Is CPS1 p.Pro939Ser (c.2815C>T) pathogenic?

CPS1 p.Pro939Ser (c.2815C>T) is classified Uncertain significance in CPS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-16). AlphaMissense: likely pathogenic (0.7881); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with CPS1 p.Pro939Ser (c.2815C>T)?

CPS1 p.Pro939Ser (c.2815C>T) is associated with Inborn genetic diseases, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Pro939Ser (c.2815C>T) in the general population?

CPS1 p.Pro939Ser (c.2815C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CPS1 p.Pro939Ser (c.2815C>T)?

AlphaMissense predicts likely pathogenic (score 0.7881) — an in-silico prediction, not a clinical call.

CPS1 p.Pro939Ser

c.2815C>T · rs1047579926 · VCV1032778

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7881	likely pathogenic
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -12.29	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,988 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00161% 26/1,613,776 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,996
European (non-Finnish)	0.00178%	56,184
Remaining individualsnot grpmax-eligible	0.0016%	62,468
African / African-American	0.00134%	74,898

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.Pro939Ser
Coding: c.2815C>T
MANE Select: NM_001875
dbSNP: rs1047579926
Type: single nucleotide variant
Location: chr2:210637829 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

CPS1 p.Pro939= 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-pro939ser (accessed [today's date]).

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