Variegate porphyria, childhood-onset

Summary

Variegate porphyria, childhood-onset (MONDO:0957577) is a disease caused by PPOX (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PPOX (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	variegate porphyria, childhood-onset
Mondo ID	MONDO:0957577
OMIM	620483
UMLS	C5882681
MedGen	1849794
GARD	0026867
Is cancer (heuristic)	no

Data availability: 16 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › hepatic porphyria › PPOX-related hepatic porphyria › variegate porphyria › variegate porphyria, childhood-onset

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

16 retrieved; paginated sample, class counts are floors:

9 pathogenic, 4 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2577464	NM_001122764.3(PPOX):c.506G>A (p.Gly169Glu)	PPOX	Pathogenic	no assertion criteria provided
2577466	NM_001122764.3(PPOX):c.1043A>G (p.Tyr348Cys)	PPOX	Pathogenic	no assertion criteria provided
2577467	NM_001122764.3(PPOX):c.413G>C (p.Arg138Pro)	PPOX	Pathogenic	no assertion criteria provided
2577468	NM_001122764.3(PPOX):c.808G>T (p.Val270Leu)	PPOX	Pathogenic	no assertion criteria provided
8694	NM_001122764.3(PPOX):c.502C>T (p.Arg168Cys)	PPOX	Pathogenic/Likely pathogenic	no assertion criteria provided
8696	NM_001122764.3(PPOX):c.175C>T (p.Arg59Trp)	PPOX	Pathogenic	criteria provided, multiple submitters, no conflicts
8698	NM_001122764.3(PPOX):c.1046A>C (p.Asp349Ala)	PPOX	Pathogenic	no assertion criteria provided
8701	NM_001122764.3(PPOX):c.657_658insAAGGCCAGCGCC (p.Ala219_Leu220insLysAlaSerAla)	PPOX	Pathogenic	no assertion criteria provided
8702	PPOX, IVS11DS, G-A, -1	PPOX	Pathogenic	no assertion criteria provided
8703	NM_001122764.3(PPOX):c.35T>C (p.Ile12Thr)	PPOX	Pathogenic	no assertion criteria provided
2202870	NM_001122764.3(PPOX):c.-9G>A	PPOX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3380122	NM_001122764.3(PPOX):c.164A>C (p.Glu55Ala)	PPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8704	NM_001122764.3(PPOX):c.767C>G (p.Pro256Arg)	PPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875181	NM_001122764.3(PPOX):c.844G>A (p.Val282Ile)	PPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
915371	NM_001122764.3(PPOX):c.1072G>A (p.Gly358Arg)	PPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2392551	NM_001122764.3(PPOX):c.799C>T (p.Arg267Cys)	PPOX	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PPOX	Definitive	Semidominant	variegate porphyria	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PPOX	Orphanet:79473	Variegate porphyria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PPOX	HGNC:9280	ENSG00000143224	P50336	Protoporphyrinogen oxidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPOX	Protoporphyrinogen oxidase	Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPOX	Enzyme (other)	yes	1.3.3.4	Amino_oxidase, Protoporphyrinogen_oxidase, FAD/NAD-bd_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of bronchus	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPOX	264	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPOX	1,525

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPOX	P50336	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Heme biosynthesis	1	761.3×	0.001	PPOX

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
porphyrin-containing compound biosynthetic process	1	4213.0×	1e-03	PPOX
obsolete protoporphyrinogen IX biosynthetic process	1	1685.2×	1e-03	PPOX
heme B biosynthetic process	1	1685.2×	1e-03	PPOX
heme A biosynthetic process	1	1532.0×	1e-03	PPOX
heme biosynthetic process	1	601.9×	0.002	PPOX
response to xenobiotic stimulus	1	69.1×	0.014	PPOX

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PPOX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PPOX	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPOX	1.3.3.4	protoporphyrinogen oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PPOX
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PPOX	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.