CPS1

Chr 2AR

carbamoyl-phosphate synthase 1

Also known as: CPS1D, CPSASE1, GATD6, PHN

NCBI Gene: 1373ENSG00000021826UniProt: P31327

The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.[provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

Carbamoylphosphate synthetase I deficiencyMIM #237300
AR
UniProtCarbamoyl phosphate synthetase 1 deficiency
376
ClinVar variants
56
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— CPS1
🧬
Gene-Disease Validity (ClinGen)
carbamoyl phosphate synthetase I deficiency disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
56 Pathogenic / Likely Pathogenic· 161 VUS of 376 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.52LOEUF
pLI 0.000
Z-score 5.08
OE 0.38 (0.28–0.52)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.46Z-score
OE missense 0.85 (0.80–0.91)
681 obs / 797.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.38 (0.28–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.80–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 30 / 78.7Missense obs/exp: 681 / 797.0Syn Z: -1.29

ClinVar Variant Classifications

376 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic37
VUS161
Likely Benign151
Benign3
Conflicting5
19
Pathogenic
37
Likely Pathogenic
161
VUS
151
Likely Benign
3
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
2
12
0
19
Likely Pathogenic
20
11
6
0
37
VUS
1
132
18
10
161
Likely Benign
0
2
64
85
151
Benign
0
0
3
0
3
Conflicting
—5
Total2614710395376

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CPS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CPS1-related carbamoyl phosphate synthetase 1 deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Carbamoylphosphate synthetase I deficiency

MIM #237300

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CPS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma.
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu et al.·Cell
2017
Expanding the genotypes and phenotypes for 19 rare diseases by exome sequencing performed in pediatric intensive care unit.
Liu J et al.·Hum Mutat
2021
CPS1: Looking at an ancient enzyme in a modern light.
Nitzahn M et al.·Mol Genet Metab
2020Review
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Integrative metabolomics and genomics reveal molecular signatures for type 2 diabetes and its cardiovascular complications.
Cheng C et al.·Cardiovasc Diabetol
2025
Clinical and genetic analysis of a case of late onset carbamoyl phosphate synthase I deficiency caused by CPS1 mutation and literature review.
Wang S et al.·BMC Med Genomics
2023Review
Expression and clinical significance of CPS1 in glioblastoma multiforme.
Wu G et al.·Curr Res Transl Med
2019
Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency.
Dong H et al.·BMC Pediatr
2024Cohort
Single-cell multi-omics uncovers CPS1 as a breast cancer immune evasion therapeutic target.
Yue J et al.·Sci Rep
2025
A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system.
Bakshi S et al.·Dis Model Mech
2025Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Quantitative acetylomic analysis reveals a key role of acetylation site 1168K in carbamoyl-phosphate synthase 1 (CPS1) following exposure to PFOA and PFO4DA in mouse liver.
Chen J et al.·Environ Pollut
2026Functional
CPS1: a multipurpose mitochondrial enzyme, bile protein, acute liver injury biomarker, and cytokine.
Chen L et al.·Gut
2026
Pulmonary Solid and Granular Adenocarcinomas Expressing HepPar1/CPS1: Highly Aggressive Tumors Exhibiting Mitochondrial Adaptation to STK11 Mutations Rather Than Hepatoid Differentiation.
Febres-Aldana CA et al.·Mod Pathol
2026
Targeting CPS1 attenuates lung cancer metastasis by regulating EMT through an epigenetic mechanism.
Ding Y et al.·Theranostics
2026🔓 Open AccessFunctional
CircSETD2 impairs hepatic lipid homeostasis in metabolic dysfunction-associated fatty liver disease by binding CPS1.
Xie X et al.·Int J Biol Macromol
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Congenital Adrenal Hyperplasia

A Study of Gene Therapy for Classic Congenital Adrenal Hyperplasia (CAH)

ACTIVE NOT RECRUITING
NCT04783181Phase PHASE1, PHASE2Adrenas Therapeutics IncStarted 2021-07-01
AAV BBP-631
Variant Nucleotide

Solving Challenging Diagnoses Through Ultra-long Read Sequencing

ACTIVE NOT RECRUITING
NCT06775613Phase NAIRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2023-03-10
Long-read sequencing
Esophageal Squamous Cell Carcinoma

Pembrolizumab Plus Chemo in Neoadjuvant Treatment of Esophageal Squamous Cell Carcinoma (Eastern Cooperative Thoracic Oncology Projects 2004, ECTOP-2004)

RECRUITING
NCT05281003Phase PHASE2Fudan UniversityStarted 2023-02-20
PembrolizumabPaclitaxelCisplatin
CAH - 21-Hydroxylase Deficiency

Parenting and CAH - 21-hydroxylase Deficiency

NOT YET RECRUITING
NCT06900153Assistance Publique - Hôpitaux de ParisStarted 2025-12
phone questionnaire

External Resources

Links to major genomics databases and tools