IL2RA

Summary

IL2RA (interleukin 2 receptor subunit alpha, HGNC:6008) is a protein-coding gene on chromosome 10p15.1, encoding Interleukin-2 receptor subunit alpha (P01589). Receptor for interleukin-2.

The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor. Homodimeric alpha chains (IL2RA) result in low-affinity receptor, while homodimeric beta (IL2RB) chains produce a medium-affinity receptor. Normally an integral-membrane protein, soluble IL2RA has been isolated and determined to result from extracellular proteolyisis. Alternately-spliced IL2RA mRNAs have been isolated, but the significance of each is presently unknown. Mutations in this gene are associated with interleukin 2 receptor alpha deficiency. Patients with severe Coronavirus Disease 2019 (COVID-19), the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have significantly elevated levels of IL2R in their plasma. Similarly, serum IL-2R levels are found to be elevated in patients with different types of carcinomas. Certain IL2RA and IL2RB gene polymorphisms have been associated with lung cancer risk.

Source: NCBI Gene 3559 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency due to CD25 deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 101
• Clinical variants (ClinVar): 376 total — 10 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 82
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000417

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6008
Approved symbol	IL2RA
Name	interleukin 2 receptor subunit alpha
Location	10p15.1
Locus type	gene with protein product
Status	Approved
Aliases	CD25
Ensembl gene	ENSG00000134460
Ensembl biotype	protein_coding
OMIM	147730
Entrez	3559

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000256876, ENST00000379954, ENST00000379959, ENST00000447847, ENST00000644262, ENST00000649218, ENST00000697424

RefSeq mRNA: 3 — MANE Select: NM_000417 NM_000417, NM_001308242, NM_001308243

CCDS: CCDS7076, CCDS76281, CCDS91210

Canonical transcript exons

ENST00000379959 — 8 exons

Exon	Start	End
ENSE00000915060	6019870	6019941
ENSE00000915061	6021478	6021693
ENSE00000915063	6024244	6024354
ENSE00001132124	6025834	6026025
ENSE00001194318	6019428	6019499
ENSE00001219989	6018053	6018119
ENSE00001867972	6062088	6062367
ENSE00001889413	6010689	6012896

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 81.96.

FANTOM5 (CAGE): breadth broad, TPM avg 35.3934 / max 3425.8682, expressed in 363 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108137	18.3193	297
108138	16.7142	325
108139	0.2906	84
108141	0.0390	17
108140	0.0304	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	81.96	gold quality
vermiform appendix	UBERON:0001154	80.48	gold quality
caecum	UBERON:0001153	76.91	gold quality
spleen	UBERON:0002106	74.57	gold quality
buccal mucosa cell	CL:0002336	73.45	silver quality
gall bladder	UBERON:0002110	71.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	70.68	gold quality
blood	UBERON:0000178	69.72	gold quality
small intestine	UBERON:0002108	69.23	gold quality
granulocyte	CL:0000094	67.71	gold quality
colonic epithelium	UBERON:0000397	66.74	gold quality
smooth muscle tissue	UBERON:0001135	66.60	gold quality
omental fat pad	UBERON:0010414	66.60	gold quality
peritoneum	UBERON:0002358	66.58	gold quality
tonsil	UBERON:0002372	66.47	gold quality
rectum	UBERON:0001052	66.43	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.39	gold quality
adipose tissue of abdominal region	UBERON:0007808	65.98	gold quality
ascending aorta	UBERON:0001496	64.06	gold quality
thoracic aorta	UBERON:0001515	64.02	gold quality
choroid plexus epithelium	UBERON:0003911	63.57	gold quality
tongue squamous epithelium	UBERON:0006919	62.95	gold quality
ileal mucosa	UBERON:0000331	62.53	silver quality
left adrenal gland cortex	UBERON:0035825	62.45	gold quality
left adrenal gland	UBERON:0001234	62.39	gold quality
adrenal cortex	UBERON:0001235	61.68	gold quality
epithelium of nasopharynx	UBERON:0001951	61.62	gold quality
upper lobe of left lung	UBERON:0008952	61.56	gold quality
right lung	UBERON:0002167	61.18	gold quality
intestine	UBERON:0000160	61.06	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-111727	yes	2286.85
E-HCAD-8	yes	1132.56
E-CURD-95	yes	961.84
E-GEOD-139324	yes	906.12
E-CURD-120	yes	751.48
E-MTAB-8410	yes	20.58
E-CURD-46	yes	14.97
E-HCAD-1	yes	11.85
E-ANND-3	yes	3.81
E-CURD-89	no	1205.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AIRE, AP1, ARID1B, BHLHE40, BHLHE41, CREB1, ELF1, FOS, FOXP3, GATA3, GLI3, HLX, HMGA1, HMGB1, IKZF2, IRF1, JUN, KLF2, LHX8, MSC, MYB, NFATC1, NFATC2, NFKB1, NFKB2, NFKB, NOTCH1, NR1I2, PARP1, POU2F1, PRDM1, REL, RELA, RUNX1, RXRA, SATB1, SRF, STAT1, STAT3, STAT4

miRNA regulators (miRDB)

75 targeting IL2RA, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-3064-5P	99.26	66.13	1497

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• 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., IL-2Ralpha (CD25) was also found in DRMs (PMID:11856346)
• the mechanics of this complex receptor system and to other receptor complexes in the immune system that send signals by clustering receptor subunits. (PMID:11886175)
• Secretion levels of sIL-2R, IL-6, IL-8, IL-10, and TNF-alpha, but not IL-4 and IL-12, are elevated in activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders. (PMID:11960393)
• Cells from all infected patients but from none of the controls responded specifically to ST-Ag by expressing surface CD25 on culture (PMID:11986281)
• Elevated IL-2 and IL-2 receptor serum levels correlated with the severity of cutaneous graft-versus-host disease after bone marrow transplantation, and evidence suggested that both act together in the development of cutaneous GVHD. (PMID:12171778)
• Increased CD25 expression, especially in CD4(+) T cells but also in CD8(+) T cells, without increases in expression of the beta and gamma chains of the IL-2 receptor was detected in HIV patients following long-term intermittent interleukin 2 therapy (PMID:12200381)
• investigation of the presence of IL-2alpha, and IL-2beta receptors on fresh and isolated sperm (PMID:12230826)
• Serum soluble interleukin-2 receptor correlates with probable etiology and severity of disease in eosinophilia. (PMID:12486319)
• Anti-apoptotic signaling by the interleukin-2 receptor reveals a function for cytoplasmic tyrosine residues within the common gamma (gamma c) receptor subunit. (PMID:12525482)
• Expression of cd25 on the surface of activated T lymphocytes are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer. (PMID:12698200)
• Total expression level of membrane IL-2R in peripheral blood monocytes before and after being stimulated with PHA was lower than those in normal controls. (PMID:12970897)
• The development of breast tumour is associated with an increased expression of IL-2 receptor alpha and this expression also seems to be associated with the malignancy of the tumour. (PMID:14680494)
• Mucosal induction of tolerance against dietary antigens is associated with the development of CD4(+)CD25(+) T cells. (PMID:15197226)
• IL-2R alpha, IL-15R alpha, IL-2/15R beta and gamma(c)-subunits, as well as MHC class I and II glycoproteins formed supramolecular receptor clusters in lipid rafts of the T lymphoma line. (PMID:15263076)
• Decreased levels of CD25 expression occur in T-cell lymphoma when it involves the lymph nodes. (PMID:15328201)
• interleukin-2 receptor has a role in diverse types of cancer [review] (PMID:15353339)
• Antagonists may minimize need for steroids in kidney transplantation. (review) (PMID:15365604)
• Soluble interleukin 2 receptor alone is not a good candidate marker in the diagnosis of pancreatic cancer; it can, however, be used in association with carbohydrate antigen 19-9 for this purpose (PMID:15503821)
• Cytomegalovirus infection raises the IL-2R level in serum of childbearing age women. (PMID:15617342)
• The results showed that increasing of sIL-2R is associated with the activation of CD8+ cells which is mainly of cytotoxicity T lymphoeytes that play an important role in the pathogenesis of acute and subacute serious HB. (PMID:15619904)
• decreased production of IL-2sRa by peripheral blood mononuclear cells after induction by non-sialylated serotype HS-3 C. jejuni serotypes (PMID:15649306)
