Is CPOX p.Val294Ile (c.880G>A) pathogenic?

CPOX p.Val294Ile (c.880G>A) is classified Benign in CPOX (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0689); Common (popmax 21.3%, amr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary coproporphyria.

What condition is associated with CPOX p.Val294Ile (c.880G>A)?

CPOX p.Val294Ile (c.880G>A) is associated with hereditary coproporphyria (ClinVar).

How is Hereditary coproporphyria inherited?

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

What do computational predictors say about CPOX p.Val294Ile (c.880G>A)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

CPOX p.Val294Ile

Q: How common is CPOX p.Val294Ile (c.880G>A) in the general population?

CPOX p.Val294Ile (c.880G>A) is common (popmax 21.3%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.880G>A · rs2228056 · VCV346978

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 21.3%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary coproporphyria

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.6	GERP 1.9, phastCons 0.093
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	18.06	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 21.3% Admixed American · 12,767/59,994 alleles

Filtering AF 21% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.8%

Overall 8.88% 143,315/1,614,006 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	21.3%	5
South Asian	14%	7
Ashkenazi Jewishnot grpmax-eligible	10.8%	9
Middle Eastern	10.6%	9
Remaining individualsnot grpmax-eligible	9.02%	11
European (non-Finnish)	8.4%	12
East Asian	7.29%	14
Finnishnot grpmax-eligible	5.6%	18
African / African-American	3.12%	32
Amishnot grpmax-eligible	0.877%	114

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: CPOX
Protein: p.Val294Ile
Coding: c.880G>A
MANE Select: NM_000097
dbSNP: rs2228056
Type: single nucleotide variant
Location: chr3:98588786 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 294: a UniProt-annotated variant site (in hcp); a UniProt-annotated variant site (in); an α-helix

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

Disease context

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

For Hereditary coproporphyria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CPOX p.Gln160Ter Pathogenic ★★ same condition
CPOX p.Glu201Lys Pathogenic/Likely pathogenic ★★ same condition
CPOX p.Lys404Glu Pathogenic/Likely pathogenic ★★ same condition
CPOX p.Arg60Gly Uncertain significance ★★ ⚠ same condition
CPOX p.Thr56Met Uncertain significance ★★ ⚠ same condition
CPOX p.Val16Gly Uncertain significance ★★ ⚠ same condition
CPOX c.1172+14A>G Benign ★★ same condition
CPOX c.556+9G>A Benign/Likely benign ★★ 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/cpox-p-val294ile (accessed [today's date]).

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