Is CPS1 p.Arg523= (c.1569A>G) pathogenic?

CPS1 p.Arg523= (c.1569A>G) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-29). Rare (popmax 0.165%, mid); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Arg523= (c.1569A>G)?

CPS1 p.Arg523= (c.1569A>G) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Arg523= (c.1569A>G) in the general population?

CPS1 p.Arg523= (c.1569A>G) is rare (popmax 0.165%, mid) (gnomAD).

How is Carbamoyl-phosphate synthetase 1 deficiency inherited?

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

CPS1 p.Arg523=

c.1569A>G · rs140475976 · VCV512285

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Conditions

carbamoyl phosphate synthetase I deficiency disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -3.6, phastCons 1
Overall
CADD	10.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Middle Eastern · 10/6,046 alleles

Filtering AF 0.0897% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0682%

Overall 0.0305% 491/1,612,146 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	605
Ashkenazi Jewishnot grpmax-eligible	0.0779%	1,283
Remaining individualsnot grpmax-eligible	0.0513%	1,949
European (non-Finnish)	0.0347%	2,882
Admixed American	0.0134%	7,479
South Asian	0.00769%	13,004
African / African-American	0.00267%	37,445

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.Arg523=
Coding: c.1569A>G
MANE Select: NM_001875
dbSNP: rs140475976
Type: single nucleotide variant
Location: chr2:210600574 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB

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 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
CPS1 c.1981+1G>C 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-arg523 (accessed [today's date]).

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