Is CPS1 p.Arg803Ser (c.2407C>A) pathogenic?

CPS1 p.Arg803Ser (c.2407C>A) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.9829); Very rare (popmax 0.00937%, afr); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Arg803Ser (c.2407C>A)?

CPS1 p.Arg803Ser (c.2407C>A) is associated with carbamoyl phosphate synthetase I deficiency disease, pulmonary hypertension, neonatal, susceptibility to (ClinVar).

How common is CPS1 p.Arg803Ser (c.2407C>A) in the general population?

CPS1 p.Arg803Ser (c.2407C>A) is very rare (popmax 0.00937%, afr) (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.Arg803Ser (c.2407C>A)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

CPS1 p.Arg803Ser

c.2407C>A · rs201716417 · VCV203650

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00937%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carbamoyl phosphate synthetase I deficiency disease

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -11.21	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 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.4	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 0.00937% African / African-American · 7/74,674 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.0013% 21/1,611,718 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00937%	10,668
European (non-Finnish)	0.0011%	90,663
South Asian	0.0011%	91,016

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.Arg803Ser
Coding: c.2407C>A
MANE Select: NM_001875
dbSNP: rs201716417
Type: single nucleotide variant
Location: chr2:210612132 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 803: a UniProt-annotated variant site (in cps1d); a β-strand

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

Also linked: pulmonary hypertension, neonatal, susceptibility to

For Carbamoyl-phosphate synthetase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CPS1 p.Arg803Gly Pathogenic/Likely pathogenic ★★ same residue
CPS1 p.Arg803His Likely pathogenic ★ same residue
CPS1 p.Arg803Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CPS1 p.Arg803= 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-arg803ser (accessed [today's date]).

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