carbamoyl phosphate synthetase I deficiency disease

Summary

carbamoyl phosphate synthetase I deficiency disease (MONDO:0009376) is a disease caused by CPS1 (GenCC Definitive), with 3 cohort genes and 3 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: CPS1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,958
• Phenotypes (HPO): 7
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000		Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.19	Finland	Validated
Prevalence at birth	<1 / 1 000 000	0.077	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.125	Japan	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001951	Episodic ammonia intoxication	Very frequent (80-99%)
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0003355	Aminoaciduria	Very frequent (80-99%)
HP:0005961	Hypoargininemia	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	carbamoyl phosphate synthetase I deficiency disease
Mondo ID	MONDO:0009376
EFO	EFO:0007193
MeSH	D020165
OMIM	237300
Orphanet	147
DOID	DOID:9280
ICD-11	327894003
NCIT	C84612
SNOMED CT	62522004
UMLS	C4082171
MedGen	907954
GARD	0007269
MedDRA	10058297
NORD	889
Is cancer (heuristic)	no

Also known as: carbamoyl phosphate synthetase deficiency · carbamoyl phosphate synthetase I deficiency disease · carbamoyl-phosphate synthase deficiency disease · carbamoyl-phosphate synthetase deficiency · carbamoyl-phosphate synthetase I deficiency · carbamoylphosphate synthetase I deficiency · carbamyl phosphate synthetase (CPS) deficiency · CPS1 deficiency · CPS1D · hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency

Data availability: 1,958 ClinVar variants · 5 GenCC gene-disease records · 7 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › urea cycle disorder › urea cycle disorder or inherited hyperammonemia › carbamoyl phosphate synthetase I deficiency disease

Related subtypes (9): arginase deficiency, argininosuccinic aciduria, citrullinemia type I, hyperammonemia due to N-acetylglutamate synthase deficiency, ornithine translocase deficiency, ornithine carbamoyltransferase deficiency, hyperinsulinism-hyperammonemia syndrome, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency, citrin 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

600 retrieved; paginated sample, class counts are floors:

