Hereditary coproporphyria

Summary

Hereditary coproporphyria (MONDO:0007369) is a disease caused by CPOX (GenCC Strong), with 4 cohort genes and 5 clinical trials. Top therapeutic interventions include hemin and givosiran.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal gene: CPOX (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 98
• Phenotypes (HPO): 33
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0003163	Elevated urinary delta-aminolevulinic acid	Very frequent (80-99%)
HP:0010472	Abnormal circulating porphyrin concentration	Very frequent (80-99%)
HP:0000987	Atypical scarring of skin	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002572	Episodic vomiting	Frequent (30-79%)
HP:0008994	Proximal muscle weakness in lower limbs	Frequent (30-79%)
HP:0008997	Proximal muscle weakness in upper limbs	Frequent (30-79%)
HP:0009763	Limb pain	Frequent (30-79%)
HP:0010473	Porphyrinuria	Frequent (30-79%)
HP:0011121	Abnormal skin morphology	Frequent (30-79%)
HP:0012217	Increased urinary porphobilinogen	Frequent (30-79%)
HP:0040319	Dark urine	Frequent (30-79%)
HP:0000112	Nephropathy	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000992	Cutaneous photosensitivity	Occasional (5-29%)
HP:0001030	Fragile skin	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001402	Hepatocellular carcinoma	Occasional (5-29%)
HP:0001649	Tachycardia	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0003418	Back pain	Occasional (5-29%)
HP:0005325	Extension of hair growth on temples to lateral eyebrow	Occasional (5-29%)
HP:0007178	Motor polyneuropathy	Occasional (5-29%)
HP:0008066	Abnormal blistering of the skin	Occasional (5-29%)
HP:0008528	Long hairs growing from helix of pinna	Occasional (5-29%)
HP:0009937	Facial hirsutism	Occasional (5-29%)
HP:0012850	Small intestinal dysmotility	Occasional (5-29%)
HP:0032936	Intrusion symptom	Occasional (5-29%)
HP:0001903	Anemia	Excluded (0%)
HP:0001945	Fever	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary coproporphyria
Mondo ID	MONDO:0007369
MeSH	D046349
OMIM	121300
Orphanet	79273
DOID	DOID:13269
ICD-11	1365918274
NCIT	C84759
SNOMED CT	7425008
UMLS	C0162531
MedGen	57931
GARD	0006619
MedDRA	10019866
NORD	1228
Is cancer (heuristic)	no

Also known as: coproporphyria · coproporphyria hereditary · coproporphyria, hereditary · coproporphyrinogen oxidase deficiency · CPRO deficiency · HCP · hereditary coproporphyria · porphyria hepatica coproporphyria · porphyria hepatica II

Data availability: 98 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › hepatic porphyria › hereditary coproporphyria

Related subtypes (6): erythropoietic protoporphyria, porphyria due to ALA dehydratase deficiency, porphyria cutanea tarda, HMBS-related hepatic porphyria, PPOX-related hepatic porphyria, hepatic cutaneous porphyria