• The presence of CD4+CD25+ (regulatory T cells in head and neck cancer patients might be, in part, responsible for downregulation of antitumour immune responses. (PMID:15714205)
• CD4(+)CD25(+) fetal T cells are present in the human fetus from week 14 onwards, which shows that generation of regulatory-suppressor T cells is consubstantial to the generation of a functional and self-tolerant immune system (PMID:15731180)
• We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (PMID:15776395)
• human leukocyte antigen-DR and CD25 may have a role in progression of cutaneous lupus erythematosus (PMID:15885081)
• Lipid rafts are the functional microdomains for IL-2alpha receptors. (PMID:15964425)
• Phenotypic studies demonstrated decreased frequency of CD4+CD25+ T cells in patients with chronic graft-versus-host disease (PMID:15972448)
• model of the ternary complex of interleukin-10 with its soluble receptors (PMID:15985167)
• Analysis of biopsies from cardiac allograft recipients during acute rejection by quantitative (Q)-PCR. FOXP3 mRNA expression was restricted to the CD25population that inhibited the proliferation of allostimulated CD25 cells. (PMID:16003241)
• CD25-expressing memory CD8+ T cells in elderly persons appear to be a prerequisite for intact immune responsiveness in the absence of naive T cells in old age. (PMID:16034095)
• A quantitative relationship is established between receptor alpha subunit binding affinity and mitogenic activity for IL-2 and IL-15. (PMID:16060678)
• over-expression of ITF2B protein inhibited the expression of IL-2Ralpha gene in Jurkat cells in an NRE-dependent manner (PMID:16126178)
• The soluble receptor balance (sIL-2R/sIL-4R) in patients with severe hemolytic uremic syndrome may shift, depending on the disease state of the patients (PMID:16226465)
• 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)
• Increased expression of interleukin-10 and transforming growth factor-beta1 mRNA was also detected in patients with TB but did not correlate with regulatory T-cell markers. (PMID:16339919)
• The coexpression of CD25 and the costimulatory molecule CD134 on memory T-cells provides a novel marker for type 1 diabetes-associated T-cell immunity. (PMID:16380476)
• Increase of functional CD25 in T cells in cancer patients is a response to the process of malignant transformation. (PMID:16410445)
• sIL-2R and IL-6, but not IL-2, IL-4, or IL-10, may have a role in preventing progression of aggressive non-Hodgkin’s lymphoma (PMID:16690518)
• euthyroid female relatives of autoimmune thyroid disease patients had a reduced expression of CD25 on CD4+ T cells (PMID:16698664)
• CD4 and CD25 in T cells, which are increased in breast cancer, are decreased after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine (PMID:16758122)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il2ra	ENSMUSG00000026770
rattus_norvegicus	Il2ra	ENSRNOG00000047647

Protein

Protein identifiers

Interleukin-2 receptor subunit alpha — P01589 (reviewed: P01589)

Alternative names: TAC antigen, p55

All UniProt accessions (5): A0A8V8TMM2, P01589, H0Y5Z0, Q5W005, Q5W006

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for interleukin-2. The receptor is involved in the regulation of immune tolerance by controlling regulatory T cells (TREGs) activity. TREGs suppress the activation and expansion of autoreactive T-cells.

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.

Subcellular location. Membrane.

