Is CPOX p.Ala99Val (c.296C>T) pathogenic?

CPOX p.Ala99Val (c.296C>T) is classified Uncertain significance in CPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-12). AlphaMissense: ambiguous (0.3825); Ultra-rare (popmax 0.0425%, amr); Associated with Inborn genetic diseases.

What condition is associated with CPOX p.Ala99Val (c.296C>T)?

CPOX p.Ala99Val (c.296C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CPOX p.Ala99Val (c.296C>T) in the general population?

CPOX p.Ala99Val (c.296C>T) is ultra-rare (popmax 0.0425%, amr) (gnomAD).

What do computational predictors say about CPOX p.Ala99Val (c.296C>T)?

AlphaMissense predicts ambiguous (score 0.3825) — an in-silico prediction, not a clinical call.

CPOX p.Ala99Val

c.296C>T · rs781649061 · VCV1386594

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0425%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3825	ambiguous
REVEL	0.628	indeterminate
SaProt	LLR -6.95	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 2,476 bp · p 0.32 · regional, not allelic
Overall
CADD	25.2	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 0.0425% Admixed American · 25/58,796 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0252%

Overall 0.00164% 26/1,589,696 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0425%	2,352
Remaining individualsnot grpmax-eligible	0.00163%	61,442

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.Ala99Val
Coding: c.296C>T
MANE Select: NM_000097
dbSNP: rs781649061
Type: single nucleotide variant
Location: chr3:98593209 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 99: a UniProt-annotated variant site (in hcp)

Full CPOX 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

CPOX p.Ala99Thr Uncertain significance ★ ⚠ same residue
CPOX p.Ala99= Likely benign ★ same residue
CPOX p.Arg126Cys Uncertain significance ★★ ⚠ same condition
CPOX p.Arg18Trp Uncertain significance ★★ ⚠ same condition
CPOX p.Arg25Gly Uncertain significance ★★ ⚠ same condition
CPOX p.Arg41Gly Uncertain significance ★★ ⚠ same condition
CPOX p.Asn260His Uncertain significance ★★ ⚠ same condition
CPOX p.Asp196Glu 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/cpox-p-ala99val (accessed [today's date]).

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