Is CPOX p.Pro53Leu (c.158C>T) pathogenic?

CPOX p.Pro53Leu (c.158C>T) is classified Uncertain significance in CPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.00123%, nfe).

How common is CPOX p.Pro53Leu (c.158C>T) in the general population?

CPOX p.Pro53Leu (c.158C>T) is very rare (popmax 0.00123%, nfe) (gnomAD).

What do computational predictors say about CPOX p.Pro53Leu (c.158C>T)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

CPOX p.Pro53Leu

c.158C>T · rs755245204 · VCV3023456

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.88, phastCons 0.37
Regional constraint	o/e 1.06	unconstrained · MANE · 2,476 bp · p 0.32 · regional, not allelic
Overall
CADD	19.44	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 0.00123% European (non-Finnish) · 13/1,057,158 alleles

Filtering AF 0.000686% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000529%

Overall 0.00127% 17/1,339,044 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0105%	9,527
European (non-Finnish)grpmax	0.00123%	81,320

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro53Leu
Coding: c.158C>T
MANE Select: NM_000097
dbSNP: rs755245204
Type: single nucleotide variant
Location: chr3:98593347 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 53: a UniProt-annotated variant site (in hcp); the 'disordered' region

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

Similar variants

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.Ala293Thr Uncertain significance ★★ ⚠ same type
CPOX p.Ala83Val Uncertain significance ★★ ⚠ same type
CPOX p.Ala89Val 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-pro53leu (accessed [today's date]).

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