Is PPOX p.Pro256Arg (c.767C>G) pathogenic?

PPOX p.Pro256Arg (c.767C>G) is classified Conflicting classifications of pathogenicity in PPOX (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.0968); Low-frequency (popmax 1.08%, nfe); Associated with variegate porphyria.

What condition is associated with PPOX p.Pro256Arg (c.767C>G)?

PPOX p.Pro256Arg (c.767C>G) is associated with variegate porphyria, variegate porphyria, childhood-onset (ClinVar).

How common is PPOX p.Pro256Arg (c.767C>G) in the general population?

PPOX p.Pro256Arg (c.767C>G) is low-frequency (popmax 1.08%, nfe) (gnomAD).

How is Variegate porphyria inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PPOX p.Pro256Arg (c.767C>G)?

AlphaMissense predicts likely benign (score 0.0968) — an in-silico prediction, not a clinical call.

PPOX p.Pro256Arg

c.767C>G · rs12735723 · VCV8704

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0968 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.08%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

variegate porphyria

Computational evidence

Protein change
AlphaMissense	0.0968	likely benign
REVEL	0.495	indeterminate
SaProt	LLR -5.90	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 4.1	GERP 1.6, phastCons 1
Overall
CADD	21.4	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 1.08% European (non-Finnish) · 12,787/1,180,030 alleles

Filtering AF 1.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.894% 14,423/1,614,136 alleles · low-frequency exomes 13,461/1,461,822 · genomes 962/152,314 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.13%	88
European (non-Finnish)grpmax	1.08%	92
Remaining individualsnot grpmax-eligible	0.71%	141
Admixed American	0.26%	385
Middle Eastern	0.214%	466
South Asian	0.186%	539
African / African-American	0.143%	701
Ashkenazi Jewishnot grpmax-eligible	0.0743%	1,346

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro256Arg
Coding: c.767C>G
MANE Select: NM_001122764
dbSNP: rs12735723
Type: single nucleotide variant
Location: chr1:161169143 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB
Residue 256: a UniProt-annotated variant site (in vpco; likely benign; results in reduction of activity in a prokariotyc expression system but has normal activity when expressed in an eukaryotic system)

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

Disease context

variegate porphyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: variegate porphyria, childhood-onset

For Variegate porphyria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: <1 / 1 000 000 (Europe)

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.Ala449Thr Uncertain significance ★★ ⚠ same condition
PPOX p.Arg267Cys Uncertain significance ★★ ⚠ same condition
PPOX p.Pro407Leu Uncertain significance ★★ ⚠ same condition
PPOX c.-128C>G Benign/Likely benign ★★ same condition
PPOX c.-151G>T Likely benign ★★ 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-pro256arg (accessed [today's date]).

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