CPS1

carbamoyl-phosphate synthase 1, the group of Glutamine amidotransferase class 1 domain containing

Basic information

Region (hg38): 2:210477682-210679107

Links

ENSG00000021826 ∙ NCBI:1373 ∙ OMIM:608307 ∙ HGNC:2323 ∙ Uniprot:P31327 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• carbamoyl phosphate synthetase I deficiency disease (Definitive), mode of inheritance: AR
• carbamoyl phosphate synthetase I deficiency disease (Definitive), mode of inheritance: AR
• carbamoyl phosphate synthetase I deficiency disease (Strong), mode of inheritance: AR
• carbamoyl phosphate synthetase I deficiency disease (Supportive), mode of inheritance: AR
• carbamoyl phosphate synthetase I deficiency disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Carbamoylphosphate synthetase I deficiency	AR	Biochemical; Pharmacogenomic	Specific urgent and long-term medical management (eg, dietary measures, arginine, sodium benzoate, sodium phenylbutyrate), as well as measures such as dialysis when necessary, may be beneficial to reduce morbidity and mortality; Avoidance of certain agents (eg, valproate), as well as special considerations in situations such as peregnancy, are warranted due to potential adverse events	Biochemical; Neurologic	5356974; 5471650; 4111816; 4811018; 7078580; 6427608; 3759432; 3792387; 1414247; 8486760; 8273985; 9711878; 21120950; 16708072; 17310273; 19793055; 21120950; 22173106; 25135652; 25410056

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CPS1 gene.

• Congenital hyperammonemia, type I (84 variants)
• Pulmonary hypertension, neonatal, susceptibility to (17 variants)
• not provided (2 variants)
• Congenital hyperammonemia, type I;Pulmonary hypertension, neonatal, susceptibility to (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CPS1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				532	6	538
missense	5	34	271	46	10	366
nonsense	32	65	1			98
start loss		1	2			3
frameshift	44	57				101
inframe indel	3	2	3		1	9
splice donor/acceptor (+/-2bp)	8	61	3			72
splice region		4	28	115	10	157
non coding			23	347	95	465
Total	92	220	303	925	112

Highest pathogenic variant AF is 0.0000330

Variants in CPS1

This is a list of pathogenic ClinVar variants found in the CPS1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-210477693-A-ATAGTTGCTTTCTTAGGAAATG		not specified	Likely benign (Jun 28, 2016)
2-210477748-G-A		not specified	Benign (Mar 14, 2016)
2-210477765-T-G		Congenital hyperammonemia, type I	Uncertain significance (Dec 04, 2017)
2-210477778-G-A		not specified • Congenital hyperammonemia, type I	Benign (Jul 10, 2021)
2-210556381-G-T			Likely benign (Jan 09, 2020)
2-210556398-C-A			Benign (Oct 08, 2020)
2-210556540-G-A			Benign (Oct 17, 2018)
2-210556606-G-A		Congenital hyperammonemia, type I	Likely benign (Jan 16, 2019)
2-210556658-A-G		Congenital hyperammonemia, type I	Uncertain significance (Jan 13, 2018)
2-210556705-T-G		Congenital hyperammonemia, type I • not specified • CPS1-related disorder	Benign (Jan 13, 2018)
2-210556728-A-ATCT		not specified • Congenital hyperammonemia, type I	Benign (Jul 30, 2021)
2-210556730-C-A		Congenital hyperammonemia, type I • CPS1-related disorder	Uncertain significance (Jan 12, 2018)
2-210556731-A-TTCC		Congenital hyperammonemia, type I	Uncertain significance (Dec 01, 2017)
2-210556736-G-T		Congenital hyperammonemia, type I	Likely pathogenic (Sep 26, 2017)
2-210556738-C-T		Congenital hyperammonemia, type I • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 29, 2024)
2-210556739-G-A		Congenital hyperammonemia, type I	Likely benign (Jan 29, 2024)
2-210556741-G-T		Congenital hyperammonemia, type I	Uncertain significance (Jun 16, 2022)
2-210556742-G-A		Congenital hyperammonemia, type I	Likely benign (Jun 03, 2021)
2-210556748-G-C		Congenital hyperammonemia, type I	Uncertain significance (Aug 13, 2020)
2-210556750-C-T		Congenital hyperammonemia, type I	Likely benign (Feb 11, 2023)
2-210556751-A-G		Congenital hyperammonemia, type I	Likely benign (Jun 05, 2023)
2-210556758-A-T		Congenital hyperammonemia, type I	Pathogenic/Likely pathogenic (Jan 16, 2024)
2-210556760-A-G		Congenital hyperammonemia, type I	Likely benign (Mar 07, 2023)
2-210556766-G-A		Congenital hyperammonemia, type I	Likely benign (Dec 06, 2020)
2-210556772-A-C		Congenital hyperammonemia, type I	Likely benign (May 21, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CPS1	protein_coding	protein_coding	ENST00000430249	39	201426

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.09e-9	1.00	125680	0	68	125748	0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.46	681	797	0.854	0.0000417	9875
Missense in Polyphen		231	315.4	0.7324		3872
Synonymous	-1.29	309	281	1.10	0.0000146	2928
Loss of Function	5.08	30	78.7	0.381	0.00000388	981

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000239	0.000239
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.000435	0.000435
Finnish	0.000323	0.000323
European (Non-Finnish)	0.000344	0.000316
Middle Eastern	0.000435	0.000435
South Asian	0.000196	0.000196
Other	0.000491	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
• Disease: DISEASE: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:237300]: An autosomal recessive disorder of the urea cycle causing hyperammonemia. It can present as a devastating metabolic disease dominated by severe hyperammonemia in neonates or as a more insidious late-onset condition, generally manifesting as life-threatening hyperammonemic crises under catabolic situations. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation. {ECO:0000269|PubMed:11388595, ECO:0000269|PubMed:11474210, ECO:0000269|PubMed:12655559, ECO:0000269|PubMed:12955727, ECO:0000269|PubMed:15164414, ECO:0000269|PubMed:15617192, ECO:0000269|PubMed:16737834, ECO:0000269|PubMed:17310273, ECO:0000269|PubMed:20578160, ECO:0000269|PubMed:21120950, ECO:0000269|PubMed:22173106, ECO:0000269|PubMed:23649895, ECO:0000269|PubMed:24813853, ECO:0000269|PubMed:26440671, ECO:0000269|PubMed:9711878}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pulmonary hypertension, neonatal (PHN) [MIM:615371]: A disease characterized by elevated pulmonary artery pressure. Pulmonary hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchopulmonary dysplasia, sepsis, or congenital heart disease. {ECO:0000269|PubMed:11407344}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. CPS1 variants influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr- 1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406 (PubMed:11407344). {ECO:0000269|PubMed:11407344}.
• Pathway: Alanine, aspartate and glutamate metabolism - Homo sapiens (human);Nitrogen metabolism - Homo sapiens (human);Arginine biosynthesis - Homo sapiens (human);Argininemia;2-Hydroxyglutric Aciduria (D And L Form);Hyperornithinemia with gyrate atrophy (HOGA);Creatine deficiency, guanidinoacetate methyltransferase deficiency;L-arginine:glycine amidinotransferase deficiency;Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome];Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency);Ammonia Recycling;Citrullinemia Type I;Carbamoyl Phosphate Synthetase Deficiency;Argininosuccinic Aciduria;Urea Cycle;Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Succinic semialdehyde dehydrogenase deficiency;Prolinemia Type II;Prolidase Deficiency (PD);Ornithine Transcarbamylase Deficiency (OTC Deficiency);Arginine and Proline Metabolism;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;Hyperprolinemia Type I;Hyperprolinemia Type II;Ornithine Aminotransferase Deficiency (OAT Deficiency);Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency);Glutamate Metabolism;Amino Acid metabolism;Urea cycle and metabolism of amino groups;Glutamate Glutamine metabolism;Metabolism of polyamines;Metabolism of amino acids and derivatives;Metabolism;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;urea cycle;Pyrimidine nucleotides nucleosides metabolism;Urea cycle (Consensus)

Recessive Scores

• pRec: 0.264

Intolerance Scores

• loftool: 0.0148
• rvis_EVS: -0.63
• rvis_percentile_EVS: 16.81

Haploinsufficiency Scores

• pHI: 0.704
• hipred: Y
• hipred_score: 0.698
• ghis: 0.466

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.980

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Cps1
• Phenotype: homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: cps1
• Affected structure: urea cycle
• Phenotype tag: abnormal
• Phenotype quality: disrupted

Gene ontology

• Biological process: urea cycle;proteolysis;arginine biosynthetic process;nitrogen compound metabolic process;midgut development;response to zinc ion;response to amine;citrulline biosynthetic process;triglyceride catabolic process;response to food;response to lipopolysaccharide;vasodilation;response to starvation;response to amino acid;cellular response to fibroblast growth factor stimulus;nitric oxide metabolic process;homocysteine metabolic process;anion homeostasis;response to growth hormone;hepatocyte differentiation;carbamoyl phosphate biosynthetic process;cellular response to glucagon stimulus;cellular response to oleic acid;response to dexamethasone;cellular response to ammonia
• Cellular component: nucleolus;cytoplasm;mitochondrial inner membrane;mitochondrial matrix;protein-containing complex;mitochondrial nucleoid
• Molecular function: carbamoyl-phosphate synthase (ammonia) activity;endopeptidase activity;calcium ion binding;protein binding;ATP binding;phospholipid binding;glutamate binding;protein-containing complex binding;modified amino acid binding