Is CPS1 p.Lys400= (c.1200A>G) pathogenic?

CPS1 p.Lys400= (c.1200A>G) is classified Benign/Likely benign in CPS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0922%, afr); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Lys400= (c.1200A>G)?

CPS1 p.Lys400= (c.1200A>G) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Lys400= (c.1200A>G) in the general population?

CPS1 p.Lys400= (c.1200A>G) is ultra-rare (popmax 0.0922%, afr) (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.Lys400=

c.1200A>G · rs141545954 · VCV682114

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0922%, afr)

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 0.93	GERP -4.8, phastCons 1
Overall
CADD	2.452	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0922% African / African-American · 69/74,852 alleles

Filtering AF 0.0746% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0683%

Overall 0.00478% 77/1,611,268 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0922%	1,085
Remaining individualsnot grpmax-eligible	0.00963%	10,383
South Asian	0.0022%	45,514

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.Lys400=
Coding: c.1200A>G
MANE Select: NM_001875
dbSNP: rs141545954
Type: single nucleotide variant
Location: chr2:210594543 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 400: the glutamine amidotransferase type-1 domain; a modified residue (n6-succinyllysine)

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.Lys400Thr Uncertain significance ★ ⚠ same residue
CPS1 p.Lys400fs Pathogenic ★ 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

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-lys400 (accessed [today's date]).

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