Immunodeficiency 25

Summary

Immunodeficiency 25 (MONDO:0012426) is a disease caused by CD247 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CD247 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 167

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 25
Mondo ID	MONDO:0012426
MeSH	C565712
OMIM	610163
DOID	DOID:0060007, DOID:0111942
UMLS	C1857798
MedGen	346666
GARD	0018294
Is cancer (heuristic)	no

Also known as: CD247 severe combined immunodeficiency (disease) · CD3zeta deficiency · IMD25 · immunodeficiency 25 · immunodeficiency type 25 · severe combined immunodeficiency (disease) caused by mutation in CD247

Data availability: 167 ClinVar variants · 2 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 › combined immunodeficiency › severe combined immunodeficiency › T-B+ severe combined immunodeficiency › T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta › immunodeficiency 25

Related subtypes (2): immunodeficiency 18, immunodeficiency 19

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

167 retrieved; paginated sample, class counts are floors:

88 likely benign, 58 uncertain significance, 11 benign, 8 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12749	NM_198053.3(CD247):c.208C>T (p.Gln70Ter)	CD247	Pathogenic	no assertion criteria provided
12750	NM_198053.3(CD247):c.208_209inv (p.Gln70Trp)	CD247	Pathogenic	no assertion criteria provided
12751	NM_198053.3(CD247):c.209A>T (p.Gln70Leu)	CD247	Pathogenic	no assertion criteria provided
12752	NM_198053.3(CD247):c.208_210delinsTAT (p.Gln70Tyr)	CD247	Pathogenic	no assertion criteria provided
1367517	NM_198053.3(CD247):c.235C>T (p.Arg79Ter)	CD247	Pathogenic	criteria provided, single submitter
162005	NM_198053.3(CD247):c.2T>C (p.Met1Thr)	CD247	Pathogenic	no assertion criteria provided
2427629	NC_000001.10:g.(?167487625)(167487702_?)del	CD247	Pathogenic	criteria provided, single submitter
419227	NM_198053.3(CD247):c.301C>T (p.Gln101Ter)	CD247	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
534695	NM_198053.3(CD247):c.51dup (p.Ile18fs)	CD247	Pathogenic	criteria provided, single submitter
190989	NM_198053.3(CD247):c.58+8C>T	CD247	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2427631	NC_000001.10:g.(?167400918)(168282240_?)dup	ADCY10	Uncertain significance	criteria provided, single submitter
1005445	NM_198053.3(CD247):c.148T>C (p.Phe50Leu)	CD247	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025806	NM_198053.3(CD247):c.220-3T>C	CD247	Uncertain significance	criteria provided, single submitter
1035756	NM_198053.3(CD247):c.310A>G (p.Lys104Glu)	CD247	Uncertain significance	criteria provided, multiple submitters, no conflicts
1038153	NM_198053.3(CD247):c.250G>T (p.Asp84Tyr)	CD247	Uncertain significance	criteria provided, single submitter
1040612	NM_198053.3(CD247):c.274C>T (p.Arg92Trp)	CD247	Uncertain significance	criteria provided, single submitter
1055965	NM_198053.3(CD247):c.227A>G (p.Asn76Ser)	CD247	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057409	NM_198053.3(CD247):c.397C>T (p.Arg133Trp)	CD247	Uncertain significance	criteria provided, multiple submitters, no conflicts
1064375	NM_198053.3(CD247):c.350A>G (p.Asp117Gly)	CD247	Uncertain significance	criteria provided, single submitter
1064382	NC_000001.10:g.(?167400898)(167487722_?)dup	CD247	Uncertain significance	criteria provided, single submitter
1364326	NM_198053.3(CD247):c.253G>A (p.Val85Ile)	CD247	Uncertain significance	criteria provided, single submitter
1385849	NM_198053.3(CD247):c.250G>A (p.Asp84Asn)	CD247	Uncertain significance	criteria provided, single submitter
1394874	NM_198053.3(CD247):c.167G>T (p.Ser56Ile)	CD247	Uncertain significance	criteria provided, single submitter
1416361	NM_198053.3(CD247):c.289G>A (p.Gly97Arg)	CD247	Uncertain significance	criteria provided, single submitter
1428563	NM_198053.3(CD247):c.155G>A (p.Arg52Lys)	CD247	Uncertain significance	criteria provided, multiple submitters, no conflicts
1440885	NM_198053.3(CD247):c.26C>T (p.Ala9Val)	CD247	Uncertain significance	criteria provided, single submitter
1447805	NM_198053.3(CD247):c.28G>T (p.Ala10Ser)	CD247	Uncertain significance	criteria provided, single submitter
1468834	NM_198053.3(CD247):c.269G>A (p.Arg90His)	CD247	Uncertain significance	criteria provided, single submitter
1484636	NM_198053.3(CD247):c.175G>A (p.Ala59Thr)	CD247	Uncertain significance	criteria provided, single submitter
1516957	NM_198053.3(CD247):c.251A>C (p.Asp84Ala)	CD247	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 4 · 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
CD247	Strong	Autosomal recessive	immunodeficiency 25	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD247	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
CD247	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
CD247	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
ADCY10	Orphanet:2197	Idiopathic hypercalciuria

