Is CPOX p.Arg359Ser (c.1077G>C) pathogenic?

CPOX p.Arg359Ser (c.1077G>C) is classified Uncertain significance in CPOX (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1346); Very rare (popmax 8.47e-05%, nfe).

How common is CPOX p.Arg359Ser (c.1077G>C) in the general population?

CPOX p.Arg359Ser (c.1077G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CPOX p.Arg359Ser (c.1077G>C)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

CPOX p.Arg359Ser

c.1077G>C · rs1707345051 · VCV1716081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -5.82	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 0.36	GERP 0.88, phastCons 0.99
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	17.45	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 8.47e-05% European (non-Finnish) · 1/1,179,980 alleles

Overall 6.84e-05% 1/1,461,830 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.Arg359Ser
Coding: c.1077G>C
MANE Select: NM_000097
dbSNP: rs1707345051
Type: single nucleotide variant
Location: chr3:98585536 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 359: 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.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-arg359ser (accessed [today's date]).

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