Is PPOX p.His281Arg (c.842A>G) pathogenic?

PPOX p.His281Arg (c.842A>G) is classified Uncertain significance in PPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.2792); Very rare (popmax 0.00703%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PPOX p.His281Arg (c.842A>G)?

PPOX p.His281Arg (c.842A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PPOX p.His281Arg (c.842A>G) in the general population?

PPOX p.His281Arg (c.842A>G) is very rare (popmax 0.00703%, nfe) (gnomAD).

What do computational predictors say about PPOX p.His281Arg (c.842A>G)?

AlphaMissense predicts likely benign (score 0.2792) — an in-silico prediction, not a clinical call.

PPOX p.His281Arg

c.842A>G · rs1288034269 · VCV1039163

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00703%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2792	likely benign
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -9.32	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	23.7	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 0.00703% European (non-Finnish) · 83/1,180,038 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00533% 86/1,614,078 alleles · very rare exomes 83/1,461,878 · genomes 3/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00703%	14,217
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00133%	74,914

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.His281Arg
Coding: c.842A>G
MANE Select: NM_001122764
dbSNP: rs1288034269
Type: single nucleotide variant
Location: chr1:161169694 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB
Residue 281: a β-strand; a UniProt-annotated variant site (in vp)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPOX p.His281= Likely benign ★ same residue
PPOX p.Ala221Thr Uncertain significance ★★ ⚠ same condition
PPOX p.Arg152His Uncertain significance ★★ ⚠ same condition
PPOX p.Arg267Cys Uncertain significance ★★ ⚠ same condition
PPOX p.Arg3Gln Uncertain significance ★★ ⚠ same condition
PPOX p.Gln421His Uncertain significance ★★ ⚠ same condition
PPOX p.Glu355Asp Uncertain significance ★★ ⚠ same condition
PPOX p.Gly200Asp Uncertain significance ★★ ⚠ same condition

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-his281arg (accessed [today's date]).

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