Is CPOX p.Ala293Val (c.878C>T) pathogenic?

CPOX p.Ala293Val (c.878C>T) is classified Conflicting classifications of pathogenicity in CPOX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-28). AlphaMissense: likely benign (0.2027); Ultra-rare (popmax 0.0773%, afr).

How common is CPOX p.Ala293Val (c.878C>T) in the general population?

CPOX p.Ala293Val (c.878C>T) is ultra-rare (popmax 0.0773%, afr) (gnomAD).

What do computational predictors say about CPOX p.Ala293Val (c.878C>T)?

AlphaMissense predicts likely benign (score 0.2027) — an in-silico prediction, not a clinical call.

CPOX p.Ala293Val

c.878C>T · rs140475004 · VCV650394

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0773%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2027	likely benign
REVEL	0.517	indeterminate
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	23.6	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 0.0773% African / African-American · 58/75,046 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0556%

Overall 0.0057% 92/1,614,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0773%	1,294
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.00833%	12,006
South Asian	0.00549%	18,217
European (non-Finnish)	8.47e-05%	1,179,994

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.Ala293Val
Coding: c.878C>T
MANE Select: NM_000097
dbSNP: rs140475004
Type: single nucleotide variant
Location: chr3:98588788 (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

Similar variants

CPOX p.Ala293Thr Uncertain significance ★★ ⚠ same residue
CPOX p.Ala293Pro Uncertain significance ★ ⚠ same residue
CPOX p.Cys239Ter Pathogenic ★★ same type
CPOX p.Gln160Ter Pathogenic ★★ same type
CPOX p.Glu201Lys Pathogenic/Likely pathogenic ★★ same type
CPOX p.Lys404Glu Pathogenic/Likely pathogenic ★★ same type
CPOX c.811+5G>C Uncertain significance ★★ same type
CPOX p.Ala83Val Uncertain significance ★★ ⚠ 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-ala293val (accessed [today's date]).

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