IL2RB

Summary

IL2RB (interleukin 2 receptor subunit beta, HGNC:6009) is a protein-coding gene on chromosome 22q12.3, encoding Interleukin-2 receptor subunit beta (P14784). Receptor for interleukin-2.

The interleukin 2 receptor, which is involved in T cell-mediated immune responses, is present in 3 forms with respect to ability to bind interleukin 2. The low affinity form is a monomer of the alpha subunit and is not involved in signal transduction. The intermediate affinity form consists of an alpha/beta subunit heterodimer, while the high affinity form consists of an alpha/beta/gamma subunit heterotrimer. Both the intermediate and high affinity forms of the receptor are involved in receptor-mediated endocytosis and transduction of mitogenic signals from interleukin 2. The protein encoded by this gene represents the beta subunit and is a type I membrane protein. The use of alternative promoters results in multiple transcript variants encoding the same protein. The protein is primarily expressed in the hematopoietic system. The use by some variants of an alternate promoter in an upstream long terminal repeat (LTR) results in placenta-specific expression.

Source: NCBI Gene 3560 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 63 with lymphoproliferation and autoimmunity (Strong, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 497 total — 8 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 61
• Druggable target: yes
• MANE Select transcript: NM_000878

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6009
Approved symbol	IL2RB
Name	interleukin 2 receptor subunit beta
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	CD122
Ensembl gene	ENSG00000100385
Ensembl biotype	protein_coding
OMIM	146710
Entrez	3560

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 5 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000216223, ENST00000429622, ENST00000440958, ENST00000445595, ENST00000453962, ENST00000461607, ENST00000483573, ENST00000698883, ENST00000698890, ENST00000698891, ENST00000698892, ENST00000698893, ENST00000698894, ENST00000698895, ENST00000698896, ENST00000698897, ENST00000698898, ENST00000698902, ENST00000698903, ENST00000698904, ENST00000698905, ENST00000703410, ENST00000858141, ENST00000858142, ENST00000858143, ENST00000858144

RefSeq mRNA: 3 — MANE Select: NM_000878 NM_000878, NM_001346222, NM_001346223

CCDS: CCDS13942

Canonical transcript exons

ENST00000216223 — 10 exons

Exon	Start	End
ENSE00003463772	37132384	37132468
ENSE00003975063	37144085	37144205
ENSE00003975064	37136228	37136393
ENSE00003975065	37142434	37142512
ENSE00003975067	37143521	37143635
ENSE00003975068	37139117	37139222
ENSE00003975070	37137587	37137735
ENSE00003975134	37149825	37149916
ENSE00003975139	37125843	37128848
ENSE00004475645	37135328	37135442

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 98.74.

FANTOM5 (CAGE): breadth broad, TPM avg 11.7271 / max 882.1870, expressed in 422 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194005	9.2967	335
194006	1.7377	195
194007	0.6387	12
194004	0.0364	22
194003	0.0176	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.74	gold quality
decidua	UBERON:0002450	96.04	gold quality
ileal mucosa	UBERON:0000331	91.75	gold quality
blood	UBERON:0000178	91.32	gold quality
lymph node	UBERON:0000029	88.80	gold quality
spleen	UBERON:0002106	88.75	gold quality
vermiform appendix	UBERON:0001154	87.65	gold quality
placenta	UBERON:0001987	86.52	gold quality
bone marrow cell	CL:0002092	84.02	gold quality
caecum	UBERON:0001153	83.89	gold quality
mucosa of urinary bladder	UBERON:0001259	82.29	gold quality
epithelium of nasopharynx	UBERON:0001951	82.20	gold quality
nasopharynx	UBERON:0001728	82.18	gold quality
cervix squamous epithelium	UBERON:0006922	80.71	silver quality
bone marrow	UBERON:0002371	80.69	gold quality
superficial temporal artery	UBERON:0001614	80.18	gold quality
jejunal mucosa	UBERON:0000399	80.01	gold quality
tonsil	UBERON:0002372	77.95	gold quality
gall bladder	UBERON:0002110	76.95	gold quality
tibialis anterior	UBERON:0001385	76.26	silver quality
oocyte	CL:0000023	75.80	gold quality
right lobe of liver	UBERON:0001114	75.66	gold quality
trabecular bone tissue	UBERON:0002483	75.53	gold quality
colonic epithelium	UBERON:0000397	75.51	gold quality
leukocyte	CL:0000738	75.25	gold quality
mucosa of sigmoid colon	UBERON:0004993	75.17	gold quality
periodontal ligament	UBERON:0008266	75.07	silver quality
colonic mucosa	UBERON:0000317	74.79	gold quality
endometrium	UBERON:0001295	74.32	gold quality
secondary oocyte	CL:0000655	74.22	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	2510.30
E-CURD-122	yes	1111.12
E-CURD-84	yes	1034.11
E-MTAB-10553	yes	968.57
E-MTAB-10287	yes	931.81
E-HCAD-32	yes	646.66
E-MTAB-6701	yes	149.54
E-HCAD-4	yes	94.15
E-HCAD-1	yes	94.07
E-HCAD-9	yes	24.44
E-HCAD-10	yes	23.85
E-CURD-46	yes	18.58
E-CURD-88	yes	18.58
E-ANND-3	yes	17.57
E-MTAB-8410	yes	10.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, EGR2, EOMES, ETS1, GABPA, ID3, IRF3, NFIL3, NFKB, REL, RXRA, SP1, TBX21, TP63, WT1, ZNF300

miRNA regulators (miRDB)

80 targeting IL2RB, 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-4713-3P	100.00	65.92	505
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
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-6764-5P	99.75	67.89	2304
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-486-3P	99.51	66.82	1901

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• SHB links IL2 receptor for signal transduction and mediates apoptosis (PMID:12200137)
• investigation of the presence of IL-2alpha, and IL-2beta receptors on fresh and isolated sperm (PMID:12230826)
• Peptide p1-30, which is composed of the 30 amino-terminal residues of human interleukin-2, binds as a tetramer to the dimeric IL-2Rbeta2 receptor (PMID:12676936)
• The development of breast tumour is associated with an increased expression of IL-2 receptor beta and this expression also seems to be associated with the malignancy of the tumour. (PMID:14680494)
• Cultures in the presence of peptide epitopes to this receptor inhibited T cell proliferation. (PMID:15350462)
• Interleukin-2 receptor beta-627*C homozygote and C allele correlate with higher susceptibility to endometriosis. (PMID:16084898)
• IL-15R alpha, which bears most of the binding affinity for IL-15, behaves as a potent IL-15 agonist by enhancing its binding and biological effects through the IL-15R beta/gamma heterodimer. (PMID:16284400)
• 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)
• location of the G245R polymorphism next to the proximal cytokine receptor homology segment; suggestive of a genetic association with the development of visceral leishmaniasis. (PMID:17108990)
• IL-2Rbeta chains form IL-2 binding homodimers (PMID:18299274)
• these results indicate that precise sorting of IL-2Rbeta from early to late endosomes is mediated by Hrs, a known sorting component of the ubiquitin-dependent machinery, in a manner that is independent of UIM-ubiquitin binding (PMID:18445679)
• study found PI3K & STAT5 signaling pathways are required for granulysin expression & IL-2Rbeta induction & IL-2Rbeta induction is a prerequisite for granulysin expression; both signaling pathways are defective in CD4+ T cells from HIV-infected patients (PMID:18490721)
• Report the selective expansion of genetically modified T cells using an antibody/IL2RB receptor chimera. (PMID:18589435)
• High serum IL-2R level is associated with peripheral T-cell lymphoma, unspecified. (PMID:18592269)
• 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)
• The C627T polymorphism in the IL2RB gene is not associated with risk of endometriosis in Korean women. (PMID:19602517)
• Results provide additional evidence for the association of IL2RB and IL2RA with RA by independent replication in a Dutch population, underlining the importance of the IL2 pathway in rheumatoid arthritis. (PMID:19822714)
• 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)
• Polymorphisms in IL2, IL2RA and IL2RB subunit genes were studied in 430 multiple sclerosis (MS) patients and in 550 ethnically matched controls from Madrid (Spain). (PMID:20179739)
• IL-2Rbeta is subject to ectodomain shedding generating an intracellular fragment biologically functional, because (i) it is phosphorylated, (ii) it associates with STAT5A, and (iii) it increases cell proliferation. (PMID:20495002)
• Data show that co-expression of ZNF300 and Egr1 lead to enhanced IL-2Rbeta promoter activity, and suggest that ZNF300 is another regulator of the human IL-2Rbeta promoter. (PMID:20585888)
• Lyn coimmunoprecipitates with the interleukin-2 beta receptor and JAK3 proteins in human T-cell leukemia virus type 1-infected T-cells. (PMID:21345943)
• The researchers found evidence that there were significant differences between the D22S1045 locus in the Maghreb population and other populations. (PMID:21674833)
