Is CPS1 p.Pro1411Ser (c.4231C>T) pathogenic?

CPS1 p.Pro1411Ser (c.4231C>T) is classified Uncertain significance in CPS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-24). AlphaMissense: likely pathogenic (0.6177); Very rare (popmax 0.00154%, nfe); Associated with CPS1-related disorder.

What condition is associated with CPS1 p.Pro1411Ser (c.4231C>T)?

CPS1 p.Pro1411Ser (c.4231C>T) is associated with CPS1-related disorder, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Pro1411Ser (c.4231C>T) in the general population?

CPS1 p.Pro1411Ser (c.4231C>T) is very rare (popmax 0.00154%, nfe) (gnomAD).

What do computational predictors say about CPS1 p.Pro1411Ser (c.4231C>T)?

AlphaMissense predicts likely pathogenic (score 0.6177) — an in-silico prediction, not a clinical call.

CPS1 p.Pro1411Ser

c.4231C>T · rs773857876 · VCV2151495

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00154%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CPS1-related disorder

Computational evidence

Protein change
AlphaMissense	0.6177	likely pathogenic
REVEL	0.624	indeterminate
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.1	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 0.00154% European (non-Finnish) · 18/1,168,256 alleles

Filtering AF 0.000963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000794%

Overall 0.00119% 19/1,601,106 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,016
European (non-Finnish)grpmax	0.00154%	64,903

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.Pro1411Ser
Coding: c.4231C>T
MANE Select: NM_001875
dbSNP: rs773857876
Type: single nucleotide variant
Location: chr2:210675797 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 1411: a UniProt-annotated variant site (in cps1d; modestly decreases enzyme activity); an α-helix; the mgs-like domain

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

Disease context

CPS1-related disorder

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

CPS1 p.Pro1411Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CPS1 p.Pro1411= 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

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-pro1411ser (accessed [today's date]).

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