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
CD247	HGNC:1677	ENSG00000198821	P20963	T-cell surface glycoprotein CD3 zeta chain	gencc,clinvar
ADCY10	HGNC:21285	ENSG00000143199	Q96PN6	Adenylate cyclase type 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD247	T-cell surface glycoprotein CD3 zeta chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
ADCY10	Adenylate cyclase type 10	Catalyzes the formation of the signaling molecule cAMP.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD247	Other/Unknown	no		Phos_immunorcpt_sig_ITAM, CD3_zeta/IgE_Fc_rcpt_gamma, T-cell_CD3_zeta
ADCY10	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adenylate_cyclase_typ10, P-loop_NTPase

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
blood	1
granulocyte	1
thymus	1
left testis	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD247	179	broad	marker	granulocyte, thymus, blood
ADCY10	154	tissue_specific	marker	sperm, male germ cell, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD247	2,417
ADCY10	2,182

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD247	P20963	38
ADCY10	Q96PN6	37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Nef and signal transduction	1	634.4×	0.011	CD247
FCGR activation	1	439.2×	0.011	CD247
Translocation of ZAP-70 to Immunological synapse	1	317.2×	0.011	CD247
Phosphorylation of CD3 and TCR zeta chains	1	271.9×	0.011	CD247
Co-inhibition by PD-1	1	259.6×	0.011	CD247
Role of phospholipids in phagocytosis	1	228.4×	0.011	CD247
Generation of second messenger molecules	1	173.0×	0.012	CD247
FCGR3A-mediated IL10 synthesis	1	146.4×	0.013	CD247
FCGR3A-mediated phagocytosis	1	93.6×	0.014	CD247
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.014	CD247
Signaling by Hedgehog	1	92.1×	0.014	ADCY10
Hedgehog ‘off’ state	1	89.2×	0.014	ADCY10
Downstream TCR signaling	1	64.2×	0.018	CD247
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.024	CD247
Signal Transduction	1	5.1×	0.187	ADCY10

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
negative regulation of cardiac muscle cell contraction	1	8426.0×	0.003	ADCY10
neuron projection retraction	1	4213.0×	0.003	ADCY10
positive regulation of glycogen catabolic process	1	2106.5×	0.003	ADCY10
positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	2106.5×	0.003	ADCY10
alpha-beta T cell activation	1	1685.2×	0.003	CD247
glucose catabolic process	1	1203.7×	0.003	ADCY10
gamma-delta T cell activation	1	1053.2×	0.003	CD247
positive regulation of vascular associated smooth muscle cell apoptotic process	1	1053.2×	0.003	ADCY10
Fc-gamma receptor signaling pathway	1	936.2×	0.003	CD247
mitochondrial ATP transmembrane transport	1	936.2×	0.003	ADCY10
positive regulation of mitochondrial depolarization	1	842.6×	0.003	ADCY10
cAMP biosynthetic process	1	702.2×	0.003	ADCY10
negative regulation of mitochondrial membrane potential	1	702.2×	0.003	ADCY10
regulation of membrane repolarization	1	648.1×	0.003	ADCY10
positive regulation of cardiac muscle cell apoptotic process	1	601.9×	0.003	ADCY10
regulation of mitophagy	1	601.9×	0.003	ADCY10
positive regulation of ATP biosynthetic process	1	601.9×	0.003	ADCY10
positive regulation of reactive oxygen species biosynthetic process	1	561.7×	0.003	ADCY10
neuron projection maintenance	1	561.7×	0.003	ADCY10
negative regulation of reactive oxygen species biosynthetic process	1	495.6×	0.004	ADCY10
positive regulation of ossification	1	468.1×	0.004	ADCY10
epithelial cilium movement involved in extracellular fluid movement	1	383.0×	0.004	ADCY10
positive regulation of protein localization to cell surface	1	383.0×	0.004	CD247
positive regulation of cardiac muscle hypertrophy	1	366.4×	0.004	ADCY10
protein complex oligomerization	1	337.0×	0.004	CD247
neuron projection extension	1	263.3×	0.005	ADCY10
positive regulation of axon extension	1	255.3×	0.005	ADCY10
obsolete positive regulation of protein targeting to mitochondrion	1	247.8×	0.005	ADCY10
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	109.4×	0.011	ADCY10
T cell receptor signaling pathway	1	75.9×	0.015	CD247

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CD247	0	0
ADCY10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADCY10	14	Binding:14

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADCY10	4.6.1.1	adenylate cyclase

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	ADCY10
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CD247

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)
CD247	0	—
ADCY10	14	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.