• Genetic variants of IL2RB may be associated with the development of acute rejection episodes and may help predict risk in kidney transplantation patients. (PMID:21839273)
• LTR of the THE1D retroelement family has been domesticated as an alternative promoter of human IL2RB, the gene encoding the beta subunit of the IL-2 receptor. (PMID:21865161)
• This study directly examines proximal signaling by transgenic IL-2 and IL-15 and CD8-positive T cell primary and memory responses as a consequence of varied CD122-dependent signaling. (PMID:21984699)
• sIL-2Ralpha and sIL-2Rbeta induce marked subunit- and soluble cytokine receptor-specific behavioral disturbances (PMID:22558434)
• Single nucleotide polymorphism in IL2RB is associated with lung cancer. (PMID:22573796)
• Data suggest that cross-talk occurs between cAMP/PKA and the IL-2R beta/Jak3/Stat5b cascade in T-cells. (PMID:23341462)
• Expression of the IL-2 receptor beta-chain forms functional, high-affinity receptors on naive CD4+ T cells that correlates with their increased responsiveness to IL-2. (PMID:23418630)
• Data indicate that the two genetic variants within IL-2RA and IL-2RB are not associated with genetic susceptibility to rheumatoid arthritis (RA) in Han Chinese. (PMID:23512675)
• Data indicate that both CgammaCR-CD127(+)composed of Interleukin-7 (IL-7) tethered to IL-7Ralpha/CD127, and CgammaCR-CD122(+) CD8(+) T((E/CM)) engraft in mice and persist in an absence of exogenous cytokine administration. (PMID:23628622)
• specific IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition (PMID:23676143)
• This is the first report demonstrating that heterodimeric combinations of IL-2R and IL-6R subunits are functional for signaling. (PMID:23926072)
• IL2RA and IL2RB as promising candidate genes for inflammatory bowel diseases(IBD) and suggesting a potential role of IL2R in the pathogenesis of IBD, likely involves regulatory T cells. (PMID:23972291)
• MiniSTR marker D22S1045 (locus 22q12.3) is localized near the breakpoint region of the Ewing Sarcoma gene, but was found to be neutral related to EWS in a case-control study analyzing allele frequencies and linkage disequilibrium. (PMID:24112992)
• in anti-citrullinated protein antibody positive rheumatoid arthritis, the haplotype AC of IL-2RB was associated with a higher rate of erosions at baseline and at 1 year follow-up in comparison to other haplotypes. (PMID:24200909)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	il21r.1	ENSDARG00000069961
danio_rerio	il2rb	ENSDARG00000075720
danio_rerio	csf2rb	ENSDARG00000076586
mus_musculus	Il2rb	ENSMUSG00000068227
rattus_norvegicus	Il2rb	ENSRNOG00000048636

Paralogs (7): IL4R (ENSG00000077238), CSF2RB (ENSG00000100368), IL21R (ENSG00000103522), MPL (ENSG00000117400), IL9R (ENSG00000124334), IL7R (ENSG00000168685), EPOR (ENSG00000187266)

Protein

Protein identifiers

Interleukin-2 receptor subunit beta — P14784 (reviewed: P14784)

Alternative names: High affinity IL-2 receptor subunit beta, Interleukin-15 receptor subunit beta, p70-75

All UniProt accessions (14): P14784, A0A8V8TMD3, A0A8V8TMD8, A0A8V8TMF2, A0A8V8TMF6, A0A8V8TNU9, A0A8V8TNV4, A0A8V8TP57, A0A8V8TP62, A0A8W6ANL8, B0QYC0, B0QYC1, B0QYC2, H7C1H9

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15.

Subunit / interactions. Non-covalent dimer of an alpha and a beta subunit. IL2R exists in 3 different forms: a high affinity dimer, an intermediate affinity monomer (beta subunit), and a low affinity monomer (alpha subunit). The high and intermediate affinity forms also associate with a gamma subunit. Interacts with SHB upon interleukin stimulation. (Microbial infection) Interacts with HTLV-1 accessory protein p12I.

