Is CPS1 p.Thr344= (c.1032C>T) pathogenic?

CPS1 p.Thr344= (c.1032C>T) is classified Benign in CPS1 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 66.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Thr344= (c.1032C>T)?

CPS1 p.Thr344= (c.1032C>T) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How is Carbamoyl-phosphate synthetase 1 deficiency inherited?

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

CPS1 p.Thr344=

Q: How common is CPS1 p.Thr344= (c.1032C>T) in the general population?

CPS1 p.Thr344= (c.1032C>T) is common (popmax 66.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1032C>T · rs2229589 · VCV128850

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 66.7%, afr) — too common for a highly-penetrant pathogenic allele

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 0.86	GERP 0.31, phastCons 1
Overall
CADD	8.705	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 66.7% African / African-American · 49,778/74,578 alleles

Filtering AF 66.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.1%

Overall 57% 917,099/1,610,134 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	66.7%	1
Middle Eastern	65.4%	2
Finnishnot grpmax-eligible	62.8%	2
Ashkenazi Jewishnot grpmax-eligible	60.9%	2
South Asian	60.6%	2
Remaining individualsnot grpmax-eligible	58.5%	2
European (non-Finnish)	56%	2
East Asian	55.3%	2
Admixed American	49.5%	2
Amishnot grpmax-eligible	45.7%	2

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.Thr344=
Coding: c.1032C>T
MANE Select: NM_001875
dbSNP: rs2229589
Type: single nucleotide variant
Location: chr2:210591915 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 344: a UniProt-annotated variant site (no negative effect on protein stability, enzyme activity and thermal stability); a UniProt-annotated variant site (in); the glutamine amidotransferase type-1 domain

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.Thr344Ala Benign ★★ same residue
CPS1 p.Thr344Ser Uncertain significance ★ ⚠ same residue
CPS1 p.Thr344Ile 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
CPS1 c.1549+1G>A 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-thr344 (accessed [today's date]).

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