IL2RG

Summary

IL2RG (interleukin 2 receptor subunit gamma, HGNC:6010) is a protein-coding gene on chromosome Xq13.1, encoding Cytokine receptor common subunit gamma (P31785). Common subunit for the receptors for a variety of interleukins.

The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder.

Source: NCBI Gene 3561 — RefSeq curated summary.

At a glance

• Gene–disease (curated): T-B+ severe combined immunodeficiency due to gamma chain deficiency (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 561 total — 108 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 77
• Druggable target: yes
• MANE Select transcript: NM_000206

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6010
Approved symbol	IL2RG
Name	interleukin 2 receptor subunit gamma
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	CD132
Ensembl gene	ENSG00000147168
Ensembl biotype	protein_coding
OMIM	308380
Entrez	3561

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 retained_intron, 4 protein_coding

ENST00000276110, ENST00000374202, ENST00000464642, ENST00000473378, ENST00000482750, ENST00000487883, ENST00000512747, ENST00000696903

RefSeq mRNA: 1 — MANE Select: NM_000206 NM_000206

CCDS: CCDS14406

Canonical transcript exons

ENST00000374202 — 8 exons

Exon	Start	End
ENSE00000979104	71111425	71111577
ENSE00001729247	71110156	71110295
ENSE00003473716	71109228	71109390
ENSE00003517902	71110504	71110688
ENSE00003528499	71107404	71107921
ENSE00003626559	71108599	71108695
ENSE00003678721	71108277	71108346
ENSE00003687603	71110897	71111050

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 99.45.

FANTOM5 (CAGE): breadth broad, TPM avg 56.2548 / max 1418.2739, expressed in 667 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199548	56.0937	667
199546	0.1611	96

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.45	gold quality
lymph node	UBERON:0000029	98.17	gold quality
vermiform appendix	UBERON:0001154	98.10	gold quality
rectum	UBERON:0001052	97.98	gold quality
thymus	UBERON:0002370	97.77	gold quality
spleen	UBERON:0002106	97.71	gold quality
bone marrow cell	CL:0002092	97.69	gold quality
ileal mucosa	UBERON:0000331	97.60	gold quality
blood	UBERON:0000178	97.29	gold quality
bone marrow	UBERON:0002371	95.73	gold quality
caecum	UBERON:0001153	95.68	gold quality
jejunal mucosa	UBERON:0000399	95.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.83	gold quality
colonic mucosa	UBERON:0000317	94.79	gold quality
mucosa of transverse colon	UBERON:0004991	94.19	gold quality
leukocyte	CL:0000738	93.65	gold quality
mononuclear cell	CL:0000842	93.10	gold quality
monocyte	CL:0000576	92.92	gold quality
gall bladder	UBERON:0002110	92.62	gold quality
duodenum	UBERON:0002114	92.33	gold quality
superficial temporal artery	UBERON:0001614	92.29	gold quality
colonic epithelium	UBERON:0000397	92.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.76	gold quality
small intestine	UBERON:0002108	91.09	gold quality
decidua	UBERON:0002450	89.25	gold quality
tonsil	UBERON:0002372	88.59	gold quality
upper lobe of left lung	UBERON:0008952	88.49	gold quality
lower esophagus mucosa	UBERON:0035834	88.34	gold quality
upper lobe of lung	UBERON:0008948	87.87	gold quality
trabecular bone tissue	UBERON:0002483	87.31	gold quality

Single-cell (SCXA)

Detected in 24 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	1957.30
E-GEOD-111727	yes	1900.62
E-GEOD-130473	yes	883.76
E-MTAB-6678	yes	733.72
E-CURD-112	yes	718.14
E-MTAB-6701	yes	110.13
E-HCAD-1	yes	107.81
E-CURD-122	yes	46.11
E-MTAB-10553	yes	45.62
E-HCAD-10	yes	34.94
E-MTAB-10287	yes	34.31
E-MTAB-8410	yes	32.77
E-HCAD-11	yes	28.65
E-GEOD-135922	yes	26.48
E-ANND-3	yes	24.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RXRA, TCF3

miRNA regulators (miRDB)

47 targeting IL2RG, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-4507	99.14	65.27	515
HSA-MIR-3940-5P	99.14	65.26	493
HSA-MIR-491-5P	99.13	65.98	1468

Literature-anchored findings (GeneRIF, showing 40)

• The immature form of the gamma(c) chain is a 54-58 kDa intracellular component localized in the endoplasmic reticulum of resting, unstimulated CD4 T cells. (PMID:11418669)
• Alternate signalling pathways from the interleukin-2 receptor (PMID:11750878)
• Here we show, in four cell lines of human adult T cell lymphoma/leukemia origin, that the three IL-2R subunits are compartmented together with HLA glycoproteins and CD48 molecules in the plasma membrane (PMID:11856346)
• presence of membrane-associated as well as soluble gamma c in cell lysates and cell free supernatants from peripheral blood lymphocyte cultures; panel of human serum samples was examined and compared with sIL-2R (PMID:12036606)
• SHB links IL2 receptor for signal transduction and mediates apoptosis (PMID:12200137)
• In normal lung fibroblasts IL-4 & IL-13 induce gamma c chain & its association with JAK3. In myofibroblasts, constitutive gamma c chain together with JAK3 controls TYK2 phosphorylation & the balance between functional & decoy high-affinity receptors. (PMID:12207328)
• Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain. (PMID:12504082)
• The development of breast tumour is associated with an increased expression of IL-2 receptor gamma and this expression also seems to be associated with the malignancy of the tumour. (PMID:14680494)
• A mutation in this locus resulting in severe combined immunodeficiency, initially diagnosed as HIV infection. (PMID:15702055)
• the crystal structure, at 2.3 A resolution, of the quaternary complex of IL-2 with the extracellular domains of receptors IL-2R alpha, IL-2Rss, and gamma c. (PMID:16293754)
• The common cytokine receptor gamma-chain is a required signaling subunit of the growth hormone receptor (GHR) complex in B cell lines. Genetic alteration of the IL2RG gene results in growth failure in X-linked severe combined immunodeficiency (X-SCID). (PMID:17082603)
• results confirm that signal transduction via the IL-15R, and hence NK ontogeny, is preferentially retained relative to the IL-7R as gammac expression becomes limiting. (PMID:17363735)
• Review describes current state of knowledge of how the gamma c cytokine network is affected during HIV infection, with a focus on how this impairs CD4+ and CD8+ T cell function while also benefiting the virus itself. (PMID:18417356)
• Report the selective expansion of genetically modified T cells using an antibody/IL2RG receptor chimera. (PMID:18589435)
• The uncleaved 12-kDa form of p12(I) resides in the ER and interacts with the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. (PMID:18791162)
• the preformed complexes between gamma c and IL-2Rbeta or IL-9Ralpha promote signaling by the JAK3 A572V mutant without ligand, identified in several human cancers. (PMID:18829468)
• This suggests a role for gamma(C) cytokines in the pathogenesis of diseases in which CD127 expression is altered on CD8+ T cells such as in progressive viral infections and cancer. (PMID:19011158)
• Self-sufficient growth of B lymphoblastoid cells in X-linked combined immunodeficiency disease (SCID) cell lines is strongly dependent on common gamma-chain expression. (PMID:19234229)
• Plasma sIL-7Ralpha and sgamma(c) are present as heterocomplexes and sgamma(c) was found to be mainly associated with sIL-7Ralpha (PMID:19494261)
