Is PPOX p.Val249fs (c.745dup) pathogenic?

PPOX p.Val249fs (c.745dup) is classified Pathogenic in PPOX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-25). Very rare (popmax 0.000254%, nfe); Associated with variegate porphyria.

What condition is associated with PPOX p.Val249fs (c.745dup)?

PPOX p.Val249fs (c.745dup) is associated with variegate porphyria (ClinVar).

How common is PPOX p.Val249fs (c.745dup) in the general population?

PPOX p.Val249fs (c.745dup) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Variegate porphyria inherited?

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

PPOX p.Val249fs

c.745dup · rs1571369150 · VCV664759

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

variegate porphyria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP 0.46, phastCons 0.14

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,012 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,126 alleles · very rare exomes 3/1,461,880 · genomes 0/152,246 · joint denominator

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.Val249fs
Coding: c.745dup
MANE Select: NM_001122764
dbSNP: rs1571369150
Type: Duplication
Location: chr1:161169115 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB

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

For Variegate porphyria (Orphanet):

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

Similar variants

PPOX p.Leu105fs Likely pathogenic ★ same condition
PPOX p.Val249= Likely benign ★ same residue
PPOX c.-9G>A Likely pathogenic ★★ same condition
PPOX p.Ala66_Leu67insTer Pathogenic/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

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-val249fs (accessed [today's date]).

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