393 likely benign, 81 uncertain significance, 57 likely pathogenic, 28 pathogenic, 19 benign, 12 pathogenic/likely pathogenic, 10 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1001895	NM_001875.5(CPS1):c.1141_1149del (p.Thr381_Gly383del)	CPS1	Pathogenic	criteria provided, single submitter
1066946	NM_001875.5(CPS1):c.3607T>C (p.Ser1203Pro)	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068809	NM_001875.5(CPS1):c.2051C>G (p.Ser684Ter)	CPS1	Pathogenic	criteria provided, single submitter
1069202	NM_001875.5(CPS1):c.1432C>T (p.Gln478Ter)	CPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069203	NM_001875.5(CPS1):c.1549+1G>T	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069282	NM_001875.5(CPS1):c.4191G>A (p.Trp1397Ter)	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070017	NC_000002.11:g.(?211421433)(211421593_?)del	CPS1	Pathogenic	criteria provided, single submitter
1070018	NC_000002.11:g.(?211441050)(211542729_?)del	CPS1	Pathogenic	criteria provided, single submitter
1070204	NM_001875.5(CPS1):c.1424del (p.Gly475fs)	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071808	NM_001875.5(CPS1):c.2171_2175del (p.Ala724fs)	CPS1	Pathogenic	criteria provided, single submitter
1072514	NM_001875.5(CPS1):c.2470_2482del (p.Thr824fs)	CPS1	Pathogenic	criteria provided, single submitter
1076647	NM_001875.5(CPS1):c.3520C>T (p.Arg1174Ter)	CPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076733	NM_001875.5(CPS1):c.1112del (p.Phe371fs)	CPS1	Pathogenic	criteria provided, single submitter
1076846	NM_001875.5(CPS1):c.3763G>T (p.Glu1255Ter)	CPS1	Pathogenic	criteria provided, single submitter
1172776	NM_001875.5(CPS1):c.1164+2T>C	CPS1	Pathogenic	criteria provided, single submitter
1192241	NM_001875.5(CPS1):c.2798del (p.Arg932_Leu933insTer)	CPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1321400	NM_001875.5(CPS1):c.1770T>G (p.Tyr590Ter)	CPS1	Pathogenic	criteria provided, single submitter
1343551	NM_001875.5(CPS1):c.3337-1G>T	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1360857	NM_001875.5(CPS1):c.2403dup (p.Gly802fs)	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361235	NM_001875.5(CPS1):c.420C>A (p.Tyr140Ter)	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381784	NM_001875.5(CPS1):c.3666+1G>T	CPS1	Pathogenic	criteria provided, single submitter
1400087	NM_001875.5(CPS1):c.3380T>A (p.Leu1127Ter)	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1408700	NM_001875.5(CPS1):c.1509del (p.Gly503_Leu504insTer)	CPS1	Pathogenic	criteria provided, single submitter
1435669	NM_001875.5(CPS1):c.2408dup (p.Thr804fs)	CPS1	Pathogenic	criteria provided, single submitter
1444282	NC_000002.12:g.210577425_210577431del	CPS1	Pathogenic	criteria provided, single submitter
1450174	NM_001875.5(CPS1):c.2819G>A (p.Trp940Ter)	CPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452254	NM_001875.5(CPS1):c.3307C>T (p.Gln1103Ter)	CPS1	Pathogenic	criteria provided, single submitter
1453334	NM_001875.5(CPS1):c.4159A>T (p.Lys1387Ter)	CPS1	Pathogenic	criteria provided, single submitter
1454065	NM_001875.5(CPS1):c.3935dup (p.Met1312fs)	CPS1	Pathogenic	criteria provided, single submitter
1455500	NM_001875.5(CPS1):c.1468C>T (p.Gln490Ter)	CPS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
CPS1	Definitive	Autosomal recessive	carbamoyl phosphate synthetase I deficiency disease	5
PM20D1	Definitive	Autosomal recessive	carbamoyl phosphate synthetase I deficiency disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CPS1	Orphanet:147	Carbamoyl-phosphate synthetase 1 deficiency
ABCA3	Orphanet:2032	Idiopathic pulmonary fibrosis
ABCA3	Orphanet:217563	Neonatal acute respiratory distress syndrome
ABCA3	Orphanet:440402	Interstitial lung disease due to ABCA3 deficiency
ABCA3	Orphanet:685082	Pediatric acute respiratory distress syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CPS1	HGNC:2323	ENSG00000021826	P31327	Carbamoyl-phosphate synthase [ammonia], mitochondrial	gencc,clinvar
PM20D1	HGNC:26518	ENSG00000162877	Q6GTS8	N-fatty-acyl-amino acid synthase/hydrolase PM20D1	gencc,clinvar
ABCA3	HGNC:33	ENSG00000167972	Q99758	Phospholipid-transporting ATPase ABCA3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CPS1	Carbamoyl-phosphate synthase [ammonia], mitochondrial	Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
PM20D1	N-fatty-acyl-amino acid synthase/hydrolase PM20D1	Secreted enzyme that regulates the endogenous N-fatty acyl amino acid (NAAs) tissue and circulating levels by functioning as a bidirectional NAA synthase/hydrolase.
ABCA3	Phospholipid-transporting ATPase ABCA3	Catalyzes the ATP-dependent transport of phospholipids such as phosphatidylcholine and phosphoglycerol from the cytoplasm into the lumen side of lamellar bodies, in turn participates in the lamellar bodies biogenesis and homeostasis of pul…

Protein-family classification

Druggable: 3 · 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
Transporter	1	25.9×	0.114
Protease	1	12.2×	0.120
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CPS1	Enzyme (other)	yes	6.3.4.16	CarbamoylP_synth_ssu_N, CPAse_ATP-bd, CPSase_lsu_oligo
PM20D1	Protease	yes		Peptidase_M20, Peptidase_M20_dimer, Bact_exopeptidase_dim_dom
ABCA3	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
liver	1
right lobe of liver	1
mammalian vulva	1
upper arm skin	1
upper leg skin	1
lower lobe of lung	1
upper lobe of left lung	1
upper lobe of lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CPS1	209	ubiquitous	marker	liver, right lobe of liver, jejunal mucosa
PM20D1	144	tissue_specific	marker	upper leg skin, upper arm skin, mammalian vulva
ABCA3	222	ubiquitous	marker	lower lobe of lung, upper lobe of lung, upper lobe of left lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CPS1	2,830
PM20D1	1,692
ABCA3	1,436