• the loss of NEDD4 association on IL-2Rgamma(c) is accompanied by a dramatic increase of the half-life of the receptor subunit. (PMID:19615332)
• Transgenic Jak3-dependent common gamma c cytokine signals are not required for naive primary CD4-positive T cell proliferation and cell cycle regulation in vitro. (PMID:19734221)
• dengue virus infection and virus-specific HLA-A2 restricted immune response does not require IL2rgamma (PMID:19802382)
• Tumor-shed PGE(2) impairs IL2Rgammac-signaling to inhibit CD4 T cell survival and is regulated by theaflavins (PMID:19812686)
• Data indicate that ser/thr phosphorylation negatively regulates IL-2 receptor complex formation and JAK3/STAT5 activation, and that this regulation is counteracted by PP2A. (PMID:19923221)
• IL-2Rgamma(c) reconstituted T cells may persist more efficiently than natural killer (NK) cells due to compensation for suboptimal IL-2Rgamma(c) signaling by T cell receptors. (PMID:20592278)
• IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK. (PMID:21715655)
• We report a novel X-CID family with a unique mutation in the extracellular part of CD132 with almost normal T-cell counts but defective memory induction (PMID:21831415)
• Data imply that IL-21-mediated signaling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients after hematopoietic cell transplantation. (PMID:22039266)
• the amount of the gamma-chain transducing element is able to influence the transcription of genes involved in cell cycle progression, thus being directly involved in the regulatory control of cell proliferation of malignant hematopoietic cell (PMID:22223761)
• These data highlight the central role of IL-15 and gammac-receptor signaling in renal homeostasis. (PMID:22363690)
• Interleukin-2 signalling is modulated by a labile disulfide bond in the CD132 chain of its receptor. (PMID:22645657)
• analysis of multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor (PMID:22737248)
• Data suggest that cross-talk occurs between cAMP/PKA and the IL-2R beta/Jak3/Stat5b cascade in T-cells. (PMID:23341462)
• In a patient with a novel IL2RG mutation, gene-reverted CD8+ T cells accumulate over time. (PMID:23403317)
• Massively parallel sequencing reveals maternal somatic IL2RG mosaicism in an X-linked severe combined immunodeficiency family. (PMID:23683512)
• Tax-specific cytotoxic T-lymphocyte cell treatment significantly decreases human soluble IL-2Rgamma serum concentrations and prolongation of survival time in a mouse model of adult T cell leukemia/lymphoma. (PMID:23733874)
• this is the first report on a de novo mutation in the IL2RG gene in a patient born after IVF (PMID:23790094)
• we presented here a novel IL-2Rgammac mutation in a carrier and SCID patient presenting NK cells in the peripheral blood (PMID:23940110)
• findings suggest that over-expression of the IL2RG gene may be implicated in altered immune response in schizophrenia and contribute to the pathomechanisms of this disorder (PMID:24713359)
• in humans, signaling through the gammac pathway is not required for prethymic lymphoid commitment or for DNA rearrangement. (PMID:24771849)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	ghrb	ENSDARG00000007671
danio_rerio	il11ra	ENSDARG00000026736
danio_rerio	lifrb	ENSDARG00000039863
danio_rerio	il2rgb	ENSDARG00000053702
danio_rerio	ghra	ENSDARG00000054771
danio_rerio	il2rga	ENSDARG00000068858
danio_rerio	crlf2	ENSDARG00000090632
danio_rerio	lifra	ENSDARG00000098857
danio_rerio	il6r	ENSDARG00000104474
mus_musculus	Il2rg	ENSMUSG00000031304
rattus_norvegicus	Cxhxorf65	ENSRNOG00000003954

