Is CPS1 p.Asp358His (c.1072G>C) pathogenic?

CPS1 p.Asp358His (c.1072G>C) is classified Uncertain significance in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-24). AlphaMissense: likely pathogenic (0.9877); Very rare (popmax 0.00401%, afr).

How common is CPS1 p.Asp358His (c.1072G>C) in the general population?

CPS1 p.Asp358His (c.1072G>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CPS1 p.Asp358His (c.1072G>C)?

AlphaMissense predicts likely pathogenic (score 0.9877) — an in-silico prediction, not a clinical call.

CPS1 p.Asp358His

c.1072G>C · VCV3339351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9877	likely pathogenic
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -13.09	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	29.5	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 0.00401% African / African-American · 3/74,772 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,611,354 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,924
Remaining individualsnot grpmax-eligible	0.00161%	62,298

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.Asp358His
Coding: c.1072G>C
MANE Select: NM_001875
Type: single nucleotide variant
Location: chr2:210591955 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 358: a UniProt-annotated variant site (in cps1d); the glutamine amidotransferase type-1 domain; a turn

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

Similar variants

CPS1 c.1086+1G>A Likely pathogenic ★★ same type
CPS1 c.1087-1G>T Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1165-2A>G Likely pathogenic ★★ same type
CPS1 c.1263+5G>C Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1549+1G>A Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1549+1G>T Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1837-8A>G Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1981+1G>C Likely pathogenic ★★ same type

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-asp358his (accessed [today's date]).

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