Is CPS1 p.Ala1138Pro (c.3412G>C) pathogenic?

CPS1 p.Ala1138Pro (c.3412G>C) is classified Uncertain significance in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely pathogenic (0.9967); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CPS1 p.Ala1138Pro (c.3412G>C)?

CPS1 p.Ala1138Pro (c.3412G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CPS1 p.Ala1138Pro (c.3412G>C) in the general population?

CPS1 p.Ala1138Pro (c.3412G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CPS1 p.Ala1138Pro (c.3412G>C)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

CPS1 p.Ala1138Pro

c.3412G>C · rs1484284261 · VCV2308738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic · top 6% in CPS1
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -13.77	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 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	31.0	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 0.000254% European (non-Finnish) · 3/1,179,532 alleles

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

Overall 0.000186% 3/1,613,380 alleles · very rare

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.Ala1138Pro
Coding: c.3412G>C
MANE Select: NM_001875
dbSNP: rs1484284261
Type: single nucleotide variant
Location: chr2:210650370 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 1138: the atp-grasp 2 domain

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

Similar variants

CPS1 p.Ala1138= Likely benign ★ same residue
CPS1 p.Ala1400Thr Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg1004Cys Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg238Gln Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg419Trp Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg689His Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg882Cys Uncertain significance ★★ ⚠ same condition
CPS1 p.Asn558Ser Uncertain significance ★★ ⚠ 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-ala1138pro (accessed [today's date]).

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