Paralogs (23): CRLF1 (ENSG00000006016), IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Cytokine receptor common subunit gamma — P31785 (reviewed: P31785)

Alternative names: Interleukin-2 receptor subunit gamma, gammaC, p64

All UniProt accessions (4): P31785, D6R964, D6RDW9, H0Y8J6

UniProt curated annotations — full annotation on UniProt →

Function. Common subunit for the receptors for a variety of interleukins. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15.

Subunit / interactions. The gamma subunit is common to the IL2, IL4, IL7, IL15, IL21 and probably also the IL13 receptors. Interacts with SHB upon interleukin stimulation. Interacts with IL9. (Microbial infection) Interacts with HTLV-1 accessory protein p12I.

Subcellular location. Cell membrane. Cell surface.

Disease relevance. Severe combined immunodeficiency X-linked T-cell-negative/B-cell-positive/NK-cell-negative (XSCID) [MIM:300400] A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. The disease is caused by variants affecting the gene represented in this entry. X-linked combined immunodeficiency (XCID) [MIM:312863] Less severe form of X-linked immunodeficiency with a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID. The disease is caused by variants affecting the gene represented in this entry.

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 5 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P31785-1	1	yes
P31785-2	2

RefSeq proteins (1): NP_000197* (*=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
IPR048648	CRLF2-like_D2	Domain
IPR053856	TSLPR_D1	Domain

Pfam: PF21605, PF22012

UniProt features (82 total): sequence variant 36, strand 22, glycosylation site 6, disulfide bond 3, helix 3, splice variant 2, topological domain 2, short sequence motif 2, signal peptide 1, chain 1, transmembrane region 1, domain 1, turn 1, modified residue 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9E2T	X-RAY DIFFRACTION	2.28
2B5I	X-RAY DIFFRACTION	2.3
5M5E	X-RAY DIFFRACTION	2.3
4GS7	X-RAY DIFFRACTION	2.35
7S2R	X-RAY DIFFRACTION	2.49
9JQT	ELECTRON MICROSCOPY	2.7
8ENT	X-RAY DIFFRACTION	2.83
3BPL	X-RAY DIFFRACTION	2.93
9KMC	ELECTRON MICROSCOPY	2.97
2ERJ	X-RAY DIFFRACTION	3
6OEL	X-RAY DIFFRACTION	3.1
3QB7	X-RAY DIFFRACTION	3.25
8EPA	ELECTRON MICROSCOPY	3.4
3QAZ	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31785-F1	76.75	0.50

Antibody-complex structures (SAbDab): 5 — 6OEL, 7S2R, 8EPA, 9JQT, 9KMC

Functional residue map

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

Post-translational modifications (1): 292

Disulfide bonds (3): 62–72, 102–115, 182–231

Glycosylation sites (6): 71, 75, 84, 159, 249, 24

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1266695	Interleukin-7 signaling
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8983432	Interleukin-15 signaling
R-HSA-8985947	Interleukin-9 signaling
R-HSA-9020558	Interleukin-2 signaling
R-HSA-9020958	Interleukin-21 signaling
R-HSA-912526	Interleukin receptor SHC signaling
R-HSA-9701898	STAT3 nuclear events downstream of ALK signaling

MSigDB gene sets: 631 (showing top): PID_SHP2_PATHWAY, GSE45365_NK_CELL_VS_BCELL_DN, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_INTERLEUKIN_4, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (23): mature B cell differentiation (GO:0002335), CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation (GO:0002361), positive regulation of immunoglobulin production (GO:0002639), immune response (GO:0006955), signal transduction (GO:0007165), gene expression (GO:0010467), cytokine-mediated signaling pathway (GO:0019221), cellular homeostasis (GO:0019725), lymphocyte differentiation (GO:0030098), positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation (GO:0032831), T cell differentiation in thymus (GO:0033077), positive regulation of T cell differentiation in thymus (GO:0033089), interleukin-15-mediated signaling pathway (GO:0035723), interleukin-4-mediated signaling pathway (GO:0035771), interleukin-2-mediated signaling pathway (GO:0038110), interleukin-7-mediated signaling pathway (GO:0038111), interleukin-9-mediated signaling pathway (GO:0038113), positive regulation of B cell differentiation (GO:0045579), positive regulation of phagocytosis (GO:0050766), immune system process (GO:0002376), regulation of gene expression (GO:0010468), positive regulation of gene expression (GO:0010628), B cell differentiation (GO:0030183)

