Is CPS1 p.Ala675= (c.2025C>T) pathogenic?

CPS1 p.Ala675= (c.2025C>T) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-24). Rare (popmax 0.144%, nfe); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Ala675= (c.2025C>T)?

CPS1 p.Ala675= (c.2025C>T) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Ala675= (c.2025C>T) in the general population?

CPS1 p.Ala675= (c.2025C>T) is rare (popmax 0.144%, nfe) (gnomAD).

How is Carbamoyl-phosphate synthetase 1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CPS1 p.Ala675=

c.2025C>T · rs143913650 · VCV382478

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.144%, nfe)

Conditions

carbamoyl phosphate synthetase I deficiency disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -5.8
Overall
CADD	1.745	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.144% European (non-Finnish) · 1,694/1,179,060 alleles

Filtering AF 0.138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.136%

Overall 0.111% 1,786/1,612,528 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.144%	696
Remaining individualsnot grpmax-eligible	0.0673%	1,486
African / African-American	0.024%	4,162
Finnishnot grpmax-eligible	0.0234%	4,266
South Asian	0.0143%	7,005
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,526
Admixed American	0.00334%	29,906
East Asian	0.00223%	44,796

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CPS1
Protein: p.Ala675=
Coding: c.2025C>T
MANE Select: NM_001875
dbSNP: rs143913650
Type: single nucleotide variant
Location: chr2:210606774 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 675: the atp-grasp 1 domain; an α-helix

Full CPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

carbamoyl phosphate synthetase I deficiency disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Carbamoyl-phosphate synthetase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CPS1 c.1086+1G>A Likely pathogenic ★★ same condition
CPS1 c.1087-1G>T Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1165-2A>G Likely pathogenic ★★ same condition
CPS1 c.1263+5G>C Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1549+1G>A Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1549+1G>T Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1837-8A>G Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1981+1G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cps1-p-ala675 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown