Heterotaxy, visceral, 4, autosomal

Summary

Heterotaxy, visceral, 4, autosomal (MONDO:0013403) is a disease caused by ACVR2B (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: ACVR2B (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 324

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heterotaxy, visceral, 4, autosomal
Mondo ID	MONDO:0013403
OMIM	613751
DOID	DOID:0051019
UMLS	C3151057
MedGen	462407
GARD	0024918
Is cancer (heuristic)	no

Also known as: ACVR2B visceral heterotaxy · heterotaxy, visceral, 4, autosomal · HTX4 · visceral heterotaxy caused by mutation in ACVR2B

Data availability: 324 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › visceral heterotaxy › heterotaxy, visceral, 4, autosomal

Related subtypes (18): right atrial isomerism, situs inversus, heterotaxy, visceral, 1, X-linked, laterality defects, autosomal dominant, heterotaxy, visceral, 2, autosomal, heterotaxy, visceral, 3, autosomal, heterotaxy, visceral, 6, autosomal, heterotaxy, visceral, 7, autosomal, heterotaxy, visceral, 8, autosomal, dextrocardia, levocardia, heterotaxy, visceral, 9, autosomal, with male infertility, heterotaxy, visceral, 10, autosomal, with male infertility, heterotaxy, visceral, 11, autosomal, with male infertility, heterotaxy, visceral, 5, autosomal, heterotaxy, visceral, 12, autosomal, heterotaxy, visceral, 13, autosomal, heterotaxy, visceral, 14, autosomal

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

324 retrieved; paginated sample, class counts are floors:

186 uncertain significance, 72 benign, 54 likely benign, 7 benign/likely benign, 3 likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1024343	NM_001106.4(ACVR2B):c.1148G>A (p.Arg383His)	ACVR2B	Likely pathogenic	criteria provided, single submitter
545541	NM_001106.4(ACVR2B):c.1147C>T (p.Arg383Cys)	ACVR2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075669	NM_001378183.1(PIEZO2):c.4458_4466del (p.1485VKA[1])	PIEZO2	Likely pathogenic	criteria provided, single submitter
414876	NM_001106.4(ACVR2B):c.1269G>A (p.Ser423=)	ACVR2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900468	NM_001106.4(ACVR2B):c.*4565A>G	ACVR2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014085	NM_001106.4(ACVR2B):c.1156A>C (p.Met386Leu)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1039220	NM_001106.4(ACVR2B):c.1445G>A (p.Arg482Gln)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1385638	NM_001106.4(ACVR2B):c.979G>A (p.Val327Ile)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1386729	NM_001106.4(ACVR2B):c.1219G>A (p.Val407Met)	ACVR2B	Uncertain significance	criteria provided, single submitter
1406908	NM_001106.4(ACVR2B):c.148G>A (p.Glu50Lys)	ACVR2B	Uncertain significance	criteria provided, single submitter
1426139	NM_001106.4(ACVR2B):c.343C>T (p.His115Tyr)	ACVR2B	Uncertain significance	criteria provided, single submitter
1438787	NM_001106.4(ACVR2B):c.406C>T (p.Leu136Phe)	ACVR2B	Uncertain significance	criteria provided, single submitter
1479613	NM_001106.4(ACVR2B):c.20C>T (p.Ala7Val)	ACVR2B	Uncertain significance	criteria provided, single submitter
1507058	NM_001106.4(ACVR2B):c.775G>C (p.Val259Leu)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1983435	NM_001106.4(ACVR2B):c.100G>A (p.Ala34Thr)	ACVR2B	Uncertain significance	criteria provided, single submitter
2019451	NM_001106.4(ACVR2B):c.260+1G>C	ACVR2B	Uncertain significance	criteria provided, single submitter
2066972	NM_001106.4(ACVR2B):c.1186C>G (p.Leu396Val)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2079481	NM_001106.4(ACVR2B):c.652A>T (p.Ile218Phe)	ACVR2B	Uncertain significance	criteria provided, single submitter
2142192	NM_001106.4(ACVR2B):c.553G>T (p.Val185Leu)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2164559	NM_001106.4(ACVR2B):c.1151T>C (p.Ile384Thr)	ACVR2B	Uncertain significance	criteria provided, single submitter
2170414	NM_001106.4(ACVR2B):c.542C>T (p.Pro181Leu)	ACVR2B	Uncertain significance	criteria provided, single submitter
2183847	NM_001106.4(ACVR2B):c.930C>T (p.Gly310=)	ACVR2B	Uncertain significance	criteria provided, single submitter
2190827	NM_001106.4(ACVR2B):c.22C>T (p.Leu8Phe)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438855	NM_001106.4(ACVR2B):c.62G>A (p.Arg21His)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2513360	NM_001106.4(ACVR2B):c.365C>T (p.Pro122Leu)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2628994	NM_001106.4(ACVR2B):c.738G>C (p.Gln246His)	ACVR2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2719454	NM_001106.4(ACVR2B):c.1534A>G (p.Ile512Val)	ACVR2B	Uncertain significance	criteria provided, single submitter
2721568	NM_001106.4(ACVR2B):c.772G>A (p.Glu258Lys)	ACVR2B	Uncertain significance	criteria provided, single submitter
2729958	NM_001106.4(ACVR2B):c.1252A>C (p.Ile418Leu)	ACVR2B	Uncertain significance	criteria provided, single submitter
2760494	NM_001106.4(ACVR2B):c.666+2T>C	ACVR2B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 19 · 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
ACVR2B	Strong	Autosomal dominant	heterotaxy, visceral, 4, autosomal	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACVR2B	Orphanet:157769	Situs ambiguus
SCN10A	Orphanet:101016	Romano-Ward syndrome
SCN10A	Orphanet:130	Brugada syndrome
SCN10A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN10A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN10A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN10A	Orphanet:90026	Primary erythromelalgia
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect
PIEZO2	Orphanet:1154	Arthrogryposis-oculomotor limitation-electroretinal anomalies syndrome
PIEZO2	Orphanet:2461	Marden-Walker syndrome
PIEZO2	Orphanet:376	Gordon syndrome
PIEZO2	Orphanet:707937	Distal arthrogryposis-progressive scoliosis-thumb deformity-impaired proprioception syndrome

