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…

DNmechanismAD/ARLOEUF 0.572 OMIM phenotypes

Clinical Summary— PPOX

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Gene-Disease Validity (ClinGen)

variegate porphyria · SDStrong

Strong evidence — appropriate for clinical testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

70 unique Pathogenic / Likely Pathogenic· 186 VUS of 383 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PPOX

Authoritative clinical overview · Recommended first read

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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

This gene — mechanism propensity

0.6842th %ile

GOF

0.6151th %ile

LOF

0.2873th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

383 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42

Likely Pathogenic28

VUS186

Likely Benign62

Benign10

Conflicting18

Pathogenic

Likely Pathogenic

186

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	26	14	2	0	42
Likely Pathogenic	20	6	1	1	28
VUS	0	170	13	3	186
Likely Benign	0	7	21	34	62
Benign	0	1	8	1	10
Conflicting	—				18
Total	46	198	45	39	346

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap PPOX — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →