combined immunodeficiency due to CTPS1 deficiency

Summary

combined immunodeficiency due to CTPS1 deficiency (MONDO:0014391) is a disease caused by CTPS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CTPS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 300

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to CTPS1 deficiency
Mondo ID	MONDO:0014391
OMIM	615897
Orphanet	420573
DOID	DOID:0111938
SNOMED CT	763623001
UMLS	C4014617
MedGen	863054
GARD	0017696
Is cancer (heuristic)	no

Also known as: CTPS1-related combined immunodeficiency · IMD24 · immunodeficiency 24 · immunodeficiency type 24 · SCID due to CTPS1 deficiency

Data availability: 300 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 › combined immunodeficiency due to CTPS1 deficiency

Related subtypes (32): ataxia telangiectasia, combined immunodeficiency due to ZAP70 deficiency, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia, combined immunodeficiency due to moesin deficiency, Wiskott-Aldrich syndrome, MHC class I deficiency, combined immunodeficiency due to STK4 deficiency, combined immunodeficiency due to MALT1 deficiency, combined immunodeficiency due to OX40 deficiency, combined immunodeficiency due to CD3gamma deficiency, combined immunodeficiency due to CRAC channel dysfunction, severe combined immunodeficiency, non-SCID combined immunodeficiency, combined immunodeficiency due to RELA haploinsufficiency, combined immunodeficiency due to GINS1 deficiency, combined immunodeficiency syndrome, combined immunodeficiency due to POLE2 deficiency, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN deficiency, combined immunodeficiency due to TBX1 deficiency, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, combined immunodeficiency due to dimerization defective IKAROS mutation, late-onset combined immunodeficiency due to ICOSL deficiency, combined immunodeficiency-hypogammaglobulinemia-skeletal anomalies syndrome due to IKBKA deficiency, early-onset combined immunodeficiency with low ig due to dominant negative IKAROS mutation, combined immunodeficiency with low Ig due to BCL10 deficiency, IRF4-related combined immunodeficiency, NFATC1-related combined immunodeficiency, POLD3-related combined immunodeficiency

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

300 retrieved; paginated sample, class counts are floors:

