X-linked erythropoietic protoporphyria

Summary

X-linked erythropoietic protoporphyria (MONDO:0010420) is a disease caused by ALAS2 (GenCC Strong), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include isoniazid and dersimelagon.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALAS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked erythropoietic protoporphyria
Mondo ID	MONDO:0010420
MeSH	C567464
OMIM	300752
Orphanet	443197
UMLS	C2677889
MedGen	394385
GARD	0017755
Is cancer (heuristic)	no

Also known as: ALAS2-related erythropoietic protoporphyria · erythropoietic protoporphyria, X-linked · protoporphyria, erythropoietic, X-linked · X-linked dominant erythropoietic protoporphyria · X-linked dominant protoporphyria · XLDPP · XLEPP · XLP · XLPP

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

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked erythropoietic protoporphyria

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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:

6 uncertain significance, 4 conflicting classifications of pathogenicity, 3 pathogenic, 1 pathogenic/likely pathogenic, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10482	NM_000032.5(ALAS2):c.1706_1709del (p.Glu569fs)	ALAS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10483	NM_000032.5(ALAS2):c.1699_1700del (p.Met567fs)	ALAS2	Pathogenic	no assertion criteria provided
60673	NM_000032.5(ALAS2):c.1642C>T (p.Gln548Ter)	ALAS2	Pathogenic	no assertion criteria provided
60674	NM_000032.5(ALAS2):c.1651_1676del (p.Ser551fs)	ALAS2	Pathogenic	no assertion criteria provided
3341449	NM_000032.5(ALAS2):c.304+2T>C	ALAS2	Likely pathogenic	criteria provided, single submitter
214088	NM_000032.5(ALAS2):c.1559C>T (p.Pro520Leu)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
368592	NM_000032.5(ALAS2):c.1567C>T (p.His523Tyr)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
368598	NM_000032.5(ALAS2):c.661G>A (p.Ala221Thr)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40978	NM_000032.5(ALAS2):c.1757A>T (p.Tyr586Phe)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3065338	NM_000032.5(ALAS2):c.1168+19C>A	ALAS2	Uncertain significance	criteria provided, single submitter
3234045	NM_000032.5(ALAS2):c.1532G>T (p.Arg511Leu)	ALAS2	Uncertain significance	criteria provided, single submitter
3382336	NM_000032.5(ALAS2):c.304+1G>C	ALAS2	Uncertain significance	criteria provided, single submitter
3382870	NM_000032.5(ALAS2):c.1178T>C (p.Phe393Ser)	ALAS2	Uncertain significance	criteria provided, single submitter
3779372	NM_000032.5(ALAS2):c.1651T>G (p.Ser551Ala)	ALAS2	Uncertain significance	criteria provided, single submitter
449992	NM_000032.5(ALAS2):c.1057C>G (p.Leu353Val)	ALAS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214092	NM_000032.5(ALAS2):c.-15-1790G>A	ALAS2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
ALAS2	Strong	X-linked	X-linked sideroblastic anemia 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALAS2	Orphanet:443197	X-linked erythropoietic protoporphyria
ALAS2	Orphanet:75563	X-linked sideroblastic anemia

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
ALAS2	HGNC:397	ENSG00000158578	P22557	5-aminolevulinate synthase, erythroid-specific, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALAS2	5-aminolevulinate synthase, erythroid-specific, mitochondrial	Catalyzes the pyridoxal 5’-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products.

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)
ALAS2	Enzyme (other)	yes	2.3.1.37	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, 4pyrrol_synth_NH2levulA_synth

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
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALAS2	172	broad	marker	trabecular bone tissue, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALAS2	2,037

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALAS2	P22557	27

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	ALAS2

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
hemoglobin biosynthetic process	1	2808.7×	0.001	ALAS2
obsolete protoporphyrinogen IX biosynthetic process	1	1685.2×	0.001	ALAS2
heme B biosynthetic process	1	1685.2×	0.001	ALAS2
intracellular oxygen homeostasis	1	1532.0×	0.001	ALAS2
heme biosynthetic process	1	601.9×	0.003	ALAS2
erythrocyte development	1	526.6×	0.003	ALAS2
erythrocyte differentiation	1	267.5×	0.005	ALAS2
intracellular iron ion homeostasis	1	244.2×	0.005	ALAS2
response to hypoxia	1	95.8×	0.010	ALAS2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALAS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALAS2	2.3.1.37	5-aminolevulinate synthase

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	ALAS2
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)
ALAS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE3	2

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)
NCT04402489	PHASE3	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria or X-Linked 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
NCT02979249	Not specified	COMPLETED	Oral Iron for Erythropoietic Protoporphyrias

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ISONIAZID	4	1
DERSIMELAGON	3	1