Is CPS1 p.Pro99Leu (c.296C>T) pathogenic?

CPS1 p.Pro99Leu (c.296C>T) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.7983); Very rare (popmax 0.000339%, nfe); Associated with pulmonary hypertension, neonatal, susceptibility to.

What condition is associated with CPS1 p.Pro99Leu (c.296C>T)?

CPS1 p.Pro99Leu (c.296C>T) is associated with pulmonary hypertension, neonatal, susceptibility to, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Pro99Leu (c.296C>T) in the general population?

CPS1 p.Pro99Leu (c.296C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CPS1 p.Pro99Leu (c.296C>T)?

AlphaMissense predicts likely pathogenic (score 0.7983) — an in-silico prediction, not a clinical call.

CPS1 p.Pro99Leu

c.296C>T · rs1245845692 · VCV3237531

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pulmonary hypertension, neonatal, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.7983	likely pathogenic
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -12.65	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 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	27.4	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 0.000339% European (non-Finnish) · 4/1,179,748 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,532 alleles · very rare

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.Pro99Leu
Coding: c.296C>T
MANE Select: NM_001875
dbSNP: rs1245845692
Type: single nucleotide variant
Location: chr2:210576405 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 99: a β-strand; the 'anthranilate phosphoribosyltransferase homolog' region

Full CPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pulmonary hypertension, neonatal, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

CPS1 p.Pro99Thr Uncertain significance ★★ ⚠ same residue
CPS1 p.Pro99= 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
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-pro99leu (accessed [today's date]).

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