Is CPOX p.Arg447His (c.1340G>A) pathogenic?

CPOX p.Arg447His (c.1340G>A) is classified Uncertain significance in CPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-18). AlphaMissense: likely benign (0.1029); Ultra-rare (popmax 0.0165%, mid).

How common is CPOX p.Arg447His (c.1340G>A) in the general population?

CPOX p.Arg447His (c.1340G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CPOX p.Arg447His (c.1340G>A)?

AlphaMissense predicts likely benign (score 0.1029) — an in-silico prediction, not a clinical call.

CPOX p.Arg447His

c.1340G>A · rs200810233 · VCV2961116

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1029 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1029	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -10.83	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	25.8	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00235% 38/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.012%	8,337
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00333%	30,010
East Asian	0.00223%	44,888
South Asian	0.0022%	45,539
European (non-Finnish)	0.00178%	56,190
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Arg447His
Coding: c.1340G>A
MANE Select: NM_000097
dbSNP: rs200810233
Type: single nucleotide variant
Location: chr3:98580708 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 447: a UniProt-annotated variant site (in hcp); an α-helix

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

Similar variants

CPOX p.Arg447Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg447his (accessed [today's date]).

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