Subcellular location. Cell membrane.

Disease relevance. Immunodeficiency 63 with lymphoproliferation and autoimmunity (IMD63) [MIM:618495] An autosomal recessive disorder characterized by immune dysregulation resulting in lymphoid proliferation, dermatitis, enteropathy, autoantibodies, hypergammaglobulinemia, and immunodeficiency with recurrent infections. Patients show increased susceptibility to viral infections, particularly cytomegalovirus disease. 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 4 subfamily.

RefSeq proteins (3): NP_000869, NP_001333151, NP_001333152 (=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
IPR040951	IL2RB_N1	Domain

Pfam: PF18707

UniProt features (42 total): strand 15, sequence variant 5, glycosylation site 4, disulfide bond 3, topological domain 2, mutagenesis site 2, helix 2, region of interest 2, short sequence motif 2, signal peptide 1, chain 1, transmembrane region 1, turn 1, domain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6E8K	X-RAY DIFFRACTION	1.71
7S2S	X-RAY DIFFRACTION	1.93
2B5I	X-RAY DIFFRACTION	2.3
5M5E	X-RAY DIFFRACTION	2.3
4GS7	X-RAY DIFFRACTION	2.35
9KMC	ELECTRON MICROSCOPY	2.97
2ERJ	X-RAY DIFFRACTION	3
3QAZ	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14784-F1	65.72	0.35

Antibody-complex structures (SAbDab): 2 — 7S2S, 9KMC

Functional residue map

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

Disulfide bonds (3): 36–46, 59–110, 74–86

Glycosylation sites (4): 29, 43, 71, 149

Mutagenesis-validated functional residues (2):

Position	Phenotype
418	partial loss of interaction with shb; when associated with f-536.
536	partial loss of interaction with shb; when associated with f-418.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8983432	Interleukin-15 signaling
R-HSA-9020558	Interleukin-2 signaling
R-HSA-912526	Interleukin receptor SHC signaling

MSigDB gene sets: 504 (showing top): PID_SHP2_PATHWAY, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, MODULE_169, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, MODULE_45, MODULE_64, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOCC_CELL_SURFACE, MODULE_128, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (9): signal transduction (GO:0007165), immunoglobulin mediated immune response (GO:0016064), cytokine-mediated signaling pathway (GO:0019221), interleukin-15-mediated signaling pathway (GO:0035723), interleukin-2-mediated signaling pathway (GO:0038110), negative regulation of apoptotic process (GO:0043066), positive regulation of phagocytosis (GO:0050766), protein-containing complex assembly (GO:0065003), cell surface receptor signaling pathway (GO:0007166)

GO Molecular Function (6): interleukin-2 receptor activity (GO:0004911), coreceptor activity (GO:0015026), interleukin-2 binding (GO:0019976), interleukin-15 receptor activity (GO:0042010), cytokine receptor activity (GO:0004896), protein binding (GO:0005515)

GO Cellular Component (7): endosome (GO:0005768), cytosol (GO:0005829), plasma membrane (GO:0005886), interleukin-2 receptor complex (GO:0005893), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	3
cellular anatomical structure	3
cytokine receptor activity	2
cytokine binding	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
B cell mediated immunity	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cellular response to interleukin-15	1
cellular response to interleukin-2	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1
cellular component assembly	1
protein-containing complex organization	1
signal transduction	1
interleukin-2 binding	1
interleukin-2-mediated signaling pathway	1
signaling receptor activity	1
growth factor binding	1
interleukin-15-mediated signaling pathway	1
interleukin-15 binding	1
transmembrane signaling receptor activity	1
immune receptor activity	1
binding	1
endomembrane system	1
cytoplasmic vesicle	1
cytoplasm	1
membrane	1
cell periphery	1
plasma membrane signaling receptor complex	1
plasma membrane	1
cell surface	1

Protein interactions and networks

STRING

2019 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL2RB	IL2RG	P31785	998
IL2RB	IL2	P01585	997
IL2RB	IL15	P40933	996
IL2RB	IL2RA	P01589	995
IL2RB	IL15RA	Q13261	990
IL2RB	JAK1	P23458	928
IL2RB	CD8A	P01732	858
IL2RB	IL7R	P16871	853
IL2RB	CD4	P01730	840
IL2RB	CD226	Q15762	832
IL2RB	IL7	P13232	829
IL2RB	CD44	P16070	815
IL2RB	CD27	P26842	794
IL2RB	IL10	P22301	792
IL2RB	IL4R	P24394	775

