Is CPS1 p.Ala438Pro (c.1312G>C) pathogenic?

CPS1 p.Ala438Pro (c.1312G>C) is classified Likely pathogenic in CPS1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.9965); Very rare (popmax 0.00224%, eas); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Ala438Pro (c.1312G>C)?

CPS1 p.Ala438Pro (c.1312G>C) is associated with carbamoyl phosphate synthetase I deficiency disease, pulmonary hypertension, neonatal, susceptibility to (ClinVar).

How common is CPS1 p.Ala438Pro (c.1312G>C) in the general population?

CPS1 p.Ala438Pro (c.1312G>C) is very rare (popmax 0.00224%, eas) (gnomAD).

How is Carbamoyl-phosphate synthetase 1 deficiency inherited?

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

What do computational predictors say about CPS1 p.Ala438Pro (c.1312G>C)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

CPS1 p.Ala438Pro

c.1312G>C · rs772497399 · VCV449391

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carbamoyl phosphate synthetase I deficiency disease

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic ✓ concordant with ClinVar · top 6% in CPS1
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -10.91	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 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	32.0	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 0.00224% East Asian · 1/44,718 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000548% 8/1,459,714 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,718
Remaining individualsnot grpmax-eligible	0.0016%	62,346
European (non-Finnish)	0.000509%	196,408

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.Ala438Pro
Coding: c.1312G>C
MANE Select: NM_001875
dbSNP: rs772497399
Type: single nucleotide variant
Location: chr2:210595535 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 438: a UniProt-annotated variant site (in cps1d; almost complete loss of enzyme activity); a UniProt-annotated variant site (in cps1d)

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

Also linked: pulmonary hypertension, neonatal, susceptibility to

For Carbamoyl-phosphate synthetase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CPS1 p.Ala438Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CPS1 p.Ala438Thr 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

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-ala438pro (accessed [today's date]).

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