Hirschsprung disease, susceptibility to, 2

Summary

Hirschsprung disease, susceptibility to, 2 (MONDO:0010833) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 84

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hirschsprung disease, susceptibility to, 2
Mondo ID	MONDO:0010833
OMIM	600155
UMLS	C1838564
MedGen	374002
Is cancer (heuristic)	no

Also known as: EDNRB Hirschsprung disease · Hirschsprung disease caused by mutation in EDNRB · Hirschsprung disease type 2 · Hirschsprung disease, susceptibility to, 2 · Hirschsprung disease, susceptibility to, type 2 · HSCR2

Data availability: 84 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › Hirschsprung disease, susceptibility to › Hirschsprung disease, susceptibility to, 2

Related subtypes (8): Hirschsprung disease, susceptibility to, 1, Hirschsprung disease, susceptibility to, 5, Hirschsprung disease, susceptibility to, 6, Hirschsprung disease, susceptibility to, 7, Hirschsprung disease, susceptibility to, 8, Hirschsprung disease, susceptibility to, 9, Hirschsprung disease, susceptibility to, 3, Hirschsprung disease, susceptibility to, 4

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

84 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 15 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 risk factor, 3 benign, 3 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1683916	NM_001122659.3(EDNRB):c.596+1G>A	EDNRB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16635	NM_001122659.3(EDNRB):c.824G>A (p.Trp275Ter)	EDNRB	risk factor	no assertion criteria provided
16636	NM_001122659.3(EDNRB):c.877dup (p.Tyr293fs)	EDNRB	risk factor	no assertion criteria provided
16641	NM_000115.5(EDNRB):c.-51-949A>T	EDNRB	risk factor	no assertion criteria provided
16637	NM_001122659.3(EDNRB):c.169G>A (p.Gly57Ser)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16638	NM_001122659.3(EDNRB):c.914G>A (p.Ser305Asn)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225346	NM_001122659.3(EDNRB):c.-26G>A	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
226623	NM_001122659.3(EDNRB):c.49C>T (p.Leu17Phe)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255140	NM_001122659.3(EDNRB):c.1239C>G (p.Ser413=)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255141	NM_001122659.3(EDNRB):c.731C>T (p.Thr244Met)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312453	NM_001122659.3(EDNRB):c.*1662T>C	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312467	NM_001122659.3(EDNRB):c.*296A>G	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312471	NM_001122659.3(EDNRB):c.777C>T (p.Pro259=)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504853	NM_001122659.3(EDNRB):c.778G>A (p.Val260Ile)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
619136	NM_001122659.3(EDNRB):c.553G>A (p.Val185Met)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882483	NM_001122659.3(EDNRB):c.483+15C>T	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884203	NM_001122659.3(EDNRB):c.99T>C (p.Pro33=)	EDNRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16633	NM_001122659.3(EDNRB):c.828G>T (p.Trp276Cys)	EDNRB-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312469	NM_001122659.3(EDNRB):c.1194+15C>T	EDNRB-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1218338	NM_001122659.3(EDNRB):c.1212G>A (p.Trp404Ter)	EDNRB	Uncertain significance	criteria provided, multiple submitters, no conflicts
228662	NM_001122659.3(EDNRB):c.1285G>A (p.Gly429Arg)	EDNRB	Uncertain significance	criteria provided, multiple submitters, no conflicts
312442	NM_001122659.3(EDNRB):c.*2426A>C	EDNRB	Uncertain significance	criteria provided, single submitter
312443	NM_001122659.3(EDNRB):c.*2355T>C	EDNRB	Uncertain significance	criteria provided, single submitter
312444	NM_001122659.3(EDNRB):c.*2309T>C	EDNRB	Uncertain significance	criteria provided, single submitter
312445	NM_001122659.3(EDNRB):c.*2258G>T	EDNRB	Uncertain significance	criteria provided, single submitter
312446	NM_001122659.3(EDNRB):c.*2219A>G	EDNRB	Uncertain significance	criteria provided, single submitter
312447	NM_001122659.3(EDNRB):c.*2167C>G	EDNRB	Uncertain significance	criteria provided, single submitter
312448	NM_001122659.3(EDNRB):c.*2165C>T	EDNRB	Uncertain significance	criteria provided, single submitter
312449	NM_001122659.3(EDNRB):c.*2064T>G	EDNRB	Uncertain significance	criteria provided, single submitter
312450	NM_001122659.3(EDNRB):c.*2055A>G	EDNRB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
EDNRB	Limited	Unknown	Hirschsprung disease, susceptibility to, 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EDNRB	Orphanet:388	Hirschsprung disease
EDNRB	Orphanet:895	Waardenburg syndrome type 2
EDNRB	Orphanet:897	Waardenburg-Shah syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	gencc,clinvar
EDNRB-AS1	HGNC:49045	ENSG00000225579		EDNRB antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EDNRB	Endothelin receptor type B	Non-specific receptor for endothelin 1, 2, and 3.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt
EDNRB-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral globus pallidus	1
lower lobe of lung	1
parotid gland	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EDNRB	274	broad	marker	parotid gland, lateral globus pallidus, lower lobe of lung
EDNRB-AS1	101		yes	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EDNRB	2,415
EDNRB-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EDNRB	P24530	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.017	EDNRB
Peptide ligand-binding receptors	1	74.2×	0.017	EDNRB
G alpha (q) signalling events	1	57.4×	0.017	EDNRB

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
enteric smooth muscle cell differentiation	1	16852.0×	1e-03	EDNRB
response to endothelin	1	16852.0×	1e-03	EDNRB
posterior midgut development	1	8426.0×	1e-03	EDNRB
negative regulation of neuron maturation	1	8426.0×	1e-03	EDNRB
regulation of fever generation	1	8426.0×	1e-03	EDNRB
aldosterone metabolic process	1	8426.0×	1e-03	EDNRB
positive regulation of penile erection	1	5617.3×	0.001	EDNRB
chordate pharynx development	1	5617.3×	0.001	EDNRB
renin secretion into blood stream	1	4213.0×	0.001	EDNRB
vein smooth muscle contraction	1	4213.0×	0.001	EDNRB
renal sodium excretion	1	4213.0×	0.001	EDNRB
renal albumin absorption	1	3370.4×	0.001	EDNRB
neuroblast migration	1	3370.4×	0.001	EDNRB
heparin proteoglycan metabolic process	1	2808.7×	0.001	EDNRB
epithelial fluid transport	1	2106.5×	0.001	EDNRB
developmental pigmentation	1	2106.5×	0.001	EDNRB
negative regulation of protein metabolic process	1	2106.5×	0.001	EDNRB
endothelin receptor signaling pathway	1	1685.2×	0.002	EDNRB
response to sodium phosphate	1	1685.2×	0.002	EDNRB
regulation of pH	1	1404.3×	0.002	EDNRB
negative regulation of adenylate cyclase activity	1	1404.3×	0.002	EDNRB
podocyte differentiation	1	1404.3×	0.002	EDNRB
positive regulation of urine volume	1	1296.3×	0.002	EDNRB
protein transmembrane transport	1	1296.3×	0.002	EDNRB
enteric nervous system development	1	991.3×	0.002	EDNRB
renal sodium ion absorption	1	991.3×	0.002	EDNRB
macrophage chemotaxis	1	936.2×	0.002	EDNRB
regulation of epithelial cell proliferation	1	936.2×	0.002	EDNRB
vasoconstriction	1	887.0×	0.002	EDNRB
response to pain	1	887.0×	0.002	EDNRB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
EDNRB	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRB	16	4
EDNRB-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EDNRB	270	Binding:229, Functional:41

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EDNRB	270

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

16 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)
AMBRISENTAN	4	EDNRB
MODAFINIL	4	EDNRB
MACITENTAN	4	EDNRB
APROCITENTAN	4	EDNRB
SITAXENTAN	4	EDNRB
SULFISOXAZOLE	4	EDNRB
MAZINDOL	4	EDNRB
BOSENTAN	4	EDNRB
CLAZOSENTAN	3	EDNRB
DARUSENTAN	3	EDNRB
AVOSENTAN	3	EDNRB
TEZOSENTAN	3	EDNRB
ATRASENTAN	3	EDNRB
FELOPRENTAN	2	EDNRB
ENRASENTAN	2	EDNRB
ENDOTHELIN	2	EDNRB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EDNRB
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EDNRB-AS1

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)
EDNRB-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.