Is CPS1 p.Pro346Ser (c.1036C>T) pathogenic?

CPS1 p.Pro346Ser (c.1036C>T) is classified Benign in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). AlphaMissense: likely benign (0.2364); Very rare (popmax 8.48e-05%, nfe); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Pro346Ser (c.1036C>T)?

CPS1 p.Pro346Ser (c.1036C>T) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Pro346Ser (c.1036C>T) in the general population?

CPS1 p.Pro346Ser (c.1036C>T) is very rare (popmax 8.48e-05%, nfe) (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.Pro346Ser (c.1036C>T)?

AlphaMissense predicts likely benign (score 0.2364) — an in-silico prediction, not a clinical call.

CPS1 p.Pro346Ser

c.1036C>T · rs1559093517 · VCV2171457

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carbamoyl phosphate synthetase I deficiency disease

Computational evidence

Protein change
AlphaMissense	0.2364	likely benign
REVEL	0.759	pathogenic-leaning
SaProt	LLR -11.84	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.5	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 8.48e-05% European (non-Finnish) · 1/1,178,996 alleles

Overall 0.000137% 2/1,460,234 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,368
European (non-Finnish)grpmax	8.48e-05%	1,178,996

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro346Ser
Coding: c.1036C>T
MANE Select: NM_001875
dbSNP: rs1559093517
Type: single nucleotide variant
Location: chr2:210591919 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 346: the glutamine amidotransferase type-1 domain

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.Pro346= Likely benign ★ 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-pro346ser (accessed [today's date]).

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