PPOX

Chr 1ADAR

protoporphyrinogen oxidase

Also known as: PPO, V290M, VP, VPCO

NCBI Gene: 5498ENSG00000143224UniProt: P50336

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]

Primary Disease Associations & Inheritance

Variegate porphyriaMIM #176200
AD
Variegate porphyria, childhood-onsetMIM #620483
AR
359
ClinVar variants
79
Pathogenic / LP
0.03
pLI score
4
Active trials
Clinical Summary— PPOX
🧬
Gene-Disease Validity (ClinGen)
variegate porphyria · SDStrong

Strong evidence — appropriate for clinical testing

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.
📋
ClinVar Variants
79 Pathogenic / Likely Pathogenic· 190 VUS of 359 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.98Z-score
OE missense 0.83 (0.74–0.93)
216 obs / 260.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.30 (0.17–0.57)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.74–0.93)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 7 / 23.0Missense obs/exp: 216 / 260.3Syn Z: -0.43

ClinVar Variant Classifications

359 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50
Likely Pathogenic29
VUS190
Likely Benign62
Benign10
Conflicting18
50
Pathogenic
29
Likely Pathogenic
190
VUS
62
Likely Benign
10
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
13
23
0
50
Likely Pathogenic
14
6
8
1
29
VUS
0
161
26
3
190
Likely Benign
0
7
21
34
62
Benign
0
1
8
1
10
Conflicting
—18
Total281888639359

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

View in ClinVar →

Protein Context — Lollipop Plot

PPOX · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Variegate porphyria

MIM #176200

Molecular basis of disorder known

Autosomal dominant

Variegate porphyria, childhood-onset

MIM #620483

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PPOX
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Trujillano D et al.·Eur J Hum Genet
2017
AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review.
Wang B et al.·Gastroenterology
2023Review
Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome.
Clough CA et al.·Blood
2022
Myelodysplastic syndromes with ring sideroblasts.
Bruzzese A et al.·Hematol Oncol
2023Review
Further Characterization of the Neuroendocrine Phenotype Associated With the PPOX-Related Variegate Porphyria.
Assaleh YA et al.·Pediatr Neurol
2023
A boy with blistering of sun-exposed skin and finger shortening: the first case of Variegate Porphyria with a novel mutation in protoporphyrinogen oxidase (PPOX) gene in Iran: a case report and literature review.
Vafaee-Shahi M et al.·Ital J Pediatr
2022Review
Molecular characterization of a novel His333Arg variant of human protoporphyrinogen oxidase IX.
Novakova Z et al.·Biochem Biophys Res Commun
2022
The assessment of noncoding variant of PPOX gene in variegate porphyria reveals post-transcriptional role of the 5' untranslated exon 1.
Fiorentino V et al.·Blood Cells Mol Dis
2016
Molecular characterization of homozygous variegate porphyria.
Roberts AG et al.·Hum Mol Genet
1998
Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria.
Cho SY et al.·Clin Chim Acta
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Anorexia Nervosa

Orexin Gene in Anorexia Nervosa

RECRUITING
NCT06800898Istituto Auxologico ItalianoStarted 2024-06-19
Blood samples and Questionnaires
ObesityWeight Loss

The Effect of Different Diets on Arterial Stiffness in Obese Patients on Semaglutide

RECRUITING
NCT04990024Phase NAAmerican University of Beirut Medical CenterStarted 2021-07-01
Dietary Intervention Med DietDietary Intervention HP/LC Diet
Narcolepsy

Genetic and Clinical Characterization of Type 1 and 2 Narcolepsy in Adult and Pediatric Black and North African Populations

NOT YET RECRUITING
NCT06786377Assistance Publique - Hôpitaux de ParisStarted 2025-01-30
saliva sampling
Acute Intermittent PorphyriaHereditary CoproporphyriaVariegate Porphyria

Acute Porphyria Biomarkers for Disease Activity

ACTIVE NOT RECRUITING
NCT02935400The University of Texas Medical Branch, GalvestonStarted 2014-04-28
Hemin

External Resources

Links to major genomics databases and tools