Is PPOX p.Ser261Arg (c.781A>C) pathogenic?

PPOX p.Ser261Arg (c.781A>C) is classified Uncertain significance in PPOX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-03). AlphaMissense: likely benign (0.2175); Ultra-rare (popmax 0.0582%, sas).

How common is PPOX p.Ser261Arg (c.781A>C) in the general population?

PPOX p.Ser261Arg (c.781A>C) is ultra-rare (popmax 0.0582%, sas) (gnomAD).

What do computational predictors say about PPOX p.Ser261Arg (c.781A>C)?

AlphaMissense predicts likely benign (score 0.2175) — an in-silico prediction, not a clinical call.

PPOX p.Ser261Arg

c.781A>C · VCV3380125

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2175 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0582%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2175	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -6.91	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 5.4	GERP 0.51, phastCons 1
Overall
CADD	18.7	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 0.0582% South Asian · 53/91,090 alleles

Filtering AF 0.0457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.0105% 170/1,614,130 alleles · ultra-rare exomes 160/1,461,770 · genomes 10/152,360 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0582%	1,719
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.00898%	11,132
African / African-American	0.00133%	75,068

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.Ser261Arg
Coding: c.781A>C
MANE Select: NM_001122764
Type: single nucleotide variant
Location: chr1:161169157 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB
Residue 261: a β-strand

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

Similar variants

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
PPOX c.471+3G>A 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/ppox-p-ser261arg (accessed [today's date]).

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