GO Molecular Function (9): cytokine receptor activity (GO:0004896), coreceptor activity (GO:0015026), cytokine binding (GO:0019955), interleukin-2 binding (GO:0019976), interleukin-15 receptor activity (GO:0042010), interleukin-2 receptor activity (GO:0004911), interleukin-4 receptor activity (GO:0004913), interleukin-7 receptor activity (GO:0004917), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), endosome (GO:0005768), cytosol (GO:0005829), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020), signaling receptor complex (GO:0043235)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Interleukin-2 family signaling	5
Signaling by Interleukins	2
MAPK1/MAPK3 signaling	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
Signaling by ALK	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	6
cytokine receptor activity	4
cellular anatomical structure	4
B cell differentiation	2
cytokine binding	2
CD4-positive, alpha-beta T cell differentiation	1
regulatory T cell differentiation	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
homeostatic process	1
lymphocyte activation	1
mononuclear cell differentiation	1
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1
regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1
positive regulation of CD4-positive, alpha-beta T cell differentiation	1
positive regulation of regulatory T cell differentiation	1
T cell differentiation	1
T cell differentiation in thymus	1
regulation of T cell differentiation in thymus	1
positive regulation of T cell differentiation	1
cellular response to interleukin-15	1
cellular response to interleukin-4	1
cellular response to interleukin-2	1
cellular response to interleukin-7	1
cellular response to interleukin-9	1
regulation of B cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of B cell activation	1
phagocytosis	1

Protein interactions and networks

STRING

2402 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL2RG	IL2RB	P14784	998
IL2RG	IL2	P01585	998
IL2RG	IL15	P40933	998
IL2RG	IL7R	P16871	998
IL2RG	JAK3	P52333	998
IL2RG	IL7	P13232	997
IL2RG	IL2RA	P01589	997
IL2RG	IL4R	P24394	997
IL2RG	IL15RA	Q13261	997
IL2RG	IL4	P05112	996
IL2RG	JAK1	P23458	994
IL2RG	IL9	P15248	986
IL2RG	IL21R	Q9HBE5	952
IL2RG	RAG2	P55895	878
IL2RG	CD8A	P01732	825

IntAct

33 interactions, top by confidence:

A	B	Type	Score
IL4R	IL4	psi-mi:“MI:0914”(association)	0.810
IL2RG	REEP6	psi-mi:“MI:0914”(association)	0.710
IL2RG	REEP6	psi-mi:“MI:0915”(physical association)	0.710
NOTCH2NLA	IL2RG	psi-mi:“MI:0915”(physical association)	0.670
IL2RG	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.670
IL2RG	IL4	psi-mi:“MI:0407”(direct interaction)	0.670
IL2RG	IL4	psi-mi:“MI:0914”(association)	0.670
IL15RA	IL2RB	psi-mi:“MI:0915”(physical association)	0.590
	IL2RG	psi-mi:“MI:0915”(physical association)	0.560
IL2RG		psi-mi:“MI:0915”(physical association)	0.560
IL2RG	KRTAP5-7	psi-mi:“MI:0915”(physical association)	0.560
IL2RG	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
IL2RG	GRB2	psi-mi:“MI:0915”(physical association)	0.400
IL2RG	IL7	psi-mi:“MI:0915”(physical association)	0.400
IL2RG	IL7R	psi-mi:“MI:0915”(physical association)	0.400
STK4	IL2RG	psi-mi:“MI:0915”(physical association)	0.370
IL2RG	PTPRD	psi-mi:“MI:0914”(association)	0.350
IL2RG	BBOX1	psi-mi:“MI:0914”(association)	0.350
IL2RG	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.000
IL2RG	KRTAP5-7	psi-mi:“MI:0915”(physical association)	0.000
purL	IL2RG	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), NDFIP2 (Affinity Capture-MS), FLVCR1 (Affinity Capture-MS), PTPRD (Affinity Capture-MS), REEP6 (Affinity Capture-MS), IL2 (Affinity Capture-Western), IL21 (Affinity Capture-Western), IL2RG (Two-hybrid), REEP6 (Affinity Capture-MS), CD320 (Affinity Capture-MS), PTPRD (Affinity Capture-MS), FLVCR1 (Affinity Capture-MS), JAK3 (Affinity Capture-Western), GRB10 (Affinity Capture-Western)