Disease relevance. Type 1 diabetes mellitus 10 (T1D10) [MIM:601942] A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry. Immunodeficiency 41 with lymphoproliferation and autoimmunity (IMD41) [MIM:606367] A disorder of immune dysregulation characterized by recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (3): NP_000408, NP_001295171, NP_001295172 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR015486	IL-2_rcpt_alpha	Family
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily

Pfam: PF00084

UniProt features (39 total): strand 14, glycosylation site 6, disulfide bond 5, sequence variant 3, compositionally biased region 2, topological domain 2, domain 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
6YIO	X-RAY DIFFRACTION	1.83
2B5I	X-RAY DIFFRACTION	2.3
1Z92	X-RAY DIFFRACTION	2.8
3NFP	X-RAY DIFFRACTION	2.86
3IU3	X-RAY DIFFRACTION	2.9
9KMC	ELECTRON MICROSCOPY	2.97
2ERJ	X-RAY DIFFRACTION	3
7F9W	ELECTRON MICROSCOPY	3.2
7ZMZ	X-RAY DIFFRACTION	3.2
6VWU	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01589-F1	72.72	0.43

Antibody-complex structures (SAbDab): 5 — 3IU3, 3NFP, 6YIO, 7F9W, 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 (5): 24–168, 49–80, 51–82, 67–125, 152–184

Glycosylation sites (6): 70, 89, 218, 224, 229, 237

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8877330	RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)
R-HSA-9020558	Interleukin-2 signaling
R-HSA-912526	Interleukin receptor SHC signaling

MSigDB gene sets: 647 (showing top): PID_SHP2_PATHWAY, VALK_AML_WITH_FLT3_ITD, GSE45365_NK_CELL_VS_CD8_TCELL_UP, GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, CREL_01, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_TOLERANCE_INDUCTION, LU_IL4_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (22): inflammatory response to antigenic stimulus (GO:0002437), regulation of T cell tolerance induction (GO:0002664), apoptotic process (GO:0006915), activation-induced cell death of T cells (GO:0006924), inflammatory response (GO:0006954), immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), Notch signaling pathway (GO:0007219), interleukin-2-mediated signaling pathway (GO:0038110), positive regulation of activated T cell proliferation (GO:0042104), negative regulation of T cell proliferation (GO:0042130), positive regulation of T cell differentiation (GO:0045582), regulation of T cell homeostatic proliferation (GO:0046013), negative regulation of inflammatory response (GO:0050728), activated T cell proliferation (GO:0050798), regulation of CD4-positive, alpha-beta T cell proliferation (GO:2000561), immune system process (GO:0002376), regulation of immune system process (GO:0002682), positive regulation of T cell proliferation (GO:0042102), T cell homeostasis (GO:0043029), lymphocyte proliferation (GO:0046651), negative regulation of lymphocyte proliferation (GO:0050672)

GO Molecular Function (3): interleukin-2 receptor activity (GO:0004911), interleukin-2 binding (GO:0019976), protein binding (GO:0005515)

GO Cellular Component (5): 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-4 pathways:

Category	Pathways
Interleukin-2 family signaling	2
MAPK1/MAPK3 signaling	1
Transcriptional regulation by RUNX1	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
T cell proliferation	3
regulation of T cell proliferation	3
inflammatory response	2
immune system process	2
positive regulation of T cell activation	2
cellular anatomical structure	2
immune response	1
T cell tolerance induction	1
regulation of tolerance induction	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
T cell homeostasis	1
T cell apoptotic process	1
defense response	1
response to stimulus	1
signal transduction	1
cell surface receptor signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-2	1
positive regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
T cell differentiation	1
regulation of T cell differentiation	1
positive regulation of lymphocyte differentiation	1
T cell homeostatic proliferation	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
CD4-positive, alpha-beta T cell proliferation	1
regulation of alpha-beta T cell proliferation	1
regulation of CD4-positive, alpha-beta T cell activation	1
biological_process	1
regulation of biological process	1
positive regulation of lymphocyte proliferation	1
lymphocyte homeostasis	1
cytokine receptor activity	1

