Protoporphyria, erythropoietic, 1

Summary

Protoporphyria, erythropoietic, 1 (MONDO:0008319) is a disease caused by FECH (GenCC Definitive), with 2 cohort genes and 28 clinical trials. Top therapeutic interventions include afamelanotide, cysteine hydrochloride, and cimetidine.

At a glance

• Causal gene: FECH (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 60
• Clinical trials: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	protoporphyria, erythropoietic, 1
Mondo ID	MONDO:0008319
OMIM	177000
NCIT	C84698
UMLS	C4692546
MedGen	1643471
GARD	0024616
Is cancer (heuristic)	no

Also known as: EPP · EPP1 · erythrohepatic protoporphyria · erythropoietic protoporphyria · FECH-related erythropoietic protoporphyria · ferrochelatase deficiency · heme synthetase deficiency · protoporphyria, erythropoietic · protoporphyria, erythropoietic, 1

Data availability: 60 ClinVar variants · 4 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › hepatic porphyria › erythropoietic protoporphyria › autosomal erythropoietic protoporphyria › protoporphyria, erythropoietic, 1

Related subtypes (1): protoporphyria, erythropoietic, 2

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

60 retrieved; paginated sample, class counts are floors:

19 pathogenic, 9 uncertain significance, 7 benign/likely benign, 7 conflicting classifications of pathogenicity, 6 likely pathogenic, 6 pathogenic/likely pathogenic, 5 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
561	NM_000140.3(FECH):c.[1224T>A;1225C>T;1231T>G]		Pathogenic	no assertion criteria provided
1069596	NM_000140.5(FECH):c.901_902del (p.Trp301fs)	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
1322894	NM_000140.5(FECH):c.286C>T (p.Arg96Ter)	FECH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1409435	NM_000140.5(FECH):c.1217G>A (p.Cys406Tyr)	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
1457371	NM_000140.5(FECH):c.463+1G>C	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
1805745	NM_000140.5(FECH):c.40del (p.Ala14fs)	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
2574562	NM_000140.5(FECH):c.343C>T (p.Arg115Ter)	FECH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30951	NM_000140.5(FECH):c.553G>A (p.Ala185Thr)	FECH	Pathogenic	no assertion criteria provided
3255565	NM_000140.5(FECH):c.205dup (p.Thr69fs)	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
327428	NM_000140.5(FECH):c.854A>G (p.Gln285Arg)	FECH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3393342	NM_000140.5(FECH):c.757_761del (p.Ser254fs)	FECH	Pathogenic	criteria provided, single submitter
3393344	NM_000140.5(FECH):c.400del (p.Ile134fs)	FECH	Pathogenic	criteria provided, single submitter
375409	NM_000140.5(FECH):c.1001C>T (p.Pro334Leu)	FECH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551	NM_000140.5(FECH):c.1250T>C (p.Phe417Ser)	FECH	Pathogenic	no assertion criteria provided
552	NM_000140.5(FECH):c.1077+1G>A	FECH	Pathogenic	no assertion criteria provided
553	NM_000140.5(FECH):c.1137+3A>G	FECH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554	NM_000140.5(FECH):c.1085T>G (p.Val362Gly)	FECH	Pathogenic	no assertion criteria provided
555	NM_000140.5(FECH):c.314+2T>G	FECH	Pathogenic	criteria provided, single submitter
556	NM_000140.5(FECH):c.314+6A>C	FECH	Pathogenic	no assertion criteria provided
557	NM_000140.3(FECH):c.1078_1137del	FECH	Pathogenic	criteria provided, single submitter
558	NM_000140.5(FECH):c.1136del (p.Lys379fs)	FECH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559	NM_000140.5(FECH):c.194+11A>G	FECH	Pathogenic	no assertion criteria provided
560	NM_000140.5(FECH):c.580_584del (p.Tyr194fs)	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
631802	NM_000140.5(FECH):c.820G>A (p.Asp274Asn)	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
803500	NM_000140.5(FECH):c.598+1G>T	FECH	Pathogenic	criteria provided, multiple submitters, no conflicts
1184619	NM_000140.5(FECH):c.181C>T (p.Gln61Ter)	FECH	Likely pathogenic	no assertion criteria provided
3068479	NM_000140.5(FECH):c.672T>G (p.Ile224Met)	FECH	Likely pathogenic	criteria provided, single submitter
3775311	NM_000140.5(FECH):c.863T>C (p.Met288Thr)	FECH	Likely pathogenic	criteria provided, single submitter
4813852	NM_000140.5(FECH):c.876_878dup (p.Tyr293Ter)	FECH	Likely pathogenic	criteria provided, single submitter
623168	NM_000140.5(FECH):c.913G>T (p.Val305Phe)	FECH	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 10 · 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
FECH	Definitive	Autosomal recessive	protoporphyria, erythropoietic, 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FECH	Orphanet:79278	Autosomal erythropoietic protoporphyria
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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FECH	HGNC:3647	ENSG00000066926	P22830	Ferrochelatase, mitochondrial	gencc,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)
FECH	Ferrochelatase, mitochondrial	Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal 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.

Protein-family classification

Druggable: 2 · 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
Transporter	1	38.9×	0.051
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FECH	Enzyme (other)	yes	4.99.1.1	Ferrochelatase, Ferrochelatase_AS, Ferrochelatase_C
ABCB6	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
bone marrow cell	1
trabecular bone tissue	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
FECH	269	ubiquitous	marker	trabecular bone tissue, bone marrow, bone marrow 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
FECH	2,825
ABCB6	1,480

Intra-cohort edges

A	B	Sources
ABCB6	FECH	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FECH	P22830	25
ABCB6	Q9NP58	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 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	5710.0×	0.002	ABCB6
Mitochondrial ABC transporters	1	1427.5×	0.003	ABCB6
Heme biosynthesis	1	380.7×	0.008	FECH
ABC transporter disorders	1	219.6×	0.010	ABCB6
Disorders of transmembrane transporters	1	69.6×	0.022	ABCB6
ABC-family protein mediated transport	1	60.7×	0.022	ABCB6
Mitochondrial protein degradation	1	57.1×	0.022	FECH
Transport of small molecules	1	12.6×	0.088	ABCB6
Disease	1	6.5×	0.147	ABCB6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of UV	1	8426.0×	0.001	FECH
tetrapyrrole metabolic process	1	8426.0×	0.001	ABCB6
regulation of hemoglobin biosynthetic process	1	8426.0×	0.001	FECH
heme transmembrane transport	1	4213.0×	0.002	ABCB6
obsolete protoporphyrinogen IX metabolic process	1	4213.0×	0.002	FECH
cellular detoxification of cadmium ion	1	2808.7×	0.002	ABCB6
porphyrin-containing compound metabolic process	1	2106.5×	0.002	ABCB6
porphyrin-containing compound biosynthetic process	1	2106.5×	0.002	ABCB6
heme transport	1	2106.5×	0.002	ABCB6
response to platinum ion	1	2106.5×	0.002	FECH
heme metabolic process	1	1685.2×	0.002	ABCB6
response to insecticide	1	1404.3×	0.002	FECH
response to methylmercury	1	1203.7×	0.002	FECH
heme B biosynthetic process	1	842.6×	0.003	FECH
heme A biosynthetic process	1	766.0×	0.003	FECH
very-low-density lipoprotein particle assembly	1	601.9×	0.003	FECH
response to arsenic-containing substance	1	601.9×	0.003	FECH
intracellular copper ion homeostasis	1	468.1×	0.004	ABCB6
response to lead ion	1	468.1×	0.004	FECH
response to light stimulus	1	443.5×	0.004	FECH
melanosome assembly	1	443.5×	0.004	ABCB6
heme biosynthetic process	1	300.9×	0.005	FECH
multicellular organismal-level iron ion homeostasis	1	290.6×	0.005	FECH
cellular response to dexamethasone stimulus	1	290.6×	0.005	FECH
skin development	1	221.7×	0.006	ABCB6
generation of precursor metabolites and energy	1	172.0×	0.007	FECH
erythrocyte differentiation	1	133.8×	0.009	FECH
intracellular iron ion homeostasis	1	122.1×	0.010	ABCB6
cholesterol metabolic process	1	98.0×	0.012	FECH
transmembrane transport	1	84.3×	0.013	ABCB6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
FECH	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FECH	34	4
ABCB6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	FECH
LENVATINIB	4	FECH
AXITINIB	4	FECH
NERATINIB	4	FECH
PACRITINIB	4	FECH
CABOZANTINIB	4	FECH
NILOTINIB	4	FECH
RIBOCICLIB	4	FECH
TUCATINIB	4	FECH
ERLOTINIB	4	FECH
GEFITINIB	4	FECH
LINSITINIB	3	FECH
RIGOSERTIB	3	FECH
CRENOLANIB	3	FECH
MK-2206	2	FECH
CC-401	2	FECH
MK-2461	2	FECH
ZOTIRACICLIB	2	FECH
VARLITINIB	2	FECH
RABUSERTIB	2	FECH
OSI-027	2	FECH
BGT-226 FREE BASE	2	FECH
R-406	2	FECH
CP-724714	2	FECH
BI-2536	2	FECH
PELITINIB	2	FECH
GSK-1070916	1	FECH
AZD-8055	1	FECH
MK-8033	1	FECH
JNJ-26483327	1	FECH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FECH	9	Binding:9
ABCB6	3	Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FECH	4.99.1.1	protoporphyrin ferrochelatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
VEMURAFENIB	4	FECH
LENVATINIB	4	FECH
AXITINIB	4	FECH
NERATINIB	4	FECH
PACRITINIB	4	FECH
CABOZANTINIB	4	FECH
NILOTINIB	4	FECH
RIBOCICLIB	4	FECH
TUCATINIB	4	FECH
ERLOTINIB	4	FECH
GEFITINIB	4	FECH
LINSITINIB	3	FECH
RIGOSERTIB	3	FECH
CRENOLANIB	3	FECH
MK-2206	2	FECH
CC-401	2	FECH
MK-2461	2	FECH
ZOTIRACICLIB	2	FECH
VARLITINIB	2	FECH
RABUSERTIB	2	FECH
OSI-027	2	FECH
BGT-226 FREE BASE	2	FECH
R-406	2	FECH
CP-724714	2	FECH
BI-2536	2	FECH
PELITINIB	2	FECH
GSK-1070916	1	FECH
AZD-8055	1	FECH
MK-8033	1	FECH
JNJ-26483327	1	FECH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FECH
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCB6
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)
ABCB6	3	FECH

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE3	9
PHASE2	5
PHASE2/PHASE3	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05005975	PHASE3	RECRUITING	Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)
NCT05883748	PHASE2/PHASE3	ENROLLING_BY_INVITATION	HELIOS: Open-Label, Long-Term Extension Study to Investigate the Safety, Tolerability, and Efficacy of DISC-1459 (Bitopertin) in Participants With EPP or XLP
NCT06144840	PHASE3	ACTIVE_NOT_RECRUITING	INcreased Sun Exposure Without Pain In Research Participants With EPP or XLP
NCT06910358	PHASE3	ACTIVE_NOT_RECRUITING	Study of Bitopertin in Participants With EPP or XLP (APOLLO)
NCT00004940	PHASE3	COMPLETED	Phase III Study of L-Cysteine in Patients With Erythropoietic Protoporphyria
NCT00979745	PHASE3	COMPLETED	Phase III Confirmatory Study in Erythropoietic Protoporphyria (EPP)
NCT01422915	PHASE2/PHASE3	COMPLETED	Sorbent Therapy of the Cutaneous Porphyrias
NCT01605136	PHASE3	COMPLETED	Phase III Confirmatory Study in Erythropoietic Protoporphyria
NCT04053270	PHASE3	COMPLETED	Multicentre Phase III Erythropoietic Protoporphyria Study
NCT04402489	PHASE3	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria or X-Linked Protoporphyria
NCT04578496	PHASE3	COMPLETED	A Safety Extension Study in Patients With Erythropoietic Protoporphyria (EPP)
NCT06971900	PHASE2	ENROLLING_BY_INVITATION	GATEWAY: A Phase 2a Study of PORT-77 in Adults With Erythropoietic Protoporphyria
NCT01097044	PHASE2	COMPLETED	Phase II Confirmatory Study in Erythropoietic Protoporphyria (EPP)
NCT03520036	PHASE2	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria
NCT05020184	PHASE2	COMPLETED	Effect of Oral Cimetidine in the Protoporphyrias
NCT05308472	PHASE2	COMPLETED	Study of Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and PPIX Concentrations in Participants With EPP
NCT06388642	PHASE1/PHASE2	COMPLETED	Pharmacokinetics of Afamelanotide in Erythropoietic Protoporphyria Patients
NCT07567131	Not specified	RECRUITING	Observational Study of Adults and Adolescents With Erythropoietic Protoporphyria (EPP) and X-linked Porphyria (XLP)
NCT00004831	Not specified	COMPLETED	Study of Cysteine Hydrochloride for Erythropoietic Protoporphyria
NCT00206869	Not specified	UNKNOWN	Does Exercise and Heat Increase the Lightsensibility in Patients With Erythropoietic Protoporphyria
NCT01550705	Not specified	TERMINATED	Effect of Isoniazid on Protoporphyrin Levels in Erythropoietic Protoporphyria
NCT01688895	Not specified	COMPLETED	Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact
NCT01880983	Not specified	COMPLETED	Mitoferrin-1 Expression in Erythropoietic Protoporphyria (Porphyria Rare Disease Clinical Research Consortium (RDCRC))
NCT02979249	Not specified	COMPLETED	Oral Iron for Erythropoietic Protoporphyrias
NCT03682731	Not specified	COMPLETED	Light Exposure Patterns and Symptoms Among Patients With Erythropoietic Protoporphyria
NCT05572125	Not specified	COMPLETED	Iron Therapy in Erythropoietic Protoporphyria
NCT05780840	Not specified	UNKNOWN	Protection Against Visible Light by Dihydroxyacetone in Erythropoietic Protoporphyria
NCT07603401	Not specified	TEMPORARILY_NOT_AVAILABLE	Expanded Access Program of Bitopertin For Participants With EPP or XLP

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AFAMELANOTIDE	4	5
CYSTEINE HYDROCHLORIDE	4	2
CIMETIDINE	4	1
COLESTIPOL HYDROCHLORIDE	4	1
ISONIAZID	4	1
BITOPERTIN	3	4
DERSIMELAGON	3	2
COLESTIPOL	0	1
DIHYDROXYACETONE	-1	1