Is PPOX p.Arg464Cys (c.1390C>T) pathogenic?

PPOX p.Arg464Cys (c.1390C>T) is classified Uncertain significance in PPOX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-30). AlphaMissense: likely benign (0.1899); Very rare (popmax 0.00668%, afr).

How common is PPOX p.Arg464Cys (c.1390C>T) in the general population?

PPOX p.Arg464Cys (c.1390C>T) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about PPOX p.Arg464Cys (c.1390C>T)?

AlphaMissense predicts likely benign (score 0.1899) — an in-silico prediction, not a clinical call.

PPOX p.Arg464Cys

c.1390C>T · rs147480828 · VCV3000073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1899	likely benign
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -12.01	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 6	GERP 1.4, phastCons 1
Overall
CADD	29.7	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 0.00668% African / African-American · 5/74,896 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000992% 16/1,613,576 alleles · very rare exomes 11/1,461,422 · genomes 5/152,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,979
South Asian	0.00659%	15,177
European (non-Finnish)	0.000424%	236,008

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.Arg464Cys
Coding: c.1390C>T
MANE Select: NM_001122764
dbSNP: rs147480828
Type: single nucleotide variant
Location: chr1:161171132 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB
Residue 464: an α-helix

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

Similar variants

PPOX p.Arg464His Uncertain significance ★ ⚠ 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
PPOX p.Glu191Ter Pathogenic/Likely 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-arg464cys (accessed [today's date]).

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