Acute intermittent porphyria

Summary

Acute intermittent porphyria (MONDO:0008294) is a disease caused by HMBS (GenCC Strong), with 5 cohort genes and 15 clinical trials. The dominant Reactome pathway is Heme biosynthesis (3 cohort genes). Top therapeutic interventions include chlorpromazine hydrochloride, givosiran, and hemin.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: HMBS (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 141
• Phenotypes (HPO): 51
• Clinical trials: 15

Clinical features

Epidemiology

Prevalence records

22 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.013	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.54	Europe	Validated
Annual incidence	<1 / 1 000 000	0.012	France	Validated
Annual incidence	<1 / 1 000 000	0.011	Italy	Validated
Annual incidence	<1 / 1 000 000	0.013	Finland	Validated
Annual incidence	<1 / 1 000 000	0.018	Netherlands	Validated
Annual incidence	<1 / 1 000 000	0.014	Norway	Validated
Annual incidence	<1 / 1 000 000	0.016	Poland	Validated
Annual incidence	<1 / 1 000 000	0.014	Spain	Validated
Annual incidence	<1 / 1 000 000	0.051	Sweden	Validated
Annual incidence	<1 / 1 000 000	0.022	Switzerland	Validated
Annual incidence	<1 / 1 000 000	0.016	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000	0.55	France	Validated
Point prevalence	1-9 / 1 000 000	0.5	Italy	Validated
Point prevalence	1-9 / 1 000 000	0.59	Finland	Validated
Point prevalence	1-9 / 1 000 000	0.81	Netherlands	Validated
Point prevalence	1-9 / 1 000 000	0.63	Norway	Validated
Point prevalence	1-9 / 1 000 000	0.72	Poland	Validated
Point prevalence	1-9 / 1 000 000	0.63	Spain	Validated
Point prevalence	1-5 / 10 000	10	Sweden	Validated

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 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:0010473	Porphyrinuria	Very frequent (80-99%)
HP:0012217	Increased urinary porphobilinogen	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0003418	Back pain	Frequent (30-79%)
HP:0006824	Cranial nerve paralysis	Frequent (30-79%)
HP:0009763	Limb pain	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0030833	Neck pain	Frequent (30-79%)
HP:0000711	Restlessness	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001262	Excessive daytime somnolence	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001402	Hepatocellular carcinoma	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002203	Respiratory paralysis	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002460	Distal muscle weakness	Occasional (5-29%)
HP:0002595	Ileus	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)
HP:0004347	Weakness of muscles of respiration	Occasional (5-29%)
HP:0007002	Motor axonal neuropathy	Occasional (5-29%)
HP:0007024	Pseudobulbar paralysis	Occasional (5-29%)
HP:0007178	Motor polyneuropathy	Occasional (5-29%)
HP:0008994	Proximal muscle weakness in lower limbs	Occasional (5-29%)
HP:0008997	Proximal muscle weakness in upper limbs	Occasional (5-29%)
HP:0011999	Paranoia	Occasional (5-29%)
HP:0040319	Dark urine	Occasional (5-29%)
HP:0100785	Insomnia	Occasional (5-29%)
HP:0410263	Brain imaging abnormality	Occasional (5-29%)
HP:0011121	Abnormal skin morphology	Excluded (0%)
HP:0000016	Urinary retention	Very rare (<1-4%)
HP:0000020	Urinary incontinence	Very rare (<1-4%)
HP:0000975	Hyperhidrosis	Very rare (<1-4%)
HP:0001259	Coma	Very rare (<1-4%)
HP:0001337	Tremor	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acute intermittent porphyria
Mondo ID	MONDO:0008294
MeSH	D017118
OMIM	176000
Orphanet	79276
DOID	DOID:3890
ICD-11	1565229118
NCIT	C84536
SNOMED CT	234422006
UMLS	C0162565
MedGen	56452
GARD	0005732
NORD	729
Is cancer (heuristic)	no

Also known as: acute intermittent porphyria · AIP · HMBS deficiency · hydroxymethylbilane synthase deficiency · porphyria, acute intermittent

Data availability: 141 ClinVar variants · 4 GenCC gene-disease records · 16 cell lines.

Disease family

Classification path: disease › human disease › acute disease › acute intermittent porphyria

Related subtypes (118): encephalopathy, acute, infection-induced, seminal vesicle acute gonorrhea, acute diarrhea, acute hydrops keratoconus, acute pericementitis, purulent acute otitis media, acute otitis externa, acute eustachian salpingitis, acute cervicitis, acute gonococcal epididymo-orchitis, acute salpingitis, acute respiratory failure, acute conjunctivitis, acute laryngopharyngitis, acute orbital inflammation, acute dacryocystitis, acute sphenoidal sinusitis, acute proliferative glomerulonephritis, acute cystitis, acute tympanitis, acute closed-angle glaucoma, acute gonococcal prostatitis, acute poststreptococcal glomerulonephritis, acute diffuse glomerulonephritis, acute retrobulbar neuritis, acute frontal sinusitis, acute cholangitis, acute thyroiditis, acute maxillary sinusitis, acute kidney injury, acute transudative otitis media, acute myocarditis, subacute glomerulonephritis, acute pyelonephritis, acute urate nephropathy, acute stress disorder, acute inflammation of lacrimal passage, acute endometritis, acute cor pulmonale, acute intestinal ischemia, subacute delirium, acute laryngitis, acute myocardial infarction, acute ethmoiditis, acute dacryoadenitis, acute female pelvic peritonitis, acute quadriplegic myopathy, severe acute respiratory syndrome, acute hypotension, acute coronary syndrome, acute chest syndrome, acute pancreatitis, acute retinal necrosis syndrome, subacute bacterial endocarditis, necrotizing encephalomyelopathy, subacute, of Leigh, adult, leukemia, acute myelocytic, with polyposis coli and colon cancer, surfactant metabolism dysfunction, pulmonary, 1, myoglobinuria, acute recurrent, autosomal recessive, acute leukemia, acute insulin response, alcohol sensitivity, acute, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, acute transverse myelitis, subacute cutaneous lupus erythematosus, acute lung injury, subacute inflammatory demyelinating polyneuropathy, Marburg acute multiple sclerosis, acute pure sensory neuropathy, autoimmune autonomic ganglionopathy, acute sensory ataxic neuropathy, acute fatty liver of pregnancy, acute neonatal citrullinemia type I, acute endophthalmitis, acute zonal occult outer retinopathy, acute annular outer retinopathy, poliomyelitis, acute generalized exanthematous pustulosis, acute opioid poisoning, acute encephalopathy with biphasic seizures and late reduced diffusion, acute tricyclic antidepressant poisoning, acute poisoning by drugs with membrane-stabilizing effect, recurrent acute pancreatitis, bilateral acute depigmentation of the iris, idiopathic acute eosinophilic pneumonia, acute ackee fruit intoxication, acute interstitial pneumonia, acute liver failure, acute adrenal insufficiency, encephalitis, acute inflammatory demyelinating polyradiculoneuropathy, acute motor and sensory axonal neuropathy, acute motor axonal neuropathy, acute graft versus host disease, acute pharyngitis, sudden hearing loss disorder, acute bronchiolitis, acute tonsillitis, acute rheumatic heart disease, acute cholinergic dysautonomia, acute mountain sickness, acute lymphoblastic leukemia congenital sporadic aniridia, acute lichenoid pityriasis, leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate, acute radiation syndrome, acute bilirubin encephalopathy, acute mast cell leukemia, subacute bursitis, acute papillary necrosis, acute posterior multifocal placoid pigment epitheliopathy, acute idiopathic urticaria, acute macular neuroretinopathy, acute flaccid myelitis, acute hepatitis B virus infection, acute hepatitis C virus infection, acute fibrinous and organizing pneumonia, acute transplant rejection

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

141 retrieved; paginated sample, class counts are floors:

48 pathogenic, 31 uncertain significance, 20 conflicting classifications of pathogenicity, 12 benign/likely benign, 11 pathogenic/likely pathogenic, 10 likely pathogenic, 7 benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030659	NM_000190.4(HMBS):c.826-2A>T	HMBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070048	NM_000190.4(HMBS):c.973C>T (p.Arg325Ter)	HMBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1120222	NM_000190.4(HMBS):c.210+1G>C	HMBS	Pathogenic	criteria provided, single submitter
1164095	NM_000190.4(HMBS):c.211-1G>T	HMBS	Pathogenic	criteria provided, single submitter
1443	NM_000190.4(HMBS):c.77G>A (p.Arg26His)	HMBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1445	NM_000190.4(HMBS):c.346C>T (p.Arg116Trp)	HMBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1446	NM_000190.4(HMBS):c.500G>A (p.Arg167Gln)	HMBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447	NM_000190.4(HMBS):c.518G>A (p.Arg173Gln)	HMBS	Pathogenic	criteria provided, single submitter
1448	NM_000190.4(HMBS):c.463C>T (p.Gln155Ter)	HMBS	Pathogenic	no assertion criteria provided
1449	NM_000190.4(HMBS):c.446G>A (p.Arg149Gln)	HMBS	Pathogenic	no assertion criteria provided
1450	NM_000190.4(HMBS):c.734T>G (p.Leu245Arg)	HMBS	Pathogenic	no assertion criteria provided
1451	NM_000190.4(HMBS):c.900del (p.His300fs)	HMBS	Pathogenic	no assertion criteria provided
1453	NM_000190.4(HMBS):c.593G>A (p.Trp198Ter)	HMBS	Pathogenic	no assertion criteria provided
1454	NM_000190.4(HMBS):c.91G>A (p.Ala31Thr)	HMBS	Pathogenic	no assertion criteria provided
1455	NM_000190.4(HMBS):c.100C>A (p.Gln34Lys)	HMBS	Pathogenic	no assertion criteria provided
1456	NM_000190.4(HMBS):c.499C>T (p.Arg167Trp)	HMBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1457	NM_000190.4(HMBS):c.500G>T (p.Arg167Leu)	HMBS	Pathogenic	no assertion criteria provided
1459	NM_000190.4(HMBS):c.174del (p.Thr59fs)	HMBS	Pathogenic	no assertion criteria provided
1460	NM_000190.4(HMBS):c.181dup (p.Asp61fs)	HMBS	Pathogenic	no assertion criteria provided
1461	NM_000190.4(HMBS):c.211-1G>A	HMBS	Pathogenic	no assertion criteria provided
1464	NM_000190.4(HMBS):c.331G>A (p.Gly111Arg)	HMBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1465	NM_000190.4(HMBS):c.499-1G>A	HMBS	Pathogenic	criteria provided, single submitter
1466	NM_000190.4(HMBS):c.530T>G (p.Leu177Arg)	HMBS	Pathogenic	criteria provided, single submitter
1468	NM_000190.4(HMBS):c.730_731del (p.Leu244fs)	HMBS	Pathogenic	criteria provided, single submitter
1470	NM_000190.4(HMBS):c.734_741dup (p.Ile248fs)	HMBS	Pathogenic	no assertion criteria provided
1471	NM_000190.4(HMBS):c.748G>A (p.Glu250Lys)	HMBS	Pathogenic	no assertion criteria provided
1473	NM_000190.4(HMBS):c.755C>T (p.Ala252Val)	HMBS	Pathogenic	no assertion criteria provided
1474	NM_000190.4(HMBS):c.766C>A (p.His256Asn)	HMBS	Pathogenic	no assertion criteria provided
1475	NM_000190.4(HMBS):c.771+1G>C	HMBS	Pathogenic	no assertion criteria provided
1476	NM_000190.4(HMBS):c.913-1G>A	HMBS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 15 · 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
HMBS	Strong	Autosomal dominant	acute intermittent porphyria	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HMBS	Orphanet:79276	Acute intermittent porphyria
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy
CPOX	Orphanet:659672	Harderoporphyria
CPOX	Orphanet:79273	Hereditary coproporphyria
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
PPOX	Orphanet:79473	Variegate porphyria

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HMBS	HGNC:4982	ENSG00000256269	P08397	Porphobilinogen deaminase	gencc,clinvar
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	clinvar
CPOX	HGNC:2321	ENSG00000080819	P36551	Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial	clinvar
ABCB6	HGNC:47	ENSG00000115657	Q9NP58	ATP-binding cassette sub-family B member 6	clinvar
PPOX	HGNC:9280	ENSG00000143224	P50336	Protoporphyrinogen oxidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HMBS	Porphobilinogen deaminase	As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen.
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
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.
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.
PPOX	Protoporphyrinogen oxidase	Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.

Protein-family classification

Druggable: 5 · 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)	4	9.6×	4e-04
Transporter	1	15.6×	0.063

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HMBS	Enzyme (other)	yes	2.5.1.61	HemC, Porphobilin_deaminase_N, Porphobilinogen_deaminase_C
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
CPOX	Enzyme (other)	yes	1.3.3.3	Coprogen_oxidase_aer, Coprogen_oxidase_CS, Coprogen_oxidase_aer_sf
ABCB6	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
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.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
trabecular bone tissue	2
bone marrow	1
bone marrow cell	1
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1
C1 segment of cervical spinal cord	1
jejunal mucosa	1
left ovary	1
right hemisphere of cerebellum	1
right ovary	1
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
HMBS	271	ubiquitous	marker	trabecular bone tissue, bone marrow, bone marrow cell
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
CPOX	268	tissue_specific	marker	trabecular bone tissue, C1 segment of cervical spinal cord, jejunal mucosa
ABCB6	140	ubiquitous	marker	right ovary, right hemisphere of cerebellum, left ovary
PPOX	264	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACO2	4,776
CPOX	2,015
PPOX	1,525
ABCB6	1,480
HMBS	44

Intra-cohort edges

A	B	Sources
ABCB6	CPOX	string_interaction
ABCB6	PPOX	string_interaction
ACO2	CPOX	string_interaction
CPOX	PPOX	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCB6	Q9NP58	16
HMBS	P08397	11
PPOX	P50336	3
CPOX	P36551	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Heme biosynthesis	3	456.8×	3e-07	HMBS, CPOX, PPOX
Defective ABCB6 causes MCOPCB7	1	2284.0×	0.004	ABCB6
Mitochondrial ABC transporters	1	571.0×	0.009	ABCB6
Maturation of TCA enzymes and regulation of TCA cycle	1	114.2×	0.031	ACO2
ABC transporter disorders	1	87.8×	0.031	ABCB6
Citric acid cycle (TCA cycle)	1	84.6×	0.031	ACO2
Protein localization	1	38.1×	0.059	ACO2
Mitochondrial protein import	1	33.6×	0.059	ACO2
Disorders of transmembrane transporters	1	27.9×	0.063	ABCB6
ABC-family protein mediated transport	1	24.3×	0.063	ABCB6
Mitochondrial protein degradation	1	22.8×	0.063	ACO2
Aerobic respiration and respiratory electron transport	1	17.7×	0.074	ACO2
Transport of small molecules	1	5.0×	0.226	ABCB6
Disease	1	2.6×	0.362	ABCB6
Metabolism of proteins	1	2.5×	0.362	ACO2
Metabolism	1	2.3×	0.362	ACO2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete protoporphyrinogen IX biosynthetic process	3	1011.1×	2e-08	HMBS, CPOX, PPOX
heme B biosynthetic process	3	1011.1×	2e-08	HMBS, CPOX, PPOX
heme A biosynthetic process	3	919.2×	2e-08	HMBS, CPOX, PPOX
heme biosynthetic process	3	361.1×	3e-07	HMBS, CPOX, PPOX
porphyrin-containing compound biosynthetic process	2	1685.2×	2e-06	ABCB6, PPOX
tetrapyrrole metabolic process	1	3370.4×	0.001	ABCB6
heme transmembrane transport	1	1685.2×	0.002	ABCB6
cellular detoxification of cadmium ion	1	1123.5×	0.003	ABCB6
citrate metabolic process	1	842.6×	0.003	ACO2
porphyrin-containing compound metabolic process	1	842.6×	0.003	ABCB6
heme transport	1	842.6×	0.003	ABCB6
heme metabolic process	1	674.1×	0.003	ABCB6
response to insecticide	1	561.7×	0.004	CPOX
response to methylmercury	1	481.5×	0.004	CPOX
response to arsenic-containing substance	1	240.7×	0.007	CPOX
intracellular copper ion homeostasis	1	187.2×	0.008	ABCB6
response to iron ion	1	187.2×	0.008	CPOX
response to lead ion	1	187.2×	0.008	CPOX
melanosome assembly	1	177.4×	0.008	ABCB6
tricarboxylic acid cycle	1	102.1×	0.013	ACO2
skin development	1	88.7×	0.014	ABCB6
generation of precursor metabolites and energy	1	68.8×	0.017	ACO2
intracellular iron ion homeostasis	1	48.9×	0.023	ABCB6
transmembrane transport	1	33.7×	0.032	ABCB6
brain development	1	15.9×	0.064	ABCB6
response to xenobiotic stimulus	1	13.8×	0.070	PPOX

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): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HMBS	0	0
ACO2	0	0
CPOX	0	0
ABCB6	0	0
PPOX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
PPOX	5	Binding:5
HMBS	3	Binding:3
CPOX	3	Binding:3
ABCB6	3	Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HMBS	2.5.1.61	hydroxymethylbilane synthase
ACO2	4.2.1.3	aconitate hydratase
CPOX	1.3.3.3	coproporphyrinogen oxidase
PPOX	1.3.3.4	protoporphyrinogen oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	4	HMBS, CPOX, ABCB6, PPOX
D	Druggable family + AlphaFold only, no drug	1	ACO2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HMBS	3	—
ACO2	0	—
CPOX	3	—
ABCB6	3	—
PPOX	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE1	4
PHASE2/PHASE3	1
PHASE3	1
PHASE2	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00418795	PHASE2/PHASE3	COMPLETED	Porphozym in the Treatment of Acute Attacks in AIP
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
NCT02949830	PHASE1/PHASE2	COMPLETED	A Study to Evaluate Long-term Safety and Clinical Activity of Givosiran (ALN-AS1) in Patient With Acute Intermittent Porphyria (AIP)
NCT02082860	PHASE1	COMPLETED	Phase I Gene Therapy Clinical Trial Using the Vector rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria
NCT02452372	PHASE1	COMPLETED	A Phase 1 Study of Givosiran (ALN-AS1) in Patients With Acute Intermittent Porphyria (AIP)
NCT02943213	PHASE1	COMPLETED	Assessment of Intra-subject Variability in the Bioavailability of Chlorpromazine Hydrochloride
NCT03505853	PHASE1	COMPLETED	A Study to Investigate the Interaction Between Givosiran and a 5-probe Drug Cocktail in Patients With Acute Intermittent Porphyria (AIP)
NCT01617642	Not specified	ACTIVE_NOT_RECRUITING	Dental Health, Diet, Inflammation and Biomarkers in Patients With Acute Intermittent Porphyria(AIP)
NCT02935400	Not specified	ACTIVE_NOT_RECRUITING	Acute Porphyria Biomarkers for Disease Activity
NCT05502133	Not specified	RECRUITING	Identification of Acute Intermittent Porphyria Modifying Genes
NCT06273644	Not specified	RECRUITING	Clinical Research on Acute Intermittent Porphyria and the Use of Carbohydrate-Rich Diet as a Treatment
NCT01568554	Not specified	COMPLETED	Clinical Diagnosis of Acute Porphyria
NCT02076763	Not specified	COMPLETED	Observational Study of Acute Intermittent Porphyria Patients
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
CHLORPROMAZINE HYDROCHLORIDE	4	1
GIVOSIRAN	3	4
HEMIN	3	2
CHEMBL4303664	0	2
CHEMBL5308479	0	2
HEMATIN	-1	2