Is CPS1 p.Pro265Leu (c.794C>T) pathogenic?

CPS1 p.Pro265Leu (c.794C>T) is classified Likely pathogenic in CPS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-08). AlphaMissense: likely pathogenic (0.6491); Very rare (popmax 0.00223%, eas); Associated with pulmonary hypertension, neonatal, susceptibility to.

What condition is associated with CPS1 p.Pro265Leu (c.794C>T)?

CPS1 p.Pro265Leu (c.794C>T) is associated with pulmonary hypertension, neonatal, susceptibility to, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Pro265Leu (c.794C>T) in the general population?

CPS1 p.Pro265Leu (c.794C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CPS1 p.Pro265Leu (c.794C>T)?

AlphaMissense predicts likely pathogenic (score 0.6491) — an in-silico prediction, not a clinical call.

CPS1 p.Pro265Leu

c.794C>T · rs1433029121 · VCV2445716

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary hypertension, neonatal, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.6491	likely pathogenic ✓ concordant with ClinVar
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,828 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000411% 6/1,460,800 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,828
Admixed American	0.00167%	59,944
South Asian	0.0011%	91,058
European (non-Finnish)	0.000254%	393,063

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.Pro265Leu
Coding: c.794C>T
MANE Select: NM_001875
dbSNP: rs1433029121
Type: single nucleotide variant
Location: chr2:210590188 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 265: the glutamine amidotransferase type-1 domain

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

Disease context

pulmonary hypertension, neonatal, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

CPS1 p.Pro265Thr Uncertain significance ★ ⚠ same residue
CPS1 p.Pro265= Likely benign ★ same residue
CPS1 p.Pro265Arg 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

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-pro265leu (accessed [today's date]).

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