combined immunodeficiency, X-linked

Summary

combined immunodeficiency, X-linked (MONDO:0010730) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency, X-linked
Mondo ID	MONDO:0010730
EFO	EFO:1001451
OMIM	312863
GARD	0024751
Is cancer (heuristic)	no

Also known as: CIDX · combined immunodeficiency, X-linked · combined immunodeficiency, X-linked, moderate, X-linked recessive

Data availability: 19 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B+ severe combined immunodeficiency › combined immunodeficiency, X-linked

Related subtypes (9): T-B+ severe combined immunodeficiency due to gamma chain deficiency, T-B+ severe combined immunodeficiency due to JAK3 deficiency, immunodeficiency 104, lung fibrosis-immunodeficiency-46,XX gonadal dysgenesis syndrome, severe combined immunodeficiency due to CORO1A deficiency, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, T-B+ severe combined immunodeficiency due to CD45 deficiency, T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta, severe combined immunodeficiency due to LAT deficiency

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

19 retrieved; paginated sample, class counts are floors:

8 pathogenic, 3 uncertain significance, 3 likely pathogenic, 2 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10023	NM_000206.3(IL2RG):c.878T>A (p.Leu293Gln)	IL2RG	Pathogenic	criteria provided, single submitter
10027	NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys)	IL2RG	Pathogenic	reviewed by expert panel
1028611	NM_000206.3(IL2RG):c.269+1G>T	IL2RG	Pathogenic	reviewed by expert panel
225194	NM_000206.3(IL2RG):c.670C>T (p.Arg224Trp)	IL2RG	Pathogenic	reviewed by expert panel
225195	NM_000206.3(IL2RG):c.676C>T (p.Arg226Cys)	IL2RG	Pathogenic	reviewed by expert panel
3242265	NM_000206.3(IL2RG):c.511G>T (p.Glu171Ter)	IL2RG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3598423	NM_000206.3(IL2RG):c.924G>C (p.Ser308=)	IL2RG	Pathogenic	criteria provided, single submitter
379561	NM_000206.3(IL2RG):c.202G>A (p.Glu68Lys)	IL2RG	Pathogenic	reviewed by expert panel
418656	NM_000206.3(IL2RG):c.982C>T (p.Arg328Ter)	IL2RG	Pathogenic	reviewed by expert panel
1675093	NM_000206.3(IL2RG):c.74del (p.Thr25fs)	IL2RG	Likely pathogenic	criteria provided, single submitter
3256570	NM_000206.3(IL2RG):c.257C>A (p.Thr86Asn)	IL2RG	Likely pathogenic	criteria provided, single submitter
992514	NM_000206.3(IL2RG):c.374A>G (p.Tyr125Cys)	IL2RG	Likely pathogenic	criteria provided, single submitter
1199322	NM_000206.3(IL2RG):c.318A>G (p.Leu106=)	IL2RG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1301872	NM_000206.3(IL2RG):c.484C>G (p.Leu162Val)	IL2RG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1699362	NM_000206.3(IL2RG):c.75_77del (p.Thr26del)	IL2RG	Uncertain significance	criteria provided, single submitter
3891383	NM_000206.3(IL2RG):c.517A>G (p.Asn173Asp)	IL2RG	Uncertain significance	criteria provided, single submitter
1170712	NM_000206.3(IL2RG):c.857C>T (p.Thr286Met)	IL2RG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1199323	NM_000206.3(IL2RG):c.1061A>G (p.His354Arg)	IL2RG	Likely benign	reviewed by expert panel
795771	NM_000206.3(IL2RG):c.201C>T (p.Val67=)	IL2RG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL2RG	Orphanet:276	T-B+ severe combined immunodeficiency due to gamma chain deficiency
IL2RG	Orphanet:39041	Omenn syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL2RG	HGNC:6010	ENSG00000147168	P31785	Cytokine receptor common subunit gamma	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL2RG	Cytokine receptor common subunit gamma	Common subunit for the receptors for a variety of interleukins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL2RG	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
lymph node	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL2RG	213	broad	marker	granulocyte, lymph node, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL2RG	2,470

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL2RG	P31785	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-9 signaling	1	1268.9×	0.002	IL2RG
Interleukin-21 signaling	1	1142.0×	0.002	IL2RG
STAT3 nuclear events downstream of ALK signaling	1	1038.2×	0.002	IL2RG
Interleukin-2 signaling	1	951.7×	0.002	IL2RG
Interleukin-15 signaling	1	761.3×	0.002	IL2RG
Interleukin receptor SHC signaling	1	407.9×	0.004	IL2RG
Interleukin-7 signaling	1	317.2×	0.004	IL2RG
Interleukin-4 and Interleukin-13 signaling	1	102.9×	0.011	IL2RG
RAF/MAP kinase cascade	1	61.1×	0.016	IL2RG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mature B cell differentiation	1	16852.0×	0.001	IL2RG
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	5617.3×	0.001	IL2RG
positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	3370.4×	0.001	IL2RG
lymphocyte differentiation	1	2808.7×	0.001	IL2RG
interleukin-4-mediated signaling pathway	1	2407.4×	0.001	IL2RG
interleukin-2-mediated signaling pathway	1	2106.5×	0.001	IL2RG
interleukin-7-mediated signaling pathway	1	2106.5×	0.001	IL2RG
interleukin-9-mediated signaling pathway	1	2106.5×	0.001	IL2RG
interleukin-15-mediated signaling pathway	1	1685.2×	0.001	IL2RG
positive regulation of T cell differentiation in thymus	1	1532.0×	0.001	IL2RG
positive regulation of B cell differentiation	1	1123.5×	0.002	IL2RG
cellular homeostasis	1	802.5×	0.002	IL2RG
positive regulation of immunoglobulin production	1	481.5×	0.003	IL2RG
T cell differentiation in thymus	1	411.0×	0.003	IL2RG
positive regulation of phagocytosis	1	318.0×	0.004	IL2RG
cytokine-mediated signaling pathway	1	130.6×	0.009	IL2RG
gene expression	1	79.9×	0.014	IL2RG
immune response	1	47.1×	0.022	IL2RG
signal transduction	1	16.1×	0.062	IL2RG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
IL2RG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	IL2RG
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IL2RG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.