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 (top 2% of genes corpus-wide)
• Clinical variants (ClinVar): 128 total — 1 pathogenic
• Expression (HPA): Tissue enriched — highest in lymph node, tonsil, appendix
• Phenotypes (HPO): 15
• Drug target: yes — 1 curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.99 (loss-of-function intolerant), LOEUF 0.45 (moderately constrained)
• MANE Select transcript: NM_021803
• Notable: 128 clinical variants but no curated precision-oncology (CIViC) evidence yet

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

MANE Select: ENST00000648588

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000648588, ENST00000611104, ENST00000647784

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.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, olfactory bulb, type B pancreatic cell, male germ cell, diaphragm.

Genetic regulation across tissues (GTEx eQTL / sQTL)

IL21 is not an eGene in any GTEx v10 tissue: no tissue shows a variant significantly associated with its expression or splicing (q < 0.05).

Top tissues by expression

showing 100 of 274 tissues 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
myocardium	UBERON:0002349	49.16	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
vastus lateralis	UBERON:0001379	48.72	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
cervix epithelium	UBERON:0004801	48.52	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
oviduct epithelium	UBERON:0004804	48.26	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
nasal cavity epithelium	UBERON:0005384	48.08	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
gluteal muscle	UBERON:0002000	47.03	gold quality
kidney epithelium	UBERON:0004819	47.02	gold quality
triceps brachii	UBERON:0001509	47.01	gold quality
renal glomerulus	UBERON:0000074	46.99	gold quality
metanephric glomerulus	UBERON:0004736	46.96	gold quality
nephron tubule	UBERON:0001231	46.88	gold quality
skeletal muscle tissue	UBERON:0001134	45.92	gold quality
layer of synovial tissue	UBERON:0007616	45.76	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
substantia nigra pars reticulata	UBERON:0001966	45.17	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality
cranial nerve II	UBERON:0000941	44.57	silver quality
tongue	UBERON:0001723	44.32	gold quality
body of tongue	UBERON:0011876	44.23	gold quality
superior surface of tongue	UBERON:0007371	44.22	gold quality
squamous epithelium	UBERON:0006914	44.19	gold quality
dorsal plus ventral thalamus	UBERON:0001897	44.13	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
subthalamic nucleus	UBERON:0001906	43.05	gold quality
epithelium of bronchus	UBERON:0002031	43.04	gold quality
bronchus	UBERON:0002185	42.91	gold quality
epithelium of esophagus	UBERON:0001976	42.87	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
medulla oblongata	UBERON:0001896	42.52	gold quality
trachea	UBERON:0003126	42.37	gold quality
pharyngeal mucosa	UBERON:0000355	42.16	gold quality
cartilage tissue	UBERON:0002418	42.04	gold quality
superior vestibular nucleus	UBERON:0007227	41.90	gold quality
bone marrow cell	CL:0002092	41.71	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
ventral tegmental area	UBERON:0002691	41.14	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
oral cavity	UBERON:0000167	41.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
rectum	UBERON:0001052	40.68	silver quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
bone marrow	UBERON:0002371	40.53	gold quality
pleura	UBERON:0000977	40.51	gold quality
duodenum	UBERON:0002114	40.48	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
mammary gland	UBERON:0001911	40.43	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
colonic mucosa	UBERON:0000317	40.27	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
thoracic mammary gland	UBERON:0005200	40.20	gold quality
jejunum	UBERON:0002115	40.18	gold quality
globus pallidus	UBERON:0001875	40.17	gold quality
mucosa of sigmoid colon	UBERON:0004993	40.16	gold quality
metanephros	UBERON:0000081	40.09	gold quality
embryo	UBERON:0000922	39.93	gold quality
lower lobe of lung	UBERON:0008949	39.93	silver quality
saphenous vein	UBERON:0007318	39.83	gold quality
parotid gland	UBERON:0001831	39.81	gold quality
oocyte	CL:0000023	39.80	gold quality
urethra	UBERON:0000057	39.80	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

HPA expression

RNA tissue specificity: Tissue enriched

20 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Lymph node	tissue	5.5
Tonsil	tissue	2.6
Appendix	tissue	0.9
Testis	tissue	0.7
Prefrontal cortex	tissue	0.2
Cerebral cortex	tissue	0.2
Urinary bladder	tissue	0.2
Motor cortex	tissue	0.2
Somatosensory cortex	tissue	0.2
Temporal cortex	tissue	0.2
Stomach 1	tissue	0.1
Amygdala	tissue	0.1
Spleen	tissue	0.1
Thymus	tissue	0.1
Hippocampal formation	tissue	0.1
Entorhinal cortex	tissue	0.1
Retrosplenial and cingulate cortex	tissue	0.1
Retrosplenial cortex	tissue	0.1
Occipital cortex	tissue	0.1
Insular cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 1; highest nTPM — Dorsal hippocampus (0.1).

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

Functional genomics

gnomAD constraint: pLI 0.986, LOEUF 0.45, missense Z 1.63 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000648588 — one region, missense o/e 0.69.

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1890474) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 16 distinct phenotype terms.

Mouse phenotype (MP)	Records
enlarged testis	1
abnormal T cell differentiation	1
abnormal spleen germinal center morphology	1
abnormal CD4-positive, alpha beta T cell morphology	1
increased IgE level	1
increased susceptibility to experimental autoimmune encephalomyelitis	1
decreased susceptibility to experimental autoimmune encephalomyelitis	1
abnormal class switch recombination	1
abnormal CD4-positive, alpha-beta T cell physiology	1
decreased CD4-positive, alpha-beta T cell number	1
decreased germinal center B cell number	1
abnormal germinal center B cell physiology	1
abnormal gamma-delta T cell morphology	1
decreased spleen germinal center number	1
decreased IgG1 level	1
abnormal interleukin level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q76LU5	87.5%	Diamond
Sus scrofa	Q76LU6	87.5%	Diamond
Canis lupus familiaris	Q6L7I9	86.3%	Diamond
Peromyscus maniculatus	Q80XG2	80.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ADAD1	protein-coding	132612
BBS12	protein-coding	166379
IL2	protein-coding	3558
IL21-AS1	ncRNA	100996941
BLTP1	protein-coding	84162
FGF2	protein-coding	2247

Protein

Protein identifiers

Interleukin-21 — Q9HBE4 (reviewed: Q9HBE4)

Alternative names: Za11

All UniProt accessions (2): A0A224B028, Q9HBE4

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 (19 total): helix 9, disulfide bond 2, signal peptide 1, chain 1, strand 1, turn 1, region of interest 1, glycosylation site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
3TGX	IL-21:IL21R complex	X-RAY DIFFRACTION	2.8
8ENT	Interleukin-21 signaling complex with IL-21R and IL-2Rg	X-RAY DIFFRACTION	2.83
2OQP	Solution structure of human interleukin-21	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted secreted proteins, Plasma proteins, Disease related genes, Human disease related genes, Diabetes, Primary immunodeficiency

Protein evidence: Evidence at protein level

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)

Type	Positions
Disulfide bond	71–122, 78–125

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	97

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-9020958	Interleukin-21 signaling	curated
R-HSA-9938027	Affinity selection of immunoglobulins	electronic
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168256	Immune System	—
R-HSA-451927	Interleukin-2 family signaling	—
R-HSA-449147	Signaling by Interleukins	—

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 (26): positive regulation of cytokine production (GO:0001819), germinal center B cell differentiation (GO:0002314), positive regulation of immunoglobulin production (GO:0002639), signal transduction (GO:0007165), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), tyrosine phosphorylation of STAT protein (GO:0007260), positive regulation of cell population proliferation (GO:0008284), immunoglobulin mediated immune response (GO:0016064), natural killer cell activation (GO:0030101), positive regulation of B cell proliferation (GO:0030890), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-17 production (GO:0032740), positive regulation of tissue remodeling (GO:0034105), positive regulation of T cell proliferation (GO:0042102), 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), defense response (GO:0006952), immune response (GO:0006955), response to virus (GO:0009615), cell development (GO:0048468), positive regulation of lymphocyte activation (GO:0051251)

