Is CPS1 p.Thr1391= (c.4173G>A) pathogenic?

CPS1 p.Thr1391= (c.4173G>A) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0167%, amr); Associated with carbamoyl phosphate synthetase I deficiency disease.

What condition is associated with CPS1 p.Thr1391= (c.4173G>A)?

CPS1 p.Thr1391= (c.4173G>A) is associated with carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Thr1391= (c.4173G>A) in the general population?

CPS1 p.Thr1391= (c.4173G>A) is ultra-rare (popmax 0.0167%, amr) (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.Thr1391=

c.4173G>A · rs201710257 · VCV896192

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

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 -2.1	GERP -3.2
Overall
CADD	5.985	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,946 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00957%

Overall 0.0101% 159/1,579,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,995
Remaining individualsnot grpmax-eligible	0.0147%	6,821
European (non-Finnish)	0.0118%	8,446
African / African-American	0.00539%	18,556

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.Thr1391=
Coding: c.4173G>A
MANE Select: NM_001875
dbSNP: rs201710257
Type: single nucleotide variant
Location: chr2:210675739 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 1391: a UniProt-annotated variant site (in cps1d); a β-strand; the mgs-like domain; a binding site

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.Thr1391Lys Likely pathogenic ★ same residue
CPS1 p.Thr1391Met Conflicting classifications of pathogenicity ★ ⚠ 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-thr1391 (accessed [today's date]).

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