IntAct

18 interactions, top by confidence:

A	B	Type	Score
IL2RB	IL2	psi-mi:“MI:0407”(direct interaction)	0.740
IL2	IL2RB	psi-mi:“MI:0407”(direct interaction)	0.740
IL2	IL2RA	psi-mi:“MI:0915”(physical association)	0.670
IL15	IL2RB	psi-mi:“MI:0915”(physical association)	0.660
IL15	IL2RB	psi-mi:“MI:0407”(direct interaction)	0.660
IL2RB	IL15	psi-mi:“MI:0915”(physical association)	0.660
IL15RA	IL2RB	psi-mi:“MI:0915”(physical association)	0.590
IL2RB	TRIP13	psi-mi:“MI:0915”(physical association)	0.560
STAT5A	IL2RB	psi-mi:“MI:0914”(association)	0.350
STAT5B	IL2RB	psi-mi:“MI:0914”(association)	0.350
SHB	IL2RB	psi-mi:“MI:0914”(association)	0.350
IL2RB	TRIP13	psi-mi:“MI:0915”(physical association)	0.000
ubiA	IL2RB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): ECM1 (Affinity Capture-Western), IL2RB (Affinity Capture-MS), IL2RG (FRET), ACTA1 (Affinity Capture-Western), TUBA1A (Affinity Capture-Western), JAK1 (Affinity Capture-Western), JAK3 (Affinity Capture-Western), STAT5A (Affinity Capture-Western), IL2RB (Affinity Capture-MS), IL2RB (Reconstituted Complex), PIK3R1 (Affinity Capture-Western), IL2RB (Protein-peptide), IL2RB (Protein-RNA), IL2RB (Two-hybrid), SHC1 (Reconstituted Complex)

ESM2 similar proteins: A0A1B0GU29, A6NLX4, A6QNY1, A9CBA0, B7ZWI3, O14669, O88472, P14784, P16297, P25918, P26896, Q0VFL4, Q13651, Q32M26, Q38J84, Q38J85, Q3SYS8, Q58CT8, Q5BK39, Q5EAA5, Q5HZE8, Q5NCP0, Q5RCL0, Q64322, Q68DV7, Q6AXS2, Q6AXU5, Q6NUJ2, Q6UWV7, Q86UW2, Q8BHB3, Q8BLR5, Q8BSU2, Q8C353, Q8C708, Q8K1T1, Q8MII8, Q8N6P7, Q8NET5, Q8R182

Diamond homologs: P14784, P16297, P26896, Q38J84, Q38J85, P26955, P32927

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
IL2	up-regulates	IL2RB	binding
IL15RA	up-regulates	IL2RB	binding
IL2RB	up-regulates	JAK1	binding
IL2RB	up-regulates	SHC1	binding
“125-L-serine-2-133-interleukin 2 (human reduced)”	“up-regulates activity”	IL2RB	“chemical activation”
“denileukin diftitox”	“up-regulates activity”	IL2RB	“chemical activation”
PTPN6	down-regulates	IL2RB	dephosphorylation
JAK1	“up-regulates activity”	IL2RB	phosphorylation
LCK	unknown	IL2RB	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	7
Uncertain significance	213
Likely benign	223
Benign	22

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2184249	NM_000878.5(IL2RB):c.619C>T (p.Gln207Ter)	Pathogenic
2765281	NM_000878.5(IL2RB):c.480C>G (p.Tyr160Ter)	Pathogenic
2793509	NM_000878.5(IL2RB):c.97C>T (p.Gln33Ter)	Pathogenic
2960036	NM_000878.5(IL2RB):c.591_592del (p.Leu198fs)	Pathogenic
545515	NM_000878.5(IL2RB):c.286C>T (p.Gln96Ter)	Pathogenic
635829	NM_000878.5(IL2RB):c.230T>C (p.Leu77Pro)	Pathogenic
635830	NM_000878.5(IL2RB):c.119C>T (p.Ser40Leu)	Pathogenic
635831	IL2RB, GLN96TER	Pathogenic
1493110	NM_000878.5(IL2RB):c.204-2A>T	Likely pathogenic
2029906	NM_000878.5(IL2RB):c.203+1G>C	Likely pathogenic
2743756	NM_000878.5(IL2RB):c.819-2_832del	Likely pathogenic
2763822	NM_000878.5(IL2RB):c.819-1G>T	Likely pathogenic
2857640	NM_000878.5(IL2RB):c.88+1G>A	Likely pathogenic
4727425	NM_000878.5(IL2RB):c.204-84_207del	Likely pathogenic
871831	NM_000878.5(IL2RB):c.388+1G>A	Likely pathogenic