ESM2 similar proteins: A2A7V7, A2TGX5, A5D7B2, G3X8R9, O88875, O95944, P0DMS9, P11912, P12318, P15530, P16410, P22273, P31785, P31994, P31995, P34902, P40259, P50283, Q02242, Q1ERP8, Q2LA85, Q2YFS1, Q2YFS2, Q2YFS3, Q3LRV9, Q3U497, Q566E6, Q5T2D2, Q60513, Q6SJQ0, Q6SJQ5, Q6SJQ7, Q6TYI6, Q6UXG3, Q6UXN2, Q7TSN2, Q86YW5, Q8K558, Q8SPV8, Q8TDQ1

Diamond homologs: P31785, P34902, P40321, Q95118

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
IL4R	up-regulates	IL2RG	binding
IL15	up-regulates	IL2RG	binding
IL21	up-regulates	IL2RG	binding
IL4	up-regulates	IL2RG	binding
IL7	up-regulates	IL2RG	binding
IL9	up-regulates	IL2RG	binding
IL2	up-regulates	IL2RG	binding
IL2RG	up-regulates	JAK3	binding
“125-L-serine-2-133-interleukin 2 (human reduced)”	“up-regulates activity”	IL2RG	“chemical activation”
“denileukin diftitox”	“up-regulates activity”	IL2RG	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	108
Likely pathogenic	51
Uncertain significance	141
Likely benign	166
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10016	NM_000206.3(IL2RG):c.355A>T (p.Lys119Ter)	Pathogenic
10018	NM_000206.3(IL2RG):c.923C>A (p.Ser308Ter)	Pathogenic
10019	NM_000206.3(IL2RG):c.186T>A (p.Cys62Ter)	Pathogenic
10020	NM_000206.3(IL2RG):c.341G>A (p.Gly114Asp)	Pathogenic
10021	NM_000206.3(IL2RG):c.454+1G>A	Pathogenic
10022	NM_000206.3(IL2RG):c.458T>A (p.Ile153Asn)	Pathogenic
10023	NM_000206.3(IL2RG):c.878T>A (p.Leu293Gln)	Pathogenic
10024	NM_000206.3(IL2RG):c.703_711dup (p.Gln235_Trp237dup)	Pathogenic
10025	NM_000206.3(IL2RG):c.343T>C (p.Cys115Arg)	Pathogenic
10026	NM_000206.3(IL2RG):c.854G>A (p.Arg285Gln)	Pathogenic
10027	NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys)	Pathogenic
1028611	NM_000206.3(IL2RG):c.269+1G>T	Pathogenic
1066149	NM_000206.3(IL2RG):c.184T>C (p.Cys62Arg)	Pathogenic
1066800	NM_000206.3(IL2RG):c.594+5G>T	Pathogenic
1067389	NM_000206.3(IL2RG):c.340G>T (p.Gly114Cys)	Pathogenic
1068066	NM_000206.3(IL2RG):c.116-1G>A	Pathogenic
1068144	NM_000206.3(IL2RG):c.854+2T>C	Pathogenic
1068145	NM_000206.3(IL2RG):c.713G>A (p.Ser238Asn)	Pathogenic
1068146	NM_000206.3(IL2RG):c.675C>A (p.Ser225Arg)	Pathogenic
1069444	NM_000206.3(IL2RG):c.302_384dup (p.Val129fs)	Pathogenic
1070717	NC_000023.10:g.(?70328107)(70328216_?)del	Pathogenic
1074635	NM_000206.3(IL2RG):c.148del (p.Leu50fs)	Pathogenic
1175096	NM_000206.3(IL2RG):c.816_819del (p.Ile273fs)	Pathogenic
1175830	NM_000206.3(IL2RG):c.758-1G>C	Pathogenic
1251965	NM_000206.3(IL2RG):c.922del (p.Ser308fs)	Pathogenic
1323112	NM_000206.3(IL2RG):c.115+1G>T	Pathogenic
1335777	NM_000206.3(IL2RG):c.205_215del (p.Tyr69fs)	Pathogenic
1351468	NM_000206.3(IL2RG):c.359dup (p.Glu121fs)	Pathogenic
1355530	NM_000206.3(IL2RG):c.598C>T (p.Gln200Ter)	Pathogenic
1356061	NM_000206.3(IL2RG):c.546_549del (p.Cys182fs)	Pathogenic

SpliceAI

1191 predictions. Top by Δscore:

Variant	Effect	Δscore
X:71108342:TCGTC:T	acceptor_gain	1.0000
X:71108343:CGTCC:C	acceptor_gain	1.0000
X:71108344:GTCC:G	acceptor_loss	1.0000
X:71108346:CCTGA:C	acceptor_loss	1.0000
X:71108347:CT:C	acceptor_loss	1.0000
X:71108348:T:A	acceptor_loss	1.0000
X:71109222:TTTTA:T	donor_loss	1.0000
X:71109223:TTTAC:T	donor_loss	1.0000
X:71109224:TTAC:T	donor_loss	1.0000
X:71109225:TACCT:T	donor_loss	1.0000
X:71109226:ACCT:A	donor_loss	1.0000
X:71109227:CCTTT:C	donor_loss	1.0000
X:71109390:CCT:C	acceptor_gain	1.0000
X:71109392:T:C	acceptor_gain	1.0000
X:71111424:CCAG:C	donor_gain	1.0000
X:71111439:T:TA	donor_gain	1.0000
X:71108343:CGTC:C	acceptor_gain	0.9900
X:71108344:GTC:G	acceptor_gain	0.9900
X:71108345:TC:T	acceptor_gain	0.9900
X:71108346:CC:C	acceptor_gain	0.9900
X:71108347:C:CC	acceptor_gain	0.9900
X:71108351:C:CT	acceptor_gain	0.9900
X:71108352:A:T	acceptor_gain	0.9900
X:71108558:C:CT	donor_gain	0.9900
X:71108559:T:TT	donor_gain	0.9900
X:71109226:A:AC	donor_gain	0.9900
X:71109227:C:CC	donor_gain	0.9900
X:71109388:TTCC:T	acceptor_loss	0.9900
X:71109391:C:CC	acceptor_gain	0.9900
X:71109391:CTT:C	acceptor_loss	0.9900

AlphaMissense

2427 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:71110944:C:A	W74C	0.998
X:71110944:C:G	W74C	0.998
X:71109265:C:A	W240C	0.996
X:71109265:C:G	W240C	0.996
X:71110228:C:A	W174C	0.995
X:71110228:C:G	W174C	0.995
X:71110614:C:G	C115S	0.993
X:71110615:A:T	C115S	0.993
X:71109320:C:G	R222P	0.992
X:71109293:C:G	C231S	0.991
X:71109294:A:T	C231S	0.991
X:71110946:A:G	W74R	0.991
X:71110946:A:T	W74R	0.991
X:71109267:A:G	W240R	0.990
X:71109267:A:T	W240R	0.990
X:71109314:C:G	R224P	0.990
X:71110951:C:G	C72S	0.990
X:71110952:A:T	C72S	0.990
X:71110981:C:G	C62S	0.990
X:71110982:A:T	C62S	0.990
X:71109272:C:A	S238I	0.989
X:71109310:G:C	S225R	0.989
X:71109310:G:T	S225R	0.989
X:71109312:T:G	S225R	0.989
X:71110653:C:G	C102S	0.989
X:71110654:A:T	C102S	0.989
X:71110982:A:G	C62R	0.989
X:71109274:C:A	W237C	0.988
X:71109274:C:G	W237C	0.988
X:71109271:A:C	S238R	0.987

dbSNP variants (sampled 300 via entrez): RS1000667077 (X:71109752 T>C), RS1002172384 (X:71107905 G>A), RS1003446722 (X:71113489 C>G), RS1004443516 (X:71108996 C>G), RS1004973430 (X:71111619 A>G), RS1005026141 (X:71112026 T>C), RS1005449113 (X:71110139 C>T), RS1005809731 (X:71109548 T>G), RS1007533014 (X:71107204 C>A,T), RS1008922260 (X:71112989 T>A), RS1009255987 (X:71110259 T>A,C), RS1009304987 (X:71110818 G>C), RS1009915307 (X:71113443 A>G), RS1015272346 (X:71111503 A>G), RS1016244438 (X:71113541 T>C,G)

