S	0.979
4:122620866:A:G	L49P	0.976
4:122615809:C:G	C78S	0.975
4:122615810:A:T	C78S	0.975
4:122615808:G:C	C78W	0.974
4:122615810:A:G	C78R	0.971
4:122615830:C:G	C71S	0.968
4:122615831:A:T	C71S	0.968
4:122615809:C:T	C78Y	0.966
4:122620887:A:G	L42P	0.961
4:122615829:A:C	C71W	0.957
4:122612861:A:G	L143P	0.954
4:122615830:C:T	C71Y	0.954
4:122612915:C:T	C125Y	0.952
4:122615809:C:A	C78F	0.949
4:122612915:C:G	C125S	0.947
4:122612916:A:T	C125S	0.947
4:122615807:A:C	F79V	0.947
4:122615831:A:G	C71R	0.946
4:122615830:C:A	C71F	0.945
4:122620714:G:T	P64Q	0.944

dbSNP variants (sampled 300 via entrez): RS1000176482 (4:122619752 G>T), RS1000944712 (4:122614414 A>G,T), RS1000997036 (4:122614197 C>T), RS1001233888 (4:122618978 A>G,T), RS1001261698 (4:122619162 A>G), RS1001326555 (4:122618360 A>G), RS1001420608 (4:122621760 A>T), RS1002267469 (4:122620615 C>G,T), RS1002344041 (4:122611495 C>T), RS1002730292 (4:122610064 G>A,T), RS1002906040 (4:122617484 G>A), RS1002998578 (4:122616649 A>G), RS10032644 (4:122622919 T>A), RS1003327287 (4:122615244 G>A), RS1003875273 (4:122621835 A>G)

Disease associations

OMIM: gene MIM:605384 | disease phenotypes: MIM:615767

GenCC curated gene-disease

Disease	Classification	Inheritance
IL21-related infantile inflammatory bowel disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
IL21-related infantile inflammatory bowel disease	Limited	AR

Mondo (1): IL21-related infantile inflammatory bowel disease (MONDO:0014338)

Orphanet (2): Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome (Orphanet:238569), IL21-related infantile inflammatory bowel disease (Orphanet:477661)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0002037	Inflammation of the large intestine
HP:0002205	Recurrent respiratory infections
HP:0003212	Increased circulating IgE concentration
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0011839	Abnormal total T cell count
HP:0012378	Fatigue
HP:0030388	Decreased class-switched memory B cell proportion
HP:0032154	Aphthous ulcer
HP:0033343	Mucoid diarrhea
HP:0100280	Crohn’s disease
HP:0100759	Clubbing of fingers

GWAS associations

51 associations (top):

Study	Trait	p-value
GCST000048_2	Celiac disease	1.000000e-14
GCST000157_8	Celiac disease	3.000000e-13
GCST000612_34	Celiac disease	2.000000e-27
GCST000719_2	Alopecia areata	4.000000e-08
GCST000964_33	Ulcerative colitis	9.000000e-07
GCST001116_4	Progressive supranuclear palsy	1.000000e-07
GCST001725_79	Inflammatory bowel disease	3.000000e-13
GCST002084_6	Allergic sensitization	6.000000e-10
GCST002318_71	Rheumatoid arthritis	4.000000e-06
GCST002520_7	Celiac disease	3.000000e-11
GCST002737_6	Atopic dermatitis	1.000000e-06
GCST002817_3	Alzheimer’s disease in APOE e4- carriers	8.000000e-06
GCST003097_10	Pediatric autoimmune diseases	3.000000e-08
GCST003184_22	Atopic dermatitis	4.000000e-06
GCST003542_2	Night sleep phenotypes	1.000000e-06
GCST003814_13	Selective IgA deficiency	1.000000e-06
GCST003990_11	Allergy	4.000000e-11
GCST004030_4	Primary sclerosing cholangitis	1.000000e-13
GCST004131_73	Inflammatory bowel disease	1.000000e-07
GCST004132_89	Crohn’s disease	9.000000e-07
GCST004302_17	Primary biliary cholangitis	4.000000e-13
GCST004302_18	Primary biliary cholangitis	1.000000e-11
GCST004644_1	Vaso-occlusive pain in sickle-cell anemia	6.000000e-08
GCST004861_53	Itch intensity from mosquito bite	2.000000e-37
GCST004862_186	Itch intensity from mosquito bite adjusted by bite size	5.000000e-13
GCST004862_195	Itch intensity from mosquito bite adjusted by bite size	6.000000e-07
GCST004862_48	Itch intensity from mosquito bite adjusted by bite size	1.000000e-08
GCST004863_135	Mosquito bite size	3.000000e-39
GCST004865_77	Itch intensity from mosquito bite adjusted by bite size	2.000000e-11
GCST004866_24	Alopecia areata	1.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005298	allergic sensitization measurement
EFO:0008316	vaso-occlusive pain measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4665586 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	2
Simvastatin	decreases expression, decreases secretion	2
CBP30 compound	decreases expression	1
fluorene-9-bisphenol	decreases expression	1
TL8-506	affects cotreatment, increases secretion	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases methylation	1
3-chlorophenol	increases expression	1
CGP 52608	affects binding, increases reaction	1
tofacitinib	decreases reaction, increases phosphorylation	1
brevetoxin 2	increases expression	1
(+)-JQ1 compound	decreases expression	1
Folic Acid	decreases expression	1
Lipopolysaccharides	decreases reaction, increases expression	1
Pentachlorophenol	increases expression	1
Poly I-C	increases secretion, affects cotreatment	1
Silicon Dioxide	decreases expression	1
Triclosan	decreases reaction, increases expression	1

Cellosaurus cell lines

5 cell lines: 2 transformed cell line, 2 cancer cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2XK	YK6-CD40Lg-IL21	Telomerase immortalized cell line	Male
CVCL_E3RH	HS5-IL21	Transformed cell line	Male
CVCL_E3RK	HS5-CD40L-IL4-IL21	Transformed cell line	Male
CVCL_E6W8	Genomeditech K-562 H_IL21(Membrane bound)	Cancer cell line	Female
CVCL_XD95	THP-1/IL21	Cancer cell line	Male

Clinical trials (associated diseases)

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