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

98 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 30 benign, 10 conflicting classifications of pathogenicity, 8 benign/likely benign, 3 likely pathogenic, 3 likely benign, 3 pathogenic/likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3894555	NM_000097.7(CPOX):c.661C>T (p.Gln221Ter)	CPOX	Pathogenic	criteria provided, single submitter
453	NM_000097.7(CPOX):c.1210A>G (p.Lys404Glu)	CPOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801990	NM_000097.7(CPOX):c.478C>T (p.Gln160Ter)	CPOX	Pathogenic	criteria provided, multiple submitters, no conflicts
845386	NM_000097.7(CPOX):c.601G>A (p.Glu201Lys)	CPOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4087469	NM_000169.3(GLA):c.692A>G (p.Asp231Gly)	GLA	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
1709963	NM_000097.7(CPOX):c.946A>T (p.Lys316Ter)	CPOX	Likely pathogenic	criteria provided, single submitter
4537364	NM_000097.7(CPOX):c.1276C>T (p.Arg426Ter)	CPOX	Likely pathogenic	criteria provided, single submitter
1284646	NM_005689.4(ABCB6):c.1762G>A (p.Gly588Ser)	ABCB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346983	NM_000097.7(CPOX):c.487G>T (p.Val163Leu)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346984	NM_000097.7(CPOX):c.395C>T (p.Ala132Val)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346987	NM_000097.7(CPOX):c.299A>T (p.Glu100Val)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
459	NM_000097.7(CPOX):c.1339C>T (p.Arg447Cys)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872083	NM_000097.7(CPOX):c.520G>A (p.Ala174Thr)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899908	NM_000097.7(CPOX):c.510A>G (p.Val170=)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901024	NM_000097.7(CPOX):c.1138C>G (p.Gln380Glu)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901085	NM_000097.7(CPOX):c.212G>C (p.Gly71Ala)	CPOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903513	NM_000097.7(CPOX):c.557-3C>T	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
1333796	NM_000097.7(CPOX):c.348GGA[7] (p.Glu119_Glu120dup)	CPOX	Uncertain significance	criteria provided, single submitter
346949	NM_000097.7(CPOX):c.*1174G>A	CPOX	Uncertain significance	criteria provided, single submitter
346950	NM_000097.7(CPOX):c.*1153G>C	CPOX	Uncertain significance	criteria provided, single submitter
346952	NM_000097.7(CPOX):c.*1076G>A	CPOX	Uncertain significance	criteria provided, single submitter
346954	NM_000097.7(CPOX):c.*939A>G	CPOX	Uncertain significance	criteria provided, single submitter
346957	NM_000097.7(CPOX):c.*633A>C	CPOX	Uncertain significance	criteria provided, single submitter
346959	NM_000097.7(CPOX):c.*506C>T	CPOX	Uncertain significance	criteria provided, single submitter
346963	NM_000097.7(CPOX):c.*340A>G	CPOX	Uncertain significance	criteria provided, single submitter
346966	NM_000097.7(CPOX):c.*194G>T	CPOX	Uncertain significance	criteria provided, single submitter
346985	NM_000097.7(CPOX):c.348G>C (p.Pro116=)	CPOX	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 12 · 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 dominant	hereditary coproporphyria	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CPOX	Orphanet:659672	Harderoporphyria
CPOX	Orphanet:79273	Hereditary coproporphyria
GLA	Orphanet:324	Fabry disease
ABCB6	Orphanet:241	Dyschromatosis universalis hereditaria
ABCB6	Orphanet:90044	Familial pseudohyperkalemia
ABCB6	Orphanet:98938	Colobomatous microphthalmia
ABCB6	Orphanet:98942	Coloboma of choroid and retina
ABCB6	Orphanet:98943	Coloboma of eye lens
ABCB6	Orphanet:98944	Coloboma of iris
ABCB6	Orphanet:98945	Coloboma of macula
ABCB6	Orphanet:98946	Coloboma of eyelid
ABCB6	Orphanet:98947	Coloboma of optic disc

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CPOX	HGNC:2321	ENSG00000080819	P36551	Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial	gencc,clinvar
NDC1	HGNC:25525	ENSG00000058804	Q9BTX1	Nucleoporin NDC1	clinvar
GLA	HGNC:4296	ENSG00000102393	P06280	Alpha-galactosidase A	clinvar
ABCB6	HGNC:47	ENSG00000115657	Q9NP58	ATP-binding cassette sub-family B member 6	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.
NDC1	Nucleoporin NDC1	Component of the nuclear pore complex (NPC), which plays a key role in de novo assembly and insertion of NPC in the nuclear envelope.
GLA	Alpha-galactosidase A	Catalyzes the hydrolysis of glycosphingolipids and participates in their degradation in the lysosome.
ABCB6	ATP-binding cassette sub-family B member 6	ATP-dependent transporter that catalyzes the transport of a broad-spectrum of porphyrins from the cytoplasm to the extracellular space through the plasma membrane or into the vesicle lumen.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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
Transporter	1	19.4×	0.076
Enzyme (other)	2	6.0×	0.076
Other/Unknown	1	0.5×	0.962

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
NDC1	Other/Unknown	no		Nucleoporin_prot_Ndc1/Nup
GLA	Enzyme (other)	yes	3.2.1.22	Glyco_hydro_27/36_CS, Glyco_hydro_27, Glyco_hydro_b
ABCB6	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
jejunal mucosa	1
trabecular bone tissue	1
oocyte	1
primordial germ cell in gonad	1
secondary oocyte	1
monocyte	1
mononuclear cell	1
pancreatic ductal cell	1
left ovary	1
right hemisphere of cerebellum	1
right ovary	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
NDC1	262	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
GLA	263	ubiquitous	marker	pancreatic ductal cell, monocyte, mononuclear cell
ABCB6	140	ubiquitous	marker	right ovary, right hemisphere of cerebellum, left ovary

