Is CPS1 p.Arg1089His (c.3266G>A) pathogenic?

CPS1 p.Arg1089His (c.3266G>A) is classified Likely pathogenic in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.9911); Very rare (popmax 0.0022%, sas); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Arg1089His (c.3266G>A)?

CPS1 p.Arg1089His (c.3266G>A) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Arg1089His (c.3266G>A) in the general population?

CPS1 p.Arg1089His (c.3266G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Carbamoyl-phosphate synthetase 1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CPS1 p.Arg1089His (c.3266G>A)?

AlphaMissense predicts likely pathogenic (score 0.9911) — an in-silico prediction, not a clinical call.

CPS1 p.Arg1089His

c.3266G>A · rs1280211937 · VCV2994736

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carbamoyl phosphate synthetase I deficiency disease

Computational evidence

Protein change
AlphaMissense	0.9911	likely pathogenic ✓ concordant with ClinVar · top 10% in CPS1
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -13.41	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 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	32.0	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 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.00031% 5/1,613,852 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,242
South Asiangrpmax	0.0022%	45,544
Finnishnot grpmax-eligible	0.00156%	64,036

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.Arg1089His
Coding: c.3266G>A
MANE Select: NM_001875
dbSNP: rs1280211937
Type: single nucleotide variant
Location: chr2:210647987 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 1089: a UniProt-annotated variant site (in cps1d); an α-helix

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

Disease context

carbamoyl phosphate synthetase I deficiency disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Carbamoyl-phosphate synthetase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CPS1 p.Arg1089Leu Pathogenic ★ same residue
CPS1 p.Arg1089Pro Likely pathogenic ★ same residue
CPS1 p.Arg1089Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CPS1 p.Arg1089= 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

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-arg1089his (accessed [today's date]).

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