Harderoporphyria

Summary

Harderoporphyria (MONDO:0030048) is a disease caused by CPOX (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CPOX (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	harderoporphyria
Mondo ID	MONDO:0030048
MeSH	C562816
OMIM	618892
Orphanet	659672
ICD-11	1664486132
UMLS	C0342859
MedGen	137981
GARD	0025517
Is cancer (heuristic)	no

Also known as: HARDEROPORPHYRIA · harderoporphyria · HARPO

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary skin disorder › hereditary photodermatosis › inherited porphyria › CPOX-related hereditary coproporphyria › harderoporphyria

Related subtypes (1): hereditary coproporphyria

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

7 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
126445	NM_000097.7(CPOX):c.980A>G (p.His327Arg)	CPOX	Pathogenic	no assertion criteria provided
453	NM_000097.7(CPOX):c.1210A>G (p.Lys404Glu)	CPOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679116	NM_000097.7(CPOX):c.700+2T>C	CPOX	Likely pathogenic	no assertion criteria provided
459	NM_000097.7(CPOX):c.1339C>T (p.Arg447Cys)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049038	NM_000097.7(CPOX):c.178C>G (p.Arg60Gly)	CPOX	Uncertain significance	criteria provided, multiple submitters, no conflicts
1064042	NM_000097.7(CPOX):c.47T>G (p.Val16Gly)	CPOX	Uncertain significance	criteria provided, multiple submitters, no conflicts
457	NM_000097.7(CPOX):c.1277+3A>G	CPOX	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
CPOX	Strong	Autosomal recessive	harderoporphyria	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CPOX	Orphanet:659672	Harderoporphyria
CPOX	Orphanet:79273	Hereditary coproporphyria

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
CPOX	HGNC:2321	ENSG00000080819	P36551	Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CPOX	Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial	Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway.

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)
CPOX	Enzyme (other)	yes	1.3.3.3	Coprogen_oxidase_aer, Coprogen_oxidase_CS, Coprogen_oxidase_aer_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
C1 segment of cervical spinal cord	1
jejunal mucosa	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CPOX	268	tissue_specific	marker	trabecular bone tissue, C1 segment of cervical spinal cord, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CPOX	2,015

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CPOX	P36551	1

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	CPOX

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
response to insecticide	1	2808.7×	0.001	CPOX
response to methylmercury	1	2407.4×	0.001	CPOX
obsolete protoporphyrinogen IX biosynthetic process	1	1685.2×	0.001	CPOX
heme B biosynthetic process	1	1685.2×	0.001	CPOX
heme A biosynthetic process	1	1532.0×	0.001	CPOX
response to arsenic-containing substance	1	1203.7×	0.001	CPOX
response to iron ion	1	936.2×	0.001	CPOX
response to lead ion	1	936.2×	0.001	CPOX
heme biosynthetic process	1	601.9×	0.002	CPOX

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
CPOX	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
CPOX	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CPOX	1.3.3.3	coproporphyrinogen 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	CPOX
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)
CPOX	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.