Is PPOX p.Val282Ile (c.844G>A) pathogenic?

PPOX p.Val282Ile (c.844G>A) is classified Conflicting classifications of pathogenicity in PPOX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-10). AlphaMissense: likely benign (0.0886); Rare (popmax 0.49%, eas); Associated with Inborn genetic diseases.

What condition is associated with PPOX p.Val282Ile (c.844G>A)?

PPOX p.Val282Ile (c.844G>A) is associated with Inborn genetic diseases, variegate porphyria, variegate porphyria, childhood-onset (ClinVar).

How common is PPOX p.Val282Ile (c.844G>A) in the general population?

PPOX p.Val282Ile (c.844G>A) is rare (popmax 0.49%, eas) (gnomAD).

What do computational predictors say about PPOX p.Val282Ile (c.844G>A)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

PPOX p.Val282Ile

c.844G>A · rs145286580 · VCV875181

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.49%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61	GERP -1.8
Overall
CADD	1.508	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 0.49% East Asian · 220/44,892 alleles

Filtering AF 0.437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.416%

Overall 0.0142% 230/1,614,182 alleles · rare exomes 216/1,461,874 · genomes 14/152,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.49%	204
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)	0.000424%	236,004

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.Val282Ile
Coding: c.844G>A
MANE Select: NM_001122764
dbSNP: rs145286580
Type: single nucleotide variant
Location: chr1:161169696 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB
Residue 282: a β-strand; a UniProt-annotated variant site (in vp; strongly decreases enzyme activity; impairs protein folding and/or stability)

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

Also linked: variegate porphyria variegate porphyria, childhood-onset

Similar variants

PPOX c.-9G>A Likely pathogenic ★★ same condition
PPOX p.Arg168His Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPOX p.Arg59Trp Pathogenic ★★ same condition
PPOX p.Ala221Thr Uncertain significance ★★ ⚠ same condition
PPOX p.Ala449Thr 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

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-val282ile (accessed [today's date]).

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