Is CPS1 p.Leu747Phe (c.2239C>T) pathogenic?

CPS1 p.Leu747Phe (c.2239C>T) is classified Uncertain significance in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9159); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CPS1 p.Leu747Phe (c.2239C>T)?

CPS1 p.Leu747Phe (c.2239C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CPS1 p.Leu747Phe (c.2239C>T) in the general population?

CPS1 p.Leu747Phe (c.2239C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CPS1 p.Leu747Phe (c.2239C>T)?

AlphaMissense predicts likely pathogenic (score 0.9159) — an in-silico prediction, not a clinical call.

CPS1 p.Leu747Phe

c.2239C>T · VCV4616494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9159 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9159	likely pathogenic
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -11.80	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 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CPS1
Protein: p.Leu747Phe
Coding: c.2239C>T
MANE Select: NM_001875
Type: single nucleotide variant
Location: chr2:210608407 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 747: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPS1 p.Ala1400Thr Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg1004Cys Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg238Gln Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg419Trp Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg689His Uncertain significance ★★ ⚠ same condition
CPS1 p.Arg882Cys Uncertain significance ★★ ⚠ same condition
CPS1 p.Asn558Ser Uncertain significance ★★ ⚠ same condition
CPS1 p.Glu1221Gly Uncertain significance ★★ ⚠ 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-leu747phe (accessed [today's date]).

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