Is CPOX p.Ala83Val (c.248C>T) pathogenic?

CPOX p.Ala83Val (c.248C>T) is classified Uncertain significance in CPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1909); Very rare (popmax 0.000879%, nfe); Associated with CPOX-related disorder.

What condition is associated with CPOX p.Ala83Val (c.248C>T)?

CPOX p.Ala83Val (c.248C>T) is associated with CPOX-related disorder (ClinVar).

How common is CPOX p.Ala83Val (c.248C>T) in the general population?

CPOX p.Ala83Val (c.248C>T) is very rare (popmax 0.000879%, nfe) (gnomAD).

What do computational predictors say about CPOX p.Ala83Val (c.248C>T)?

AlphaMissense predicts likely benign (score 0.1909) — an in-silico prediction, not a clinical call.

CPOX p.Ala83Val

c.248C>T · rs775066459 · VCV2628506

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000879%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CPOX-related disorder

Computational evidence

Protein change
AlphaMissense	0.1909	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -6.82	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 7.4	GERP 0.25, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 2,476 bp · p 0.32 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000879% European (non-Finnish) · 10/1,138,228 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000324%

Overall 0.000659% 10/1,517,974 alleles · very rare

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.Ala83Val
Coding: c.248C>T
MANE Select: NM_000097
dbSNP: rs775066459
Type: single nucleotide variant
Location: chr3:98593257 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 83: a UniProt-annotated variant site (in hcp)

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

Disease context

CPOX-related disorder

Similar variants

CPOX p.Cys239Ter Pathogenic ★★ same condition
CPOX p.Glu201Lys Pathogenic/Likely pathogenic ★★ same condition
CPOX p.Ala89Val Uncertain significance ★★ ⚠ same condition
CPOX p.Ala81Gly Uncertain significance ★ ⚠ same condition
CPOX p.Arg332Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
CPOX p.Arg391Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
CPOX p.Pro249Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
CPOX p.Pro449Ser 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-ala83val (accessed [today's date]).

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