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CPOX	2,015
GLA	1,826
NDC1	1,815
ABCB6	1,480

Intra-cohort edges

A	B	Sources
ABCB6	CPOX	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLA	P06280	31
ABCB6	Q9NP58	16
NDC1	Q9BTX1	2
CPOX	P36551	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCB6 causes MCOPCB7	1	2855.0×	0.016	ABCB6
Disorders of transmembrane transporters	2	69.6×	0.016	NDC1, ABCB6
Export of Viral Ribonucleoproteins from Nucleus	1	951.7×	0.026	NDC1
Mitochondrial ABC transporters	1	713.8×	0.026	ABCB6
Interactions of Rev with host cellular proteins	1	713.8×	0.026	NDC1
Transport of Mature mRNAs Derived from Intronless Transcripts	1	407.9×	0.032	NDC1
Interactions of Vpr with host cellular proteins	1	356.9×	0.032	NDC1
Glucose metabolism	1	219.6×	0.032	NDC1
Heme biosynthesis	1	190.3×	0.032	CPOX
Metabolism of non-coding RNA	1	158.6×	0.032	NDC1
Nuclear Envelope Breakdown	1	114.2×	0.032	NDC1
ABC transporter disorders	1	109.8×	0.032	ABCB6
Postmitotic nuclear pore complex (NPC) reformation	1	102.0×	0.032	NDC1
Cellular response to heat stress	1	98.5×	0.032	NDC1
IPs transport between nucleus and cytosol	1	95.2×	0.032	NDC1
IP3 and IP4 transport between cytosol and nucleus	1	95.2×	0.032	NDC1
IP6 and IP7 transport between cytosol and nucleus	1	95.2×	0.032	NDC1
Transport of Mature Transcript to Cytoplasm	1	95.2×	0.032	NDC1
Mitotic Prophase	1	92.1×	0.032	NDC1
Transport of Ribonucleoproteins into the Host Nucleus	1	89.2×	0.032	NDC1
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	89.2×	0.032	NDC1
Gene Silencing by RNA	1	89.2×	0.032	NDC1
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	89.2×	0.032	NDC1
tRNA processing	1	89.2×	0.032	NDC1
NEP/NS2 Interacts with the Cellular Export Machinery	1	86.5×	0.032	NDC1
Host Interactions of HIV factors	1	84.0×	0.032	NDC1
Nuclear import of Rev protein	1	84.0×	0.032	NDC1
Vpr-mediated nuclear import of PICs	1	84.0×	0.032	NDC1
Transport of the SLBP independent Mature mRNA	1	81.6×	0.032	NDC1
SUMOylation of SUMOylation proteins	1	81.6×	0.032	NDC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tetrapyrrole metabolic process	1	4213.0×	0.004	ABCB6
heme transmembrane transport	1	2106.5×	0.004	ABCB6
negative regulation of nitric-oxide synthase activity	1	2106.5×	0.004	GLA
glycosylceramide catabolic process	1	1404.3×	0.004	GLA
cellular detoxification of cadmium ion	1	1404.3×	0.004	ABCB6
porphyrin-containing compound metabolic process	1	1053.2×	0.004	ABCB6
porphyrin-containing compound biosynthetic process	1	1053.2×	0.004	ABCB6
heme transport	1	1053.2×	0.004	ABCB6
heme metabolic process	1	842.6×	0.004	ABCB6
nuclear pore localization	1	842.6×	0.004	NDC1
glycoside catabolic process	1	702.2×	0.004	GLA
response to insecticide	1	702.2×	0.004	CPOX
response to methylmercury	1	601.9×	0.005	CPOX
nuclear pore organization	1	526.6×	0.005	NDC1
obsolete protoporphyrinogen IX biosynthetic process	1	421.3×	0.005	CPOX
heme B biosynthetic process	1	421.3×	0.005	CPOX
nuclear pore complex assembly	1	421.3×	0.005	NDC1
heme A biosynthetic process	1	383.0×	0.005	CPOX
glycosphingolipid catabolic process	1	383.0×	0.005	GLA
response to arsenic-containing substance	1	300.9×	0.006	CPOX
negative regulation of nitric oxide biosynthetic process	1	247.8×	0.006	GLA
intracellular copper ion homeostasis	1	234.1×	0.006	ABCB6
response to iron ion	1	234.1×	0.006	CPOX
response to lead ion	1	234.1×	0.006	CPOX
melanosome assembly	1	221.7×	0.006	ABCB6
oligosaccharide metabolic process	1	175.5×	0.008	GLA
heme biosynthetic process	1	150.5×	0.009	CPOX
homologous chromosome pairing at meiosis	1	150.5×	0.009	NDC1
skin development	1	110.9×	0.011	ABCB6
nucleocytoplasmic transport	1	98.0×	0.012	NDC1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Givosiran	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Hemin.

Drug target analysis

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

Druggability breadth: 4 of 4 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GLA	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLA	62	4
CPOX	0	0
NDC1	0	0
ABCB6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
MIGALASTAT	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA
ACRISORCIN	4	GLA
NOMIFENSINE MALEATE	4	GLA
INAMRINONE	4	GLA
AMILORIDE HYDROCHLORIDE	4	GLA
PHENOL	4	GLA
FLUPHENAZINE HYDROCHLORIDE	4	GLA
PRAZOSIN HYDROCHLORIDE	4	GLA
PSEUDOEPHEDRINE	4	GLA
PHENYTOIN SODIUM	4	GLA
RIBAVIRIN	4	GLA
SOTALOL HYDROCHLORIDE	4	GLA
DIGOXIN	4	GLA
PRAZOSIN	4	GLA
DOMPERIDONE	4	GLA
CIMETIDINE	4	GLA
MASOPROCOL	4	GLA
METHOTREXATE	4	GLA
AMSACRINE	4	GLA
LANSOPRAZOLE	4	GLA
PINDOLOL	4	GLA
NIMESULIDE	4	GLA
TRIAMTERENE	4	GLA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GLA	114	Binding:104, Functional:10
CPOX	3	Binding:3
ABCB6	3	Functional:3
NDC1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CPOX	1.3.3.3	coproporphyrinogen oxidase
GLA	3.2.1.22	alpha-galactosidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GLA	114

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
MIGALASTAT	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA
ACRISORCIN	4	GLA
NOMIFENSINE MALEATE	4	GLA
INAMRINONE	4	GLA
AMILORIDE HYDROCHLORIDE	4	GLA
PHENOL	4	GLA
FLUPHENAZINE HYDROCHLORIDE	4	GLA
PRAZOSIN HYDROCHLORIDE	4	GLA
PSEUDOEPHEDRINE	4	GLA
PHENYTOIN SODIUM	4	GLA
RIBAVIRIN	4	GLA
SOTALOL HYDROCHLORIDE	4	GLA
DIGOXIN	4	GLA
PRAZOSIN	4	GLA
DOMPERIDONE	4	GLA
CIMETIDINE	4	GLA
MASOPROCOL	4	GLA
METHOTREXATE	4	GLA
AMSACRINE	4	GLA
LANSOPRAZOLE	4	GLA
PINDOLOL	4	GLA
NIMESULIDE	4	GLA
TRIAMTERENE	4	GLA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GLA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CPOX, ABCB6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NDC1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CPOX	3	—
NDC1	1	—
ABCB6	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03338816	PHASE3	COMPLETED	ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
NCT02922413	PHASE2	TERMINATED	Panhematin for Prevention of Acute Attacks of Porphyria
NCT02935400	Not specified	ACTIVE_NOT_RECRUITING	Acute Porphyria Biomarkers for Disease Activity
NCT01568554	Not specified	COMPLETED	Clinical Diagnosis of Acute Porphyria
NCT03547297	Not specified	TERMINATED	INSIGHT-AHP: A Study to Characterize the Prevalence of Acute Hepatic Porphyria (AHP) in Patients With Clinical Presentation and History Consistent With AHP

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HEMIN	3	2
GIVOSIRAN	3	1
CHEMBL4303664	0	2
CHEMBL5308479	0	2
HEMATIN	-1	2