Protein interactions and networks

STRING

2503 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL2RA	IL2	P01585	999
IL2RA	IL2RG	P31785	997
IL2RA	IL2RB	P14784	995
IL2RA	IL15	P40933	972
IL2RA	IL4	P05112	957
IL2RA	JAK3	P52333	957
IL2RA	IL15RA	Q13261	946
IL2RA	CD8A	P01732	930
IL2RA	CD4	P01730	924
IL2RA	IL7	P13232	924
IL2RA	FOXP3	Q9BZS1	916
IL2RA	IL10	P22301	910
IL2RA	IL7R	P16871	906
IL2RA	STAT5A	P42229	887
IL2RA	TNFRSF18	Q9Y5U5	880

IntAct

6 interactions, top by confidence:

A	B	Type	Score
IL2	IL2RA	psi-mi:“MI:0915”(physical association)	0.670
IL2	IL2RA	psi-mi:“MI:0407”(direct interaction)	0.670
PASK	IL2RA	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
IL2RA	LTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (48): IL2RA (Affinity Capture-Western), IL2RA (FRET), METTL7B (Affinity Capture-MS), NLRX1 (Affinity Capture-MS), TMEM192 (Affinity Capture-MS), MTX1 (Affinity Capture-MS), RHOBTB3 (Affinity Capture-MS), RBM14-RBM4 (Affinity Capture-MS), SLC10A7 (Affinity Capture-MS), FASTKD1 (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), SACM1L (Affinity Capture-MS), MICA (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS)

ESM2 similar proteins: A2AR95, D5K8A9, E7FEC4, F1LW30, F1NUK7, O62802, O70535, O95256, O95727, P01589, P01590, P12342, P22934, P26897, P26898, P27931, P40200, P41690, P42702, P42703, P43303, P80370, Q03472, Q149L7, Q38IC8, Q3SXY7, Q5DTZ6, Q5MNY4, Q5XNR9, Q60736, Q61521, Q64735, Q6GMZ9, Q6UXZ4, Q7T2L7, Q7TSY4, Q86YD5, Q8BGE4, Q8BX35, Q8K1S2

Diamond homologs: O02733, O62802, P01589, P01590, P12342, P26897, P26898, P41690, Q38IC8, Q5MNY4

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
IL2	up-regulates	IL2RA	binding
PRKCA	unknown	IL2RA	phosphorylation
HMGB1	“up-regulates quantity by expression”	IL2RA	“transcriptional regulation”
ELF1	“up-regulates quantity by expression”	IL2RA	“transcriptional regulation”
“125-L-serine-2-133-interleukin 2 (human reduced)”	“up-regulates activity”	IL2RA	“chemical activation”
“denileukin diftitox”	“up-regulates activity”	IL2RA	“chemical activation”
NOTCH1	“up-regulates quantity by expression”	IL2RA	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	5
Uncertain significance	171
Likely benign	126
Benign	30

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2030202	NM_000417.3(IL2RA):c.227G>A (p.Trp76Ter)	Pathogenic
203515	NM_000417.3(IL2RA):c.301C>T (p.Gln101Ter)	Pathogenic
203516	NM_000417.3(IL2RA):c.692dup (p.Thr232fs)	Pathogenic
203517	NM_000417.3(IL2RA):c.497G>A (p.Ser166Asn)	Pathogenic
203518	NM_000417.3(IL2RA):c.122A>C (p.Tyr41Ser)	Pathogenic
3721571	NM_000417.3(IL2RA):c.130G>T (p.Gly44Ter)	Pathogenic
4277521	NM_000417.3(IL2RA):c.166del (p.Arg56fs)	Pathogenic
498730	NM_000417.3(IL2RA):c.368-2A>G	Pathogenic
57407	GRCh38/hg38 10p15.3-14(chr10:90421-8442783)x3	Pathogenic
657558	NM_000417.3(IL2RA):c.246C>A (p.Cys82Ter)	Pathogenic
1508767	NM_000417.3(IL2RA):c.583+2T>C	Likely pathogenic
1948192	NM_000417.3(IL2RA):c.655+1G>A	Likely pathogenic
2785669	NM_000417.3(IL2RA):c.368-1G>A	Likely pathogenic
3596321	NM_000417.3(IL2RA):c.148G>T (p.Glu50Ter)	Likely pathogenic
4714919	NM_000417.3(IL2RA):c.65-2A>G	Likely pathogenic

SpliceAI

1086 predictions. Top by Δscore:

Variant	Effect	Δscore
10:6014523:T:TA	donor_gain	1.0000
10:6018051:A:AC	donor_gain	1.0000
10:6018052:C:CT	donor_gain	1.0000
10:6018052:CTGT:C	donor_gain	1.0000
10:6018117:CCA:C	acceptor_gain	1.0000
10:6018118:CAC:C	acceptor_gain	1.0000
10:6018120:C:CC	acceptor_gain	1.0000
10:6026021:GAGCT:G	acceptor_gain	1.0000
10:6026022:AGCT:A	acceptor_gain	1.0000
10:6026024:CT:C	acceptor_gain	1.0000
10:6026024:CTCTG:C	acceptor_loss	1.0000
10:6026026:C:CC	acceptor_gain	1.0000
10:6026026:CTG:C	acceptor_loss	1.0000
10:6026027:T:A	acceptor_loss	1.0000
10:6062082:CCTTA:C	donor_loss	1.0000
10:6062083:CTTA:C	donor_loss	1.0000
10:6062084:TTA:T	donor_loss	1.0000
10:6062085:TAC:T	donor_loss	1.0000
10:6062086:ACCT:A	donor_loss	1.0000
10:6018046:CACT:C	donor_loss	0.9900
10:6018047:ACTT:A	donor_loss	0.9900
10:6018049:TTACT:T	donor_loss	0.9900
10:6018118:CA:C	acceptor_gain	0.9900
10:6018120:C:A	acceptor_loss	0.9900
10:6018121:T:C	acceptor_loss	0.9900
10:6019423:CT:C	donor_loss	0.9900
10:6019424:TCACC:T	donor_loss	0.9900
10:6019425:CA:C	donor_loss	0.9900
10:6019426:AC:A	donor_loss	0.9900
10:6019427:CCTGC:C	donor_loss	0.9900

AlphaMissense

1807 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:6021530:C:A	W177C	0.999
10:6021530:C:G	W177C	0.999
10:6025862:C:A	W76C	0.998
10:6025862:C:G	W76C	0.998
10:6021532:A:G	W177R	0.995
10:6021532:A:T	W177R	0.995
10:6025864:A:G	W76R	0.993
10:6025864:A:T	W76R	0.993
10:6021558:C:G	C168S	0.992
10:6021559:A:T	C168S	0.992
10:6021668:C:A	W131C	0.991
10:6021668:C:G	W131C	0.991
10:6025890:C:G	C67S	0.991
10:6025891:A:T	C67S	0.991
10:6025938:C:G	C51S	0.989
10:6025939:A:T	C51S	0.989
10:6021510:C:G	C184S	0.988
10:6021511:A:T	C184S	0.988
10:6021531:C:G	W177S	0.988
10:6021606:C:G	C152S	0.988
10:6021607:A:T	C152S	0.988
10:6025845:C:G	C82S	0.988
10:6025846:A:T	C82S	0.988
10:6021558:C:T	C168Y	0.987
10:6025851:C:G	C80S	0.986
10:6025852:A:T	C80S	0.986
10:6025925:G:C	F55L	0.985
10:6025925:G:T	F55L	0.985
10:6025927:A:G	F55L	0.985
10:6021687:C:G	C125S	0.984

dbSNP variants (sampled 300 via entrez): RS1000019538 (10:6023127 T>A), RS1000048738 (10:6062684 C>A,T), RS1000084183 (10:6039960 G>T), RS1000236598 (10:6046110 C>T), RS1000242583 (10:6052306 C>T), RS1000351622 (10:6022622 G>A,C), RS1000403317 (10:6013660 G>A), RS1000437346 (10:6027903 C>G,T), RS1000468816 (10:6058222 G>A,C), RS1000590315 (10:6046372 A>C), RS1000637993 (10:6051078 G>T), RS1000645037 (10:6063957 G>A,C), RS1000723597 (10:6029896 G>T), RS1000834850 (10:6049922 G>A), RS1000904925 (10:6057938 C>T)

Disease associations

OMIM: gene MIM:147730 | disease phenotypes: MIM:606367, MIM:601942

GenCC curated gene-disease

Disease	Classification	Inheritance
neonatal diabetes mellitus with congenital hypothyroidism	Strong	Autosomal recessive
neonatal diabetes mellitus	Strong	Autosomal recessive
type 1 diabetes mellitus 10	Strong	Autosomal recessive
immunodeficiency due to CD25 deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency due to CD25 deficiency	Definitive	AR

Mondo (4): immunodeficiency due to CD25 deficiency (MONDO:0011664), type 1 diabetes mellitus 10 (MONDO:0011168), neonatal diabetes mellitus with congenital hypothyroidism (MONDO:0012436), neonatal diabetes mellitus (MONDO:0016391)

Orphanet (1): Immunodeficiency due to CD25 deficiency (Orphanet:169100)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000554	Uveitis
HP:0000572	Visual loss
HP:0000585	Band keratopathy
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000964	Eczematoid dermatitis
HP:0001019	Erythroderma
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:0001531	Failure to thrive in infancy
HP:0001785	Ankle swelling
HP:0001824	Weight loss
HP:0001832	Abnormal metatarsal morphology
HP:0001878	Hemolytic anemia
HP:0001890	Autoimmune hemolytic anemia
HP:0001903	Anemia
HP:0002028	Chronic diarrhea

GWAS associations

101 associations (top):

Study	Trait	p-value
GCST000062_1	Multiple sclerosis	3.000000e-08
GCST000258_13	Type 1 diabetes	2.000000e-06
GCST000392_31	Type 1 diabetes	1.000000e-13
GCST000424_5	Multiple sclerosis	9.000000e-08
GCST000425_5	Multiple sclerosis	7.000000e-06
GCST000662_10	Vitiligo	3.000000e-09
GCST000719_5	Alopecia areata	2.000000e-12
GCST000879_26	Crohn’s disease	3.000000e-09
GCST001191_4	Type 1 diabetes	1.000000e-38
GCST001198_47	Multiple sclerosis	5.000000e-20
GCST001198_80	Multiple sclerosis	3.000000e-11
GCST001341_17	Multiple sclerosis	4.000000e-08
GCST001371_1	Inflammatory biomarkers	5.000000e-09
GCST001371_18	Inflammatory biomarkers	3.000000e-07
GCST001394_1	Type 1 diabetes	5.000000e-09
GCST001725_103	Inflammatory bowel disease	4.000000e-10
GCST001911_1	Asthma (bronchodilator response)	2.000000e-07
GCST002318_120	Rheumatoid arthritis	5.000000e-15
GCST002318_121	Rheumatoid arthritis	5.000000e-14
GCST002322_15	Asthma and hay fever	5.000000e-07
GCST002323_6	Rheumatoid arthritis	1.000000e-06
GCST002363_6	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 3 peripheral neuropathy)	2.000000e-09
GCST002875_32	Diisocyanate-induced asthma	2.000000e-06
GCST003088_1	Soluble interleukin-2 receptor subunit alpha	1.000000e-100
GCST003088_4	Soluble interleukin-2 receptor subunit alpha	7.000000e-35
GCST003088_5	Soluble interleukin-2 receptor subunit alpha	2.000000e-10
GCST003088_6	Soluble interleukin-2 receptor subunit alpha	3.000000e-09
GCST003097_19	Pediatric autoimmune diseases	6.000000e-09
GCST003184_15	Atopic dermatitis	2.000000e-06
GCST003184_7	Atopic dermatitis	1.000000e-10

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0006995	response to diisocyanate
EFO:0007650	soluble interleukin-2 receptor subunit alpha measurement
EFO:0007790	Epstein Barr virus nuclear antigen 1 IgG measurement
EFO:0007803	emotional symptom measurement
EFO:0004760	t-tau measurement
EFO:0008332	interleukin 2 receptor antagonist measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004747	protein measurement
EFO:0005939	parental genotype effect measurement
EFO:0007964	gestational serum measurement
EFO:1002011	adult onset asthma
EFO:0009933	Thyroid preparation use measurement
EFO:0010576	liver fibrosis measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C566602	Diabetes Mellitus, Insulin-Dependent, 10 (supp.)
C565705	Diabetes Mellitus, Neonatal, with Congenital Hypothyroidism (supp.)
C565232	Interleukin 2 Receptor, Alpha, Deficiency of (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1778 (SINGLE PROTEIN), CHEMBL2364167 (PROTEIN COMPLEX)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2104286	IL2RA		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
daclizumab	Binding	8.0	pKd

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.52	IC50	3000	nM	CHEMBL419362
5.22	IC50	6000	nM	CHEMBL419362

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
methyl (2S)-2-[[2-[(3R)-1-carbamimidoylpiperidin-3-yl]acetyl]amino]-3-[4-(2-phenylethynyl)phenyl]propanoate	1924933: Inhibition of IL-2R alpha (unknown origin)	ic50	3.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetradecanoylphorbol Acetate	affects cotreatment, increases expression, increases secretion, decreases reaction, affects expression	7
bisphenol A	increases expression, decreases methylation	3
sodium arsenite	affects reaction, increases expression, decreases expression	3
Nickel	affects expression, increases expression, decreases reaction	3
Plant Extracts	affects expression, increases expression, affects reaction	3
Zinc	affects expression, affects cotreatment, increases expression	3
Ionomycin	decreases reaction, increases secretion, affects cotreatment, increases expression	3
Beclomethasone	decreases expression	2
Calcitriol	decreases reaction, increases expression, decreases expression	2
Cyclosporine	decreases expression, decreases reaction, increases secretion	2
Simvastatin	affects expression, decreases expression	2
GSK-J4	decreases expression	1
OTX015	decreases reaction, increases expression	1
bisphenol F	decreases methylation	1
TL8-506	affects cotreatment, increases expression	1
2-anisidine	decreases expression	1
isopentenyl pyrophosphate	decreases reaction, increases expression	1
alpha phellandrene	decreases expression	1
lipophosphonoglycan	increases expression	1
trichostatin A	affects expression, decreases reaction	1
2-tert-butylhydroquinone	decreases expression	1
N-(2-mercaptoethyl)-1,3-diaminopropane	increases expression	1
tetrathiomolybdate	decreases expression	1
N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide	decreases reaction, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
N,N-diacetylcystine	decreases expression	1
cordycepin	affects expression	1
prostratin	decreases reaction, increases expression	1
B3(Fv)-PE38KDEL recombinant immunotoxin	decreases activity, affects binding	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3077414	Binding	Competitive inhibition of IL2 receptor alpha (unknown origin)	In vitro and in silico exploration of IL-2 inhibition by small drug-like molecules — Med Chem Res

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_UF26	HEK-Blue IL-2	Transformed cell line	Female
CVCL_XG61	BW125.1C	Cancer cell line
CVCL_XY88	293T human CD25	Transformed cell line	Female

Clinical trials (associated diseases)

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