Is CPOX p.Pro449Ser (c.1345C>T) pathogenic?

CPOX p.Pro449Ser (c.1345C>T) is classified Uncertain significance in CPOX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-09). AlphaMissense: likely pathogenic (0.5953); No allele count reported in gnomAD v4.1 (AN 1,614,190); Associated with CPOX-related disorder.

What condition is associated with CPOX p.Pro449Ser (c.1345C>T)?

CPOX p.Pro449Ser (c.1345C>T) is associated with CPOX-related disorder (ClinVar).

How common is CPOX p.Pro449Ser (c.1345C>T) in the general population?

CPOX p.Pro449Ser (c.1345C>T) is no allele count reported in gnomAD v4.1 (AN 1,614,190) (gnomAD).

What do computational predictors say about CPOX p.Pro449Ser (c.1345C>T)?

AlphaMissense predicts likely pathogenic (score 0.5953) — an in-silico prediction, not a clinical call.

CPOX p.Pro449Ser

c.1345C>T · rs771996976 · VCV2629606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5953 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,190)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CPOX-related disorder

Computational evidence

Protein change
AlphaMissense	0.5953	likely pathogenic
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -10.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	28.3	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

No allele count reported in gnomAD v4.1 (AN 1,614,190). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CPOX
Protein: p.Pro449Ser
Coding: c.1345C>T
MANE Select: NM_000097
dbSNP: rs771996976
Type: single nucleotide variant
Location: chr3:98580703 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 449: 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.Ala83Val Uncertain significance ★★ ⚠ 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

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-pro449ser (accessed [today's date]).

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