166 likely benign, 114 uncertain significance, 12 benign, 4 benign/likely benign, 3 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
140454	NM_001905.4(CTPS1):c.1692-1G>C	CTPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1525045	NM_001905.4(CTPS1):c.899C>G (p.Ser300Cys)	CTPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
640057	NM_001905.4(CTPS1):c.1280C>T (p.Thr427Met)	CTPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
722799	NM_001905.4(CTPS1):c.1276C>G (p.Pro426Ala)	CTPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003254	NM_001905.4(CTPS1):c.1166G>C (p.Arg389Pro)	CTPS1	Uncertain significance	criteria provided, single submitter
1003774	NM_001905.4(CTPS1):c.386C>T (p.Ala129Val)	CTPS1	Uncertain significance	criteria provided, single submitter
1005595	NM_001905.4(CTPS1):c.586C>T (p.Pro196Ser)	CTPS1	Uncertain significance	criteria provided, single submitter
1005750	NM_001905.4(CTPS1):c.1769A>G (p.His590Arg)	CTPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1008047	NM_001905.4(CTPS1):c.1274_1275delinsTT (p.Asp425Val)	CTPS1	Uncertain significance	criteria provided, single submitter
1014681	NM_001905.4(CTPS1):c.1692-3C>T	CTPS1	Uncertain significance	criteria provided, single submitter
1015162	NM_001905.4(CTPS1):c.1697C>T (p.Thr566Ile)	CTPS1	Uncertain significance	criteria provided, single submitter
1025018	NM_001905.4(CTPS1):c.1459G>C (p.Val487Leu)	CTPS1	Uncertain significance	criteria provided, single submitter
1037907	NM_001905.4(CTPS1):c.1057C>T (p.Arg353Cys)	CTPS1	Uncertain significance	criteria provided, single submitter
1040037	NM_001905.4(CTPS1):c.1007A>T (p.Tyr336Phe)	CTPS1	Uncertain significance	criteria provided, single submitter
1053480	NM_001905.4(CTPS1):c.1450-4A>G	CTPS1	Uncertain significance	criteria provided, single submitter
1054524	NM_001905.4(CTPS1):c.1237G>A (p.Val413Met)	CTPS1	Uncertain significance	criteria provided, single submitter
1061770	NM_001905.4(CTPS1):c.1253A>G (p.Asp418Gly)	CTPS1	Uncertain significance	criteria provided, single submitter
1364394	NM_001905.4(CTPS1):c.1235A>G (p.Asn412Ser)	CTPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1370369	NM_001905.4(CTPS1):c.115A>G (p.Ile39Val)	CTPS1	Uncertain significance	criteria provided, single submitter
1372863	NM_001905.4(CTPS1):c.752A>G (p.Tyr251Cys)	CTPS1	Uncertain significance	criteria provided, single submitter
1373764	NM_001905.4(CTPS1):c.361A>G (p.Ile121Val)	CTPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1393948	NM_001905.4(CTPS1):c.1327C>A (p.Gln443Lys)	CTPS1	Uncertain significance	criteria provided, single submitter
1400625	NM_001905.4(CTPS1):c.1040C>T (p.Ser347Leu)	CTPS1	Uncertain significance	criteria provided, single submitter
1410532	NC_000001.10:g.(?41474523)(41510926_?)del	CTPS1	Uncertain significance	criteria provided, single submitter
1464162	NM_001905.4(CTPS1):c.555+5G>A	CTPS1	Uncertain significance	criteria provided, single submitter
1475401	NM_001905.4(CTPS1):c.98A>G (p.His33Arg)	CTPS1	Uncertain significance	criteria provided, single submitter
1480864	NM_001905.4(CTPS1):c.438+1G>A	CTPS1	Uncertain significance	criteria provided, single submitter
1481234	NM_001905.4(CTPS1):c.137A>G (p.Asp46Gly)	CTPS1	Uncertain significance	criteria provided, single submitter
1484441	NM_001905.4(CTPS1):c.1727C>G (p.Pro576Arg)	CTPS1	Uncertain significance	criteria provided, single submitter
1495678	NM_001905.4(CTPS1):c.1622T>C (p.Phe541Ser)	CTPS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
CTPS1	Strong	Autosomal recessive	combined immunodeficiency due to CTPS1 deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTPS1	Orphanet:420573	Severe combined immunodeficiency due to CTPS1 deficiency

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
CTPS1	HGNC:2519	ENSG00000171793	P17812	CTP synthase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTPS1	CTP synthase 1	CTP synthase involved in the de novo synthesis of CTP, a precursor of DNA, RNA and phospholipids.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTPS1	Other/Unknown	no		CTP_synthase, CTP_synthase_N, GATASE

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
ascending aorta	1
parotid gland	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTPS1	236	ubiquitous	marker	parotid gland, ascending aorta, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTPS1	4,144

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTPS1	P17812	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.003	CTPS1

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
‘de novo’ CTP biosynthetic process	1	8426.0×	8e-04	CTPS1
pyrimidine nucleobase biosynthetic process	1	5617.3×	8e-04	CTPS1
negative regulation of chromosome condensation	1	4213.0×	8e-04	CTPS1
CTP biosynthetic process	1	1685.2×	0.001	CTPS1
DNA repair-dependent chromatin remodeling	1	674.1×	0.003	CTPS1
nucleobase-containing compound metabolic process	1	526.6×	0.003	CTPS1
negative regulation of type I interferon production	1	495.6×	0.003	CTPS1
B cell proliferation	1	481.5×	0.003	CTPS1
T cell proliferation	1	383.0×	0.003	CTPS1
response to xenobiotic stimulus	1	69.1×	0.014	CTPS1

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
CTPS1	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
CTPS1	11	Binding:11

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CTPS1

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)
CTPS1	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.