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACVR2B	HGNC:174	ENSG00000114739	Q13705	Activin receptor type-2B	gencc,clinvar
SCN10A	HGNC:10582	ENSG00000185313	Q9Y5Y9	Sodium channel protein type 10 subunit alpha	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
PIEZO2	HGNC:26270	ENSG00000154864	Q9H5I5	Piezo-type mechanosensitive ion channel component 2	clinvar
ACVR2B-AS1	HGNC:44161	ENSG00000229589		ACVR2B antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACVR2B	Activin receptor type-2B	Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c).
SCN10A	Sodium channel protein type 10 subunit alpha	Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes.
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
PIEZO2	Piezo-type mechanosensitive ion channel component 2	Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Ion channel	2	44.6×	0.002
Kinase	1	5.5×	0.252
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACVR2B	Kinase	yes		TGFB_receptor, Activin_recp, Prot_kinase_dom
SCN10A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
PIEZO2	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
ACVR2B-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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
ganglionic eminence	1
oocyte	1
secondary oocyte	1
diaphragm	1
olfactory bulb	1
type B pancreatic cell	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
corpus callosum	1
dorsal root ganglion	1
sural nerve	1
buccal mucosa cell	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACVR2B	248	ubiquitous	marker	secondary oocyte, oocyte, ganglionic eminence
SCN10A	21		marker	type B pancreatic cell, olfactory bulb, diaphragm
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
PIEZO2	237	broad	marker	sural nerve, corpus callosum, dorsal root ganglion
ACVR2B-AS1	160	tissue_specific	yes	buccal mucosa cell, hindlimb stylopod muscle, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACVR2B	2,304
SCN5A	2,090
SCN10A	1,802
PIEZO2	1,787
ACVR2B-AS1	0

Intra-cohort edges

A	B	Sources
PIEZO2	SCN10A	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN5A	Q14524	16
ACVR2B	Q13705	9
SCN10A	Q9Y5Y9	8
PIEZO2	Q9H5I5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	2	245.6×	2e-04	SCN10A, SCN5A
Phase 0 - rapid depolarisation	2	230.7×	2e-04	SCN10A, SCN5A
L1CAM interactions	2	80.1×	9e-04