PPOX

Chr 1ADAR

protoporphyrinogen oxidase

Also known as: PPO, V290M, VP, VPCO

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismAD/ARLOEUF 0.572 OMIM phenotypes
Clinical SummaryPPOX
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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.
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.57LOEUF
pLI 0.028
Z-score 3.09
OE 0.30 (0.170.57)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.98Z-score
OE missense 0.83 (0.740.93)
216 obs / 260.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.30 (0.170.57)
00.351.4
Missense OE0.83 (0.740.93)
00.61.4
Synonymous OE1.05
01.21.6
LoF obs/exp: 7 / 23.0Missense obs/exp: 216 / 260.3Syn Z: -0.43
DN
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

0 submitted variants 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.

3D Protein StructureAlphaFold
Clinical Literature
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