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), plasma membrane (GO:0005886)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Interleukin-2 family signaling	1
Immunoglobulin maturation	1
Immune System	1
Cytokine Signaling in Immune system	1
Signaling by Interleukins	1

GO top-level categories

showing 60 of 61 GO namespaces:

Category	Terms
positive regulation of multicellular organismal process	2
positive regulation of lymphocyte proliferation	2
positive regulation of cytokine production	2
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
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway via STAT	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
B cell mediated immunity	1
lymphocyte activation	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-17 production	1
regulation of interleukin-17 production	1
regulation of tissue remodeling	1
tissue remodeling	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of T cell activation	1
tyrosine phosphorylation of STAT protein	1
regulation of tyrosine phosphorylation of STAT protein	1
positive regulation of peptidyl-tyrosine phosphorylation	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
cell development	1
cellular developmental process	1
anatomical structure maturation	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
defense response	1
response to virus	1
T-helper cell differentiation	1
exhausted T cell differentiation	1
receptor ligand activity	1
signaling receptor binding	1
cytokine receptor binding	1
growth factor receptor binding	1
binding	1
cellular anatomical structure	1
membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 33 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
cell maturation	BP	direct assay
positive regulation of B cell proliferation	BP	direct assay
positive regulation of T cell proliferation	BP	direct assay
positive regulation of cell population proliferation	BP	direct assay
positive regulation of cytokine production	BP	direct assay
positive regulation of interleukin-17 production	BP	direct assay
positive regulation of natural killer cell mediated cytotoxicity	BP	direct assay
positive regulation of tyrosine phosphorylation of STAT protein	BP	direct assay
tyrosine phosphorylation of STAT protein	BP	direct assay
plasma membrane	CC	physical interaction
interleukin-2 receptor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 16 of 898 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL21	IL21R	Q9HBE5	856
IL21	CD4	P01730	728
IL21	IFNG	P01579	700
IL21	BCL6	P41182	691
IL21	CXCR5	P32302	689
IL21	IL2	P01585	688
IL21	CD27	P26842	688
IL21	IL4	P05112	687
IL21	PRDM1	O75626	668
IL21	CD38	P28907	664
IL21	CD19	P15391	663
IL21	IL17A	Q16552	662
IL21	CD40LG	P29965	642
IL21	IL10	P22301	635
IL21	ICOS	Q9Y6W8	632
IL21	IL6	P05231	632

IntAct

Human interaction partners of IL21 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

3 partners by confidence:

Partner	Interaction type	MIscore	Records
ASPH	physical association	0.560	3
PARP2	adp ribosylation reaction	0.440	1
DGKA	proximity	0.270	1

BioGRID (9 interactions; top human partners by supporting records): ALDH1A1 (Affinity Capture-MS), ASPH (Two-hybrid), CSK (Synthetic Lethality), DGKA (Co-localization), FBXO25 (Biochemical Activity), IL2RG (Affinity Capture-Western), POLI (Reconstituted Complex), S100A6 (Reconstituted Complex), S100P (Reconstituted Complex)

SIGNOR signaling

4 signaling 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”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexe by size:

Complex	Subunits	Members
★ IL-21 receptor-IL-21 complex	3	IL2RG, IL21, IL21R

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
IL21R;IL2RG	ligand	Signaling by Interleukin

Disease & clinical

Genetic variants

Variant evidence for IL21: 128 ClinVar records (1 pathogenic / likely pathogenic); 51 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	73
Likely benign	44
Benign	6

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
127140	NM_021803.4(IL21):c.146T>C (p.Leu49Pro)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore IL21’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 209):

Position(s)	Effect	Δscore	Sites
4:122620699–122620700	donor_loss	1.0000	5
4:122620842–122620843	donor_loss	1.0000	5
4:122615680–122615681	donor_loss	0.9900	6
4:122620737–122620738	acceptor_loss	0.9900	6
4:122615838–122615840	acceptor_loss	0.9800	7
4:122615845	acceptor_loss	0.9800
4:122620842	donor_loss	0.9800
4:122620851	donor_gain	0.9800
4:122612929–122612930	acceptor_loss	0.9700	5
4:122612929	acceptor_loss	0.9600

AlphaMissense

157 missense substitutions predicted likely pathogenic (of 1,072 scored), across 51 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F79	8	0.927	0.987
C78	7	0.965	0.975
F136	7	0.962	0.992
C71	7	0.942	0.968
C125	7	0.925	0.952
C122	7	0.878	0.929
P64	6	0.877	0.944
F76	5	0.849	0.885
R38	5	0.769	0.877
Y128	5	0.741	0.835
L144	4	0.848	0.926
G21	4	0.758	0.847
V46	4	0.724	0.926
M147	4	0.701	0.759
L137	3	0.918	0.927
L49	3	0.905	0.976
L103	3	0.877	0.940
Q80	3	0.824	0.835
A75	3	0.806	0.904
Q145	3	0.806	0.859

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:605384 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
IL21-related infantile inflammatory bowel disease	Supportive	Autosomal recessive	3

ClinGen Gene-Disease Validity

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

1 validity classifications:

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

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (3 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

3 panels:

Panel	Rating
COVID-19 research	green
Infantile enterocolitis & monogenic inflammatory bowel disease	amber
Primary immunodeficiency or monogenic inflammatory bowel disease	amber

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

HPO phenotypes

15 phenotypes (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 number
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

showing 30 of 51 associations:

Study	Trait	p-value
GCST004863_25	Mosquito bite size	3e-39
GCST005523_20	Celiac disease	2e-38
GCST004861_35	Itch intensity from mosquito bite	2e-37
GCST000612_34	Celiac disease	2e-27
GCST010984_33	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	5e-22
GCST010985_53	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	2e-17
GCST006409_9	Allergic rhinitis	3e-15
GCST000048_2	Celiac disease	1e-14
GCST007995_16	Asthma (childhood onset)	2e-14
GCST005038_51	Allergic disease (asthma, hay fever or eczema)	5e-14
GCST009798_86	Asthma	5e-14
GCST004030_4	Primary sclerosing cholangitis	1e-13
GCST000157_8	Celiac disease	3e-13
GCST001725_79	Inflammatory bowel disease	3e-13
GCST004302_17	Primary biliary cholangitis	4e-13
GCST004862_216	Itch intensity from mosquito bite adjusted by bite size	5e-13
GCST005536_42	Type 1 diabetes	6e-13
GCST006670_7	Primary sclerosing cholangitis	9e-13
GCST008916_50	Asthma	1e-12
GCST007564_23	Asthma or allergic disease (pleiotropy)	3e-12
GCST009798_70	Asthma	8e-12
GCST004302_18	Primary biliary cholangitis	1e-11
GCST004865_77	Itch intensity from mosquito bite adjusted by bite size	2e-11
GCST002520_7	Celiac disease	3e-11
GCST003990_11	Allergy	4e-11
GCST005528_6	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	6e-11
GCST002084_6	Allergic sensitization	6e-10
GCST004866_28	Alopecia areata	5e-9
GCST004862_50	Itch intensity from mosquito bite adjusted by bite size	1e-8
GCST010090_6	Atopic dermatitis	1e-8

EFO canonical traits (from GWAS)

5 canonical traits:

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)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the IL21 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
NNC0114-0006	Unknown	2

