Is CPS1 p.Arg682His (c.2045G>A) pathogenic?

CPS1 p.Arg682His (c.2045G>A) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-10). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with CPS1 p.Arg682His (c.2045G>A)?

CPS1 p.Arg682His (c.2045G>A) is associated with Inborn genetic diseases, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Arg682His (c.2045G>A) in the general population?

CPS1 p.Arg682His (c.2045G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CPS1 p.Arg682His (c.2045G>A)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

CPS1 p.Arg682His

c.2045G>A · rs778764720 · VCV2256448

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.54	GERP -5
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	16.48	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 0.00401% African / African-American · 3/74,780 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00236% 38/1,612,454 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,927
South Asian	0.00329%	30,353
European (non-Finnish)	0.00254%	39,303
Admixed American	0.00167%	59,802
Remaining individualsnot grpmax-eligible	0.0016%	62,384

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.Arg682His
Coding: c.2045G>A
MANE Select: NM_001875
dbSNP: rs778764720
Type: single nucleotide variant
Location: chr2:210606794 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 682: the atp-grasp 1 domain; an α-helix

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.Arg682Cys Uncertain significance ★ ⚠ 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-arg682his (accessed [today's date]).

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