Disease associations

OMIM: gene MIM:308380 | disease phenotypes: MIM:300400, MIM:312863

GenCC curated gene-disease

Disease	Classification	Inheritance
T-B+ severe combined immunodeficiency due to gamma chain deficiency	Definitive	X-linked
Omenn syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
T-B+ severe combined immunodeficiency due to gamma chain deficiency	Definitive	XL

Mondo (4): T-B+ severe combined immunodeficiency due to gamma chain deficiency (MONDO:0010315), combined immunodeficiency, X-linked (MONDO:0010730), combined immunodeficiency (MONDO:0015131), Omenn syndrome (MONDO:0011338)

Orphanet (2): T-B+ severe combined immunodeficiency due to gamma chain deficiency (Orphanet:276), Combined T and B cell immunodeficiency (Orphanet:101972)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000100	Nephrotic syndrome
HP:0000246	Sinusitis
HP:0000388	Otitis media
HP:0000778	Hypoplasia of the thymus
HP:0000821	Hypothyroidism
HP:0000944	Abnormal metaphysis morphology
HP:0000952	Jaundice
HP:0000958	Dry skin
HP:0000969	Edema
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001072	Thickened skin
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001831	Short toe
HP:0001880	Increased total eosinophil count
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002014	Diarrhea
HP:0002028	Chronic diarrhea
HP:0002090	Pneumonia
HP:0002240	Hepatomegaly
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2364167 (PROTEIN COMPLEX), CHEMBL4665588 (PROTEIN COMPLEX), CHEMBL4665592 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — IL-2 receptor family

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Calcitriol	increases expression, affects cotreatment	2
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
clothianidin	increases expression	1
abrine	increases expression	1
2,6-dichloro-(1,4)benzoquinone	decreases expression	1
Aripiprazole	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	affects cotreatment, increases expression	1
Fluvastatin	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Allergens	decreases expression	1
Aspirin	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Biological Factors	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Environmental Pollutants	affects expression	1
Nickel	increases expression	1
Ozone	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Dronabinol	decreases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Dinoprostone	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

8 cell lines: 5 transformed cell line, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2Z35	ID00085	Transformed cell line	Male
CVCL_D1NG	Abcam K-562 IL2RG KO	Cancer cell line	Female
CVCL_D2K1	Abcam Raji IL2RG KO	Cancer cell line	Male
CVCL_E8ED	HEK-Blue CD122/CD132	Transformed cell line	Female
CVCL_E8EI	HEK-Blue IL-7	Transformed cell line	Female
CVCL_E8EJ	HEK-Blue IL-9	Transformed cell line	Female
CVCL_UF26	HEK-Blue IL-2	Transformed cell line	Female
CVCL_UQ82	Abcam Jurkat IL2RG KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT02737384	PHASE2	TERMINATED	Hematopoietic Stem Cells Transplantation in Children With Combined Immunodeficiency (CID)
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT03601286	PHASE1	RECRUITING	Lentiviral Gene Therapy for X-linked Severe Combined Immunodeficiency
NCT00490100	PHASE1/PHASE2	TERMINATED	Treatment for Growth Failure in Patients With X-Linked Severe Combined Immunodeficiency: Phase 2 Study of Insulin-Like Growth Factor-1
NCT01306019	PHASE1/PHASE2	RECRUITING	Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)
NCT01410019	PHASE1/PHASE2	COMPLETED	Gene Therapy for X-linked Severe Combined Immunodeficiency
NCT03311503	PHASE1/PHASE2	RECRUITING	Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning
NCT06851767	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Base-Edited Hematopoietic Stem/Progenitor Cell X-Linked Severe Combined Immunodeficiency Gene Therapy
NCT01175239	Not specified	UNKNOWN	Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1)
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT02915406	Not specified	NO_LONGER_AVAILABLE	cliniMACs HUD for T Cell Depletion
NCT04902807	Not specified	RECRUITING	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
NCT06659588	Not specified	RECRUITING	Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency