immunodeficiency due to CD25 deficiency

Summary

immunodeficiency due to CD25 deficiency (MONDO:0011664) is a disease caused by IL2RA (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IL2RA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 337

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency due to CD25 deficiency
Mondo ID	MONDO:0011664
MeSH	C565232
OMIM	606367
Orphanet	169100
DOID	DOID:0111968
ICD-11	1705860123
UMLS	C1853392
MedGen	377894
GARD	0017049
Is cancer (heuristic)	no

Also known as: IMD41 · immunodeficiency 41 with lymphoproliferation and autoimmunity · immunodeficiency due to CD25 deficiency · Interleukin-2 receptor alpha chain deficiency

Data availability: 337 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency due to CD25 deficiency

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

337 retrieved; paginated sample, class counts are floors:

158 uncertain significance, 123 likely benign, 25 benign, 16 conflicting classifications of pathogenicity, 9 pathogenic, 5 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2030202	NM_000417.3(IL2RA):c.227G>A (p.Trp76Ter)	IL2RA	Pathogenic	criteria provided, single submitter
203515	NM_000417.3(IL2RA):c.301C>T (p.Gln101Ter)	IL2RA	Pathogenic	criteria provided, multiple submitters, no conflicts
203516	NM_000417.3(IL2RA):c.692dup (p.Thr232fs)	IL2RA	Pathogenic	no assertion criteria provided
203517	NM_000417.3(IL2RA):c.497G>A (p.Ser166Asn)	IL2RA	Pathogenic	no assertion criteria provided
203518	NM_000417.3(IL2RA):c.122A>C (p.Tyr41Ser)	IL2RA	Pathogenic	no assertion criteria provided
3721571	NM_000417.3(IL2RA):c.130G>T (p.Gly44Ter)	IL2RA	Pathogenic	criteria provided, single submitter
4277521	NM_000417.3(IL2RA):c.166del (p.Arg56fs)	IL2RA	Pathogenic	criteria provided, single submitter
657558	NM_000417.3(IL2RA):c.246C>A (p.Cys82Ter)	IL2RA	Pathogenic	criteria provided, single submitter
14668	NM_000417.3(IL2RA):c.62_64+1del	LOC130003232	Pathogenic	no assertion criteria provided
1508767	NM_000417.3(IL2RA):c.583+2T>C	IL2RA	Likely pathogenic	criteria provided, single submitter
1948192	NM_000417.3(IL2RA):c.655+1G>A	IL2RA	Likely pathogenic	criteria provided, single submitter
2785669	NM_000417.3(IL2RA):c.368-1G>A	IL2RA	Likely pathogenic	criteria provided, single submitter
3596321	NM_000417.3(IL2RA):c.148G>T (p.Glu50Ter)	IL2RA	Likely pathogenic	criteria provided, single submitter
4714919	NM_000417.3(IL2RA):c.65-2A>G	IL2RA	Likely pathogenic	criteria provided, single submitter
1337208	NM_000417.3(IL2RA):c.64+8C>T	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1436549	NM_000417.3(IL2RA):c.643G>A (p.Val215Ile)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1510192	NM_000417.3(IL2RA):c.554C>T (p.Thr185Ile)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300253	NM_000417.3(IL2RA):c.669G>A (p.Gln223=)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300254	NM_000417.3(IL2RA):c.656-14T>A	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300255	NM_000417.3(IL2RA):c.584-6C>T	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432884	NM_000417.3(IL2RA):c.272C>T (p.Thr91Met)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626117	NM_000417.3(IL2RA):c.584-8del	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
710776	NM_000417.3(IL2RA):c.777C>A (p.Leu259=)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732865	NM_000417.3(IL2RA):c.693G>A (p.Glu231=)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802558	NM_000417.3(IL2RA):c.100G>A (p.Ala34Thr)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
862422	NM_000417.3(IL2RA):c.788G>A (p.Arg263Gln)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878605	NM_000417.3(IL2RA):c.584-11C>T	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879204	NM_000417.3(IL2RA):c.257-11A>G	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879205	NM_000417.3(IL2RA):c.252C>T (p.Ser84=)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
953264	NM_000417.3(IL2RA):c.180C>T (p.Ser60=)	IL2RA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IL2RA	Strong	Autosomal recessive	immunodeficiency due to CD25 deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL2RA	Orphanet:169100	Immunodeficiency due to CD25 deficiency
IL2RA	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
IL2RA	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL2RA	HGNC:6008	ENSG00000134460	P01589	Interleukin-2 receptor subunit alpha	gencc,clinvar
CD44	HGNC:1681	ENSG00000026508	P16070	CD44 antigen	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL2RA	Interleukin-2 receptor subunit alpha	Receptor for interleukin-2.
CD44	CD44 antigen	Cell-surface receptor that plays a role in cell-cell interactions, cell adhesion and migration, helping them to sense and respond to changes in the tissue microenvironment.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	1	134.0×	0.015
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL2RA	Complement	yes		Sushi_SCR_CCP_dom, IL-2_rcpt_alpha, Sushi/SCR/CCP_sf
CD44	Other/Unknown	no		Link_dom, CD44_antigen, C-type_lectin-like/link_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caecum	1
lymph node	1
vermiform appendix	1
mammalian vulva	1
parotid gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL2RA	153	broad	marker	lymph node, vermiform appendix, caecum
CD44	294	ubiquitous	marker	parotid gland, stromal cell of endometrium, mammalian vulva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD44	6,810
IL2RA	2,557

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL2RA	P01589	10
CD44	P16070	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	571.0×	0.013	IL2RA
Hyaluronan metabolism	1	475.8×	0.013	CD44
Interleukin-2 signaling	1	475.8×	0.013	IL2RA
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.013	CD44
Hyaluronan degradation	1	356.9×	0.013	CD44
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.014	CD44
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	228.4×	0.014	CD44
Interleukin receptor SHC signaling	1	203.9×	0.014	IL2RA
Glycosaminoglycan metabolism	1	109.8×	0.023	CD44
Integrin cell surface interactions	1	67.2×	0.028	CD44
Interferon gamma signaling	1	62.8×	0.028	CD44
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.028	CD44
Interferon Signaling	1	60.1×	0.028	CD44
Degradation of the extracellular matrix	1	58.9×	0.028	CD44
Cell surface interactions at the vascular wall	1	47.6×	0.032	CD44
Extracellular matrix organization	1	31.6×	0.044	CD44
RAF/MAP kinase cascade	1	30.5×	0.044	IL2RA
Cytokine Signaling in Immune system	1	20.4×	0.062	CD44
Hemostasis	1	18.0×	0.066	CD44
Innate Immune System	1	12.8×	0.088	CD44
Neutrophil degranulation	1	11.5×	0.093	CD44
Immune System	1	6.5×	0.155	CD44
Metabolism	1	5.8×	0.165	CD44

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of T cell tolerance induction	1	8426.0×	0.002	IL2RA
regulation of CD4-positive, alpha-beta T cell proliferation	1	4213.0×	0.002	IL2RA
regulation of T cell homeostatic proliferation	1	2808.7×	0.002	IL2RA
monocyte aggregation	1	2808.7×	0.002	CD44
positive regulation of monocyte aggregation	1	2808.7×	0.002	CD44
regulation of lamellipodium morphogenesis	1	2808.7×	0.002	CD44
inflammatory response	2	37.7×	0.004	IL2RA, CD44
activation-induced cell death of T cells	1	1203.7×	0.004	IL2RA
interleukin-2-mediated signaling pathway	1	1053.2×	0.004	IL2RA
activated T cell proliferation	1	936.2×	0.004	IL2RA
positive regulation of heterotypic cell-cell adhesion	1	648.1×	0.005	CD44
negative regulation of DNA damage response, signal transduction by p53 class mediator	1	561.7×	0.005	CD44
wound healing, spreading of cells	1	561.7×	0.005	CD44
negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	526.6×	0.005	CD44
hyaluronan catabolic process	1	495.6×	0.005	CD44
inflammatory response to antigenic stimulus	1	468.1×	0.005	IL2RA
positive regulation of activated T cell proliferation	1	337.0×	0.006	IL2RA
cellular response to fibroblast growth factor stimulus	1	271.8×	0.007	CD44
positive regulation of T cell differentiation	1	227.7×	0.008	IL2RA
negative regulation of T cell proliferation	1	165.2×	0.011	IL2RA
T cell activation	1	129.6×	0.013	CD44
cartilage development	1	125.8×	0.013	CD44
cell-matrix adhesion	1	81.8×	0.019	CD44
Notch signaling pathway	1	70.8×	0.020	IL2RA
negative regulation of inflammatory response	1	68.5×	0.020	IL2RA
cytokine-mediated signaling pathway	1	65.3×	0.021	CD44
cell-cell adhesion	1	50.8×	0.025	CD44
endocytosis	1	47.6×	0.026	CD44
positive regulation of ERK1 and ERK2 cascade	1	42.6×	0.028	CD44
cell surface receptor signaling pathway	1	32.0×	0.036	IL2RA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL2RA	0	0
CD44	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CD44	9	Binding:9
IL2RA	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	IL2RA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CD44

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IL2RA	2	—
CD44	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.