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

22 measured of 33 human assays (34 total across all organisms); most potent 22 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[4-(5-amino-1,3,4-oxadiazol-2-yl)-1,3-thiazol-2-yl]-(1H-indol-3-yl)methanone	IC50	0.3 nM	US-11891386: Indole compounds and their use
[4-(5-amino-1,3,4-oxadiazol-2-yl)-1,3-thiazol-2-yl]-(5,6-dichloro-1H-indol-3-yl)methanone	IC50	0.3 nM	US-11891386: Indole compounds and their use
[4-(5-amino-1,3,4-oxadiazol-2-yl)-1,3-thiazol-2-yl]-(7-fluoro-1H-indol-3-yl)methanone	IC50	0.8 nM	US-11891386: Indole compounds and their use
2-(1H-indole-3-carbonyl)-N-methyl-1,3-thiazole-4-carboxamide	EC50	1.6 nM	US-11891386: Indole compounds and their use
1H-indol-3-yl-[4-(1,3,4-oxadiazol-2-yl)-1,3-thiazol-2-yl]methanone	IC50	4.9 nM	US-11891386: Indole compounds and their use
[4-(5-amino-1,3,4-oxadiazol-2-yl)-1,3-thiazol-2-yl]-(5-fluoro-1H-indol-3-yl)methanone	IC50	5.9 nM	US-11891386: Indole compounds and their use
1-[2-(5-chloro-1H-indole-3-carbonyl)-1,3-thiazol-4-yl]propan-1-one	IC50	6.3 nM	US-11891386: Indole compounds and their use
[4-(5-amino-1,3,4-thiadiazol-2-yl)-1,3-thiazol-2-yl]-(1H-indol-3-yl)methanone	IC50	8.4 nM	US-11891386: Indole compounds and their use
1-[2-(7-fluoro-1H-indole-3-carbonyl)-1,3-thiazol-4-yl]propan-1-one	IC50	8.6 nM	US-11891386: Indole compounds and their use
2-(5-chloro-1H-indole-3-carbonyl)-N-methyl-1,3-thiazole-4-carboxamide	IC50	10.1 nM	US-11891386: Indole compounds and their use
[4-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-1,3-thiazol-2-yl]-(7-fluoro-1H-indol-3-yl)methanone	IC50	13.4 nM	US-11891386: Indole compounds and their use
2-(5-fluoro-1H-indole-3-carbonyl)-N-methyl-1,3-thiazole-4-carboxamide	IC50	14 nM	US-11891386: Indole compounds and their use
1-[2-(6-fluoro-1H-indole-3-carbonyl)-1,3-thiazol-4-yl]propan-1-one	IC50	18.8 nM	US-11891386: Indole compounds and their use
1-[2-(5-fluoro-1H-indole-3-carbonyl)-1,3-thiazol-4-yl]propan-1-one	IC50	25.4 nM	US-11891386: Indole compounds and their use
1-[2-(5,6-difluoro-1H-indole-3-carbonyl)-1,3-thiazol-4-yl]propan-1-one	IC50	30.3 nM	US-11891386: Indole compounds and their use
1H-indol-3-yl-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-thiazol-2-yl]methanone	IC50	40 nM	US-11891386: Indole compounds and their use
1H-indol-3-yl-[4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3-thiazol-2-yl]methanone	IC50	42.6 nM	US-11891386: Indole compounds and their use
[4-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl]-(7-fluoro-1H-indol-3-yl)methanone	IC50	46.9 nM	US-11891386: Indole compounds and their use
methyl 2-(5-fluoro-1H-indole-3-carbonyl)-1,3-thiazole-4-carboxylate	IC50	48.6 nM	US-11891386: Indole compounds and their use
methyl 2-(5-chloro-1H-indole-3-carbonyl)-1,3-thiazole-4-carboxylate	IC50	73.6 nM	US-11891386: Indole compounds and their use
1H-indol-3-yl-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-thiazol-2-yl]methanone	IC50	110 nM	US-11891386: Indole compounds and their use
1-[2-(4-fluoro-1H-indole-3-carbonyl)-1,3-thiazol-4-yl]propan-1-one	IC50	209 nM	US-11891386: Indole compounds and their use

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 secretion, decreases expression	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	affects cotreatment, increases secretion	1
Silicon Dioxide	decreases expression	1
Triclosan	increases expression, decreases reaction	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)

Via MONDO — disease-level, not drug-specific.