SpliceAI

1386 predictions. Top by Δscore:

Variant	Effect	Δscore
22:37132382:A:AG	donor_loss	1.0000
22:37132383:C:T	donor_loss	1.0000
22:37132465:CAGC:C	acceptor_gain	1.0000
22:37132468:CCTG:C	acceptor_loss	1.0000
22:37132469:C:CA	acceptor_loss	1.0000
22:37132469:C:CC	acceptor_gain	1.0000
22:37132470:T:C	acceptor_loss	1.0000
22:37135322:TCTTA:T	donor_loss	1.0000
22:37135323:CTTA:C	donor_loss	1.0000
22:37135324:TTA:T	donor_loss	1.0000
22:37135325:TACCA:T	donor_loss	1.0000
22:37135326:A:AC	donor_gain	1.0000
22:37135326:A:T	donor_loss	1.0000
22:37135327:C:CC	donor_gain	1.0000
22:37135327:C:CG	donor_loss	1.0000
22:37135439:AGGG:A	acceptor_gain	1.0000
22:37135440:GGG:G	acceptor_gain	1.0000
22:37135441:GG:G	acceptor_gain	1.0000
22:37135443:C:CC	acceptor_gain	1.0000
22:37135448:C:CT	acceptor_gain	1.0000
22:37135448:C:T	acceptor_gain	1.0000
22:37135449:A:T	acceptor_gain	1.0000
22:37135453:G:C	acceptor_gain	1.0000
22:37135453:G:GC	acceptor_gain	1.0000
22:37136391:CTC:C	acceptor_gain	1.0000
22:37136394:CTGG:C	acceptor_loss	1.0000
22:37136395:T:C	acceptor_loss	1.0000
22:37137583:TCACC:T	donor_loss	1.0000
22:37137585:ACC:A	donor_loss	1.0000
22:37137586:C:G	donor_loss	1.0000

AlphaMissense

3564 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:37137670:A:G	W152R	0.997
22:37137670:A:T	W152R	0.997
22:37137668:C:A	W152C	0.996
22:37137668:C:G	W152C	0.996
22:37136268:G:C	S221R	0.995
22:37136268:G:T	S221R	0.995
22:37136270:T:G	S221R	0.995
22:37136262:C:A	W223C	0.994
22:37136262:C:G	W223C	0.994
22:37136305:C:G	R209P	0.993
22:37136259:G:C	S224R	0.992
22:37136259:G:T	S224R	0.992
22:37136261:T:G	S224R	0.992
22:37136264:A:G	W223R	0.991
22:37136264:A:T	W223R	0.991
22:37136271:C:A	W220C	0.991
22:37136271:C:G	W220C	0.991
22:37137720:G:T	P135H	0.991
22:37128845:A:G	W303R	0.990
22:37128845:A:T	W303R	0.990
22:37136245:A:G	F229S	0.990
22:37137675:A:T	I150K	0.990
22:37143607:G:C	N39K	0.989
22:37143607:G:T	N39K	0.989
22:37128606:A:C	F382L	0.988
22:37128606:A:T	F382L	0.988
22:37128608:A:G	F382L	0.988
22:37142459:C:T	C86Y	0.988
22:37128843:C:A	W303C	0.987
22:37128843:C:G	W303C	0.987

dbSNP variants (sampled 300 via entrez): RS1000051017 (22:37135691 A>G), RS1000095628 (22:37170688 C>A,T), RS1000266712 (22:37159385 C>T), RS1000342787 (22:37164794 T>C), RS1000345182 (22:37164990 T>C), RS1000474130 (22:37169425 C>T), RS1000498323 (22:37133994 C>T), RS1000570997 (22:37156648 G>A,C,T), RS1000628717 (22:37150584 A>G), RS1000683553 (22:37176036 G>C), RS1000694408 (22:37138948 C>A,T), RS1000694655 (22:37161485 G>A), RS1000869819 (22:37149206 G>A), RS1000892073 (22:37132062 G>A), RS1000942961 (22:37149408 T>A)

Disease associations

OMIM: gene MIM:146710 | disease phenotypes: MIM:618495

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 63 with lymphoproliferation and autoimmunity	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 63 with lymphoproliferation and autoimmunity	Moderate	AR

Mondo (2): immunodeficiency 63 with lymphoproliferation and autoimmunity (MONDO:0032782), ichthyosis (MONDO:0019269)

Orphanet (1): Ichthyosis (Orphanet:79354)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000403	Recurrent otitis media
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000554	Uveitis
HP:0000572	Visual loss
HP:0000585	Band keratopathy
HP:0001094	Iridocyclitis
HP:0001155	Abnormality of the hand
HP:0001369	Arthritis
HP:0001370	Rheumatoid arthritis
HP:0001371	Flexion contracture
HP:0001382	Joint hypermobility
HP:0001384	Abnormal hip joint morphology
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001530	Mild postnatal growth retardation
HP:0001558	Decreased fetal movement
HP:0001744	Splenomegaly
HP:0001785	Ankle swelling
HP:0001824	Weight loss
HP:0001832	Abnormal metatarsal morphology
HP:0001890	Autoimmune hemolytic anemia
HP:0001903	Anemia
HP:0002014	Diarrhea
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000804_5	Asthma	1.000000e-08
GCST001191_9	Type 1 diabetes	2.000000e-06
GCST002198_1	Tuberculosis	2.000000e-07
GCST002318_122	Rheumatoid arthritis	6.000000e-06
GCST004602_252	Mean corpuscular volume	2.000000e-16
GCST005528_20	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	2.000000e-08
GCST005568_14	Rheumatoid arthritis (ACPA-positive)	2.000000e-07
GCST005569_37	Rheumatoid arthritis	6.000000e-06
GCST006048_51	Rheumatoid arthritis (ACPA-positive)	7.000000e-07
GCST007623_2	Lack of premeditation	9.000000e-07
GCST010043_43	Asthma	2.000000e-09
GCST010107_6	L-selectin levels	4.000000e-06
GCST90002381_446	Eosinophil count	1.000000e-23
GCST90002381_447	Eosinophil count	1.000000e-09
GCST90002382_508	Eosinophil percentage of white cells	2.000000e-24
GCST90002382_509	Eosinophil percentage of white cells	2.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006946	behavioural disinhibition measurement
EFO:0008202	L-Selectin measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2364167 (PROTEIN COMPLEX), CHEMBL3276 (SINGLE PROTEIN), CHEMBL4665588 (PROTEIN COMPLEX), CHEMBL4665592 (PROTEIN COMPLEX)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3218253	IL2RB		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — IL-2 receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
bempegaldesleukin	Agonist	5.75	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, increases expression	3
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol F	decreases methylation	1
triphenyl phosphate	affects expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases expression, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
bathocuproine sulfonate	affects cotreatment, decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
CP 31398	increases expression	1
beta-hydroxy simvastatin acid	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
licochalcone B	decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Arsenic	affects expression	1
Aspirin	increases expression	1
Vehicle Emissions	decreases expression	1
Benzene	increases expression	1
Benzoates	increases expression	1
Catechin	affects cotreatment, decreases expression	1
Choline	affects expression	1
Dexamethasone	affects expression, decreases expression, decreases reaction	1
Diethylhexyl Phthalate	increases expression	1
Drugs, Chinese Herbal	increases expression	1
Methapyrilene	increases methylation	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1177370	Binding	Binding affinity to human p75 expressed in mouse NIH/3T3 cells by FACS analysis	Bivalent diketopiperazine-based tropomysin receptor kinase C (TrkC) antagonists. — J Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8IF	Abcam HCT 116 IL2RB KO	Cancer cell line	Male
CVCL_B8XD	Abcam MCF-7 IL2RB KO	Cancer cell line	Female
CVCL_B9KP	Abcam A-549 IL2RB KO	Cancer cell line	Male
CVCL_E8ED	HEK-Blue CD122/CD132	Transformed cell line	Female
CVCL_UF26	HEK-Blue IL-2	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement