Encephalopathy, porphyria-related

Summary

Encephalopathy, porphyria-related (MONDO:0958224) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy, porphyria-related
Mondo ID	MONDO:0958224
OMIM	620704
UMLS	C5935574
MedGen	1859316
GARD	0028081
Is cancer (heuristic)	no

Data availability: 9 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Mendelian encephalopathy › encephalopathy, porphyria-related

Related subtypes (18): encephalopathy, recurrent, of childhood, encephalopathy, axonal, with necrotizing myopathy, cardiomyopathy, and cataracts, Bonnemann-Meinecke-Reich syndrome, severe neonatal-onset encephalopathy with microcephaly, ethylmalonic encephalopathy, familial encephalopathy with neuroserpin inclusion bodies, spongiform encephalopathy with neuropsychiatric features, familial acute necrotizing encephalopathy, encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, severe neurodegenerative syndrome with lipodystrophy, encephalopathy due to defective mitochondrial and peroxisomal fission 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, encephalopathy, progressive, with amyotrophy and optic atrophy, encephalitis/encephalopathy, mild, with reversible myelin vacuolization, encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities

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

9 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 uncertain significance, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
1456	NM_000190.4(HMBS):c.499C>T (p.Arg167Trp)	HMBS	Pathogenic	criteria provided, multiple submitters, no conflicts
1485	NM_000190.4(HMBS):c.242T>C (p.Leu81Pro)	HMBS	Pathogenic	no assertion criteria provided
1509204	NM_000190.4(HMBS):c.500G>C (p.Arg167Pro)	HMBS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1462	NM_000190.4(HMBS):c.601C>T (p.Arg201Trp)	HMBS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161252	NM_000190.4(HMBS):c.257A>T (p.Glu86Val)	HMBS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1382821	NM_000190.4(HMBS):c.661G>A (p.Gly221Ser)	HMBS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2735769	NM_000190.4(HMBS):c.604G>T (p.Val202Leu)	HMBS	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HMBS	Orphanet:79276	Acute intermittent porphyria

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
HMBS	HGNC:4982	ENSG00000256269	P08397	Porphobilinogen deaminase	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.

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)
HMBS	Enzyme (other)	yes	2.5.1.61	HemC, Porphobilin_deaminase_N, Porphobilinogen_deaminase_C

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
HMBS	271	ubiquitous	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
HMBS	44

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HMBS	P08397	11

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	HMBS

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
obsolete protoporphyrinogen IX biosynthetic process	1	1685.2×	9e-04	HMBS
heme B biosynthetic process	1	1685.2×	9e-04	HMBS
heme A biosynthetic process	1	1532.0×	9e-04	HMBS
heme biosynthetic process	1	601.9×	0.002	HMBS

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
HMBS	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
HMBS	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HMBS	2.5.1.61	hydroxymethylbilane 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	HMBS
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)
HMBS	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.