Is CPOX p.Pro249Ser (c.745C>T) pathogenic?

CPOX p.Pro249Ser (c.745C>T) is classified Conflicting classifications of pathogenicity in CPOX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-03). AlphaMissense: likely pathogenic (0.7629); Very rare (popmax 0.000169%, nfe); Associated with CPOX-related disorder.

What condition is associated with CPOX p.Pro249Ser (c.745C>T)?

CPOX p.Pro249Ser (c.745C>T) is associated with CPOX-related disorder (ClinVar).

How common is CPOX p.Pro249Ser (c.745C>T) in the general population?

CPOX p.Pro249Ser (c.745C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CPOX p.Pro249Ser (c.745C>T)?

AlphaMissense predicts likely pathogenic (score 0.7629) — an in-silico prediction, not a clinical call.

CPOX p.Pro249Ser

c.745C>T · rs1707462390 · VCV1365903

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CPOX-related disorder

Computational evidence

Protein change
AlphaMissense	0.7629	likely pathogenic
REVEL	0.977	strongly pathogenic-leaning
SaProt	LLR -9.99	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	29.0	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 0.000169% European (non-Finnish) · 2/1,179,958 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,832 alleles · very rare exomes 1/1,461,780 · genomes 1/152,052 · joint denominator

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.Pro249Ser
Coding: c.745C>T
MANE Select: NM_000097
dbSNP: rs1707462390
Type: single nucleotide variant
Location: chr3:98590698 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 249: a UniProt-annotated variant site (in hcp); a β-strand

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.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-pro249ser (accessed [today's date]).

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