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CPS1	P31327	14
ABCA3	Q99758	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PM20D1	Q6GTS8	89.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCA3 causes SMDP3	1	3806.7×	0.001	ABCA3
CPS1 variants cause CPS1 deficiency	1	3806.7×	0.001	CPS1
Oleoyl-phe metabolism	1	1903.3×	0.002	PM20D1
Diseases associated with surfactant metabolism	1	951.7×	0.003	ABCA3
Urea cycle	1	292.8×	0.009	CPS1
ABC transporters in lipid homeostasis	1	200.3×	0.011	ABCA3
ABC transporter disorders	1	146.4×	0.013	ABCA3
Surfactant metabolism	1	122.8×	0.014	ABCA3
Disorders of transmembrane transporters	1	46.4×	0.032	ABCA3
ABC-family protein mediated transport	1	40.5×	0.033	ABCA3
Diseases of metabolism	1	26.8×	0.046	ABCA3
Transport of small molecules	1	8.4×	0.132	ABCA3
Disease	1	4.4×	0.223	ABCA3
Metabolism of proteins	1	4.1×	0.223	ABCA3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of protein homooligomerization	1	5617.3×	0.004	ABCA3
carbamoyl phosphate biosynthetic process	1	5617.3×	0.004	CPS1
obsolete amide biosynthetic process	1	2808.7×	0.004	PM20D1
monoatomic anion homeostasis	1	2808.7×	0.004	CPS1
regulation of phosphatidylcholine metabolic process	1	2808.7×	0.004	ABCA3
xenobiotic export from cell	1	1872.4×	0.004	ABCA3
cellular response to oleic acid	1	1872.4×	0.004	CPS1
L-citrulline biosynthetic process	1	1404.3×	0.004	CPS1
positive regulation of phospholipid efflux	1	1404.3×	0.004	ABCA3
response to xenobiotic stimulus	2	46.0×	0.004	CPS1, ABCA3
cellular response to ammonium ion	1	1123.5×	0.004	CPS1
‘de novo’ pyrimidine nucleobase biosynthetic process	1	936.2×	0.004	CPS1
regulation of lipid biosynthetic process	1	936.2×	0.004	ABCA3
organelle assembly	1	936.2×	0.004	ABCA3
positive regulation of phospholipid transport	1	802.5×	0.004	ABCA3
midgut development	1	702.2×	0.005	CPS1
obsolete amide catabolic process	1	702.2×	0.005	PM20D1
response to amine	1	624.1×	0.005	CPS1
homocysteine metabolic process	1	624.1×	0.005	CPS1
response to alcohol	1	510.7×	0.005	CPS1
nitric oxide metabolic process	1	468.1×	0.005	CPS1
phosphatidylglycerol metabolic process	1	468.1×	0.005	ABCA3
urea cycle	1	432.1×	0.005	CPS1
L-glutamine metabolic process	1	432.1×	0.005	CPS1
hepatocyte differentiation	1	401.2×	0.005	CPS1
response to dexamethasone	1	401.2×	0.005	CPS1
response to growth hormone	1	374.5×	0.005	CPS1
adaptive thermogenesis	1	351.1×	0.005	PM20D1
response to amino acid	1	330.4×	0.005	CPS1
phospholipid homeostasis	1	330.4×	0.005	ABCA3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CPS1	0	0
PM20D1	0	0
ABCA3	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
CPS1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CPS1	6.3.4.16	carbamoyl-phosphate synthase (ammonia)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	CPS1, ABCA3
D	Druggable family + AlphaFold only, no drug	1	PM20D1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CPS1	3	—
PM20D1	0	—
ABCA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00718627	PHASE2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan