Is CPS1 p.Asp654= (c.1962T>C) pathogenic?

CPS1 p.Asp654= (c.1962T>C) is classified Likely benign in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-03). Very rare (popmax 0.00769%, sas); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Asp654= (c.1962T>C)?

CPS1 p.Asp654= (c.1962T>C) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Asp654= (c.1962T>C) in the general population?

CPS1 p.Asp654= (c.1962T>C) is very rare (popmax 0.00769%, sas) (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.Asp654=

c.1962T>C · rs1293382951 · VCV2913679

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.15	GERP -5.4, phastCons 0.99
Overall
CADD	4.624	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,044 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000496% 8/1,612,000 alleles · very rare exomes 7/1,460,048 · genomes 1/151,952 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,006
European (non-Finnish)	8.48e-05%	1,178,692

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.Asp654=
Coding: c.1962T>C
MANE Select: NM_001875
dbSNP: rs1293382951
Type: single nucleotide variant
Location: chr2:210605227 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 654: a UniProt-annotated variant site (in cps1d); the atp-grasp 1 domain; a β-strand

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 p.Asp654Val Uncertain significance ★ ⚠ same residue
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

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-asp654 (accessed [today's date]).

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