Is PPOX p.Arg23Trp (c.67C>T) pathogenic?

PPOX p.Arg23Trp (c.67C>T) is classified Uncertain significance in PPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-10). AlphaMissense: likely benign (0.2168); Very rare (popmax 0.00223%, eas).

How common is PPOX p.Arg23Trp (c.67C>T) in the general population?

PPOX p.Arg23Trp (c.67C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PPOX p.Arg23Trp (c.67C>T)?

AlphaMissense predicts likely benign (score 0.2168) — an in-silico prediction, not a clinical call.

PPOX p.Arg23Trp

c.67C>T · rs373956753 · VCV2446702

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2168	likely benign
REVEL	0.741	pathogenic-leaning
SaProt	LLR -11.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.88, phastCons 1
Overall
CADD	28.6	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 0.00223% East Asian · 1/44,884 alleles

Overall 0.000124% 2/1,613,932 alleles · very rare exomes 2/1,461,576 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
European (non-Finnish)	8.47e-05%	1,180,018

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: PPOX
Protein: p.Arg23Trp
Coding: c.67C>T
MANE Select: NM_001122764
dbSNP: rs373956753
Type: single nucleotide variant
Location: chr1:161166914 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB

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

Similar variants

PPOX p.Arg23= Uncertain significance ★ same residue
PPOX p.Arg23Gln Likely benign ★ same residue
PPOX c.-9G>A Likely pathogenic ★★ same type
PPOX p.Arg168His Pathogenic/Likely pathogenic ★★ ⚠ same type
PPOX p.Arg59Trp Pathogenic ★★ same type
PPOX p.Gln189Ter Pathogenic ★★ same type
PPOX p.Gln435Ter Pathogenic/Likely pathogenic ★★ same type
PPOX p.Glu133Ter Pathogenic ★★ 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/ppox-p-arg23trp (accessed [today's date]).

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