PPOX

Chr 1ADAR

protoporphyrinogen oxidase

Also known as: PPO, V290M, VP, VPCO

NCBI Gene: 5498 ENSG00000143224 UniProt: P50336 OMIM: 600923

The protein catalyzes the 6-electron oxidation of protoporphyrinogen IX to protoporphyrin IX as the penultimate enzyme in heme biosynthesis, located on the inner mitochondrial membrane. Mutations cause variegate porphyria, a disorder of heme metabolism that can present with childhood onset or later in life. Inheritance is autosomal dominant, though autosomal recessive forms have also been reported.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. Mutations in this gene cause variegate porphyria, an autosomal dominant disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Variegate porphyriaMIM #176200

Variegate porphyria, childhood-onsetMIM #620483

Clinical highlights

Gene–disease validity (ClinGen)

Strong · variegate porphyria · SD · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.57

LOEUF

Mechanism· predicted

📖

GeneReview available — PPOX

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.028

Z-score 3.09

OE 0.30 (0.17–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.98Z-score

OE missense 0.83 (0.74–0.93)

216 obs / 260.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.17–0.57)

0≤0.351.4

Missense OE?0.83 (0.74–0.93)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 7 / 23.0Missense obs/exp: 216 / 260.3Syn Z: -0.43

Background carrier burden — how many people carry a rare variant somewhere in PPOX?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

637 rare PASS variants

Rare truncating (LoF)

1 in 1,200

91 rare PASS variants

Rare synonymous (reference)

1 in 250

289 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPOX. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 1,500
South Asian	~43k	1 in 97	1 in 3,000
Remaining (unassigned)	~30k	1 in 89	1 in 880
European (Finnish)	~27k	1 in 290	1 in 4,300
Admixed American	~22k	1 in 120	1 in 1,400
African / African American	~21k	1 in 140	1 in 560
East Asian	~20k	1 in 90	1 in 580
Ashkenazi Jewish	~13k	1 in 570	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 140	≈ 1 in 710

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 12 coding exons well covered in gnomAD exomes and genomes.? see exons ↓