Is CPOX p.Ala293Pro (c.877G>C) pathogenic?

CPOX p.Ala293Pro (c.877G>C) is classified Uncertain significance in CPOX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.9587); Absent from gnomAD v4.1; Associated with CPOX-related hereditary coproporphyria.

What condition is associated with CPOX p.Ala293Pro (c.877G>C)?

CPOX p.Ala293Pro (c.877G>C) is associated with CPOX-related hereditary coproporphyria (ClinVar).

How common is CPOX p.Ala293Pro (c.877G>C) in the general population?

CPOX p.Ala293Pro (c.877G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CPOX p.Ala293Pro (c.877G>C)?

AlphaMissense predicts likely pathogenic (score 0.9587) — an in-silico prediction, not a clinical call.

CPOX p.Ala293Pro

c.877G>C · VCV4531914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9587 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CPOX-related hereditary coproporphyria

Computational evidence

Protein change
AlphaMissense	0.9587	likely pathogenic
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -14.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	33.0	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: CPOX
Protein: p.Ala293Pro
Coding: c.877G>C
MANE Select: NM_000097
Type: single nucleotide variant
Location: chr3:98588789 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 293: a UniProt-annotated variant site (in hcp); an α-helix

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

Disease context

CPOX-related hereditary coproporphyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPOX p.Ala293Thr Uncertain significance ★★ ⚠ same residue
CPOX p.Ala293Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CPOX p.Lys404Glu Pathogenic/Likely pathogenic ★★ same condition
CPOX p.Glu100Val Conflicting classifications of pathogenicity ★ ⚠ same condition
CPOX p.Val163fs Likely pathogenic ★ same condition
CPOX p.Cys239Ter Pathogenic ★★ same type
CPOX p.Gln160Ter Pathogenic ★★ same type
CPOX p.Glu201Lys Pathogenic/Likely pathogenic ★★ same type

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/cpox-p-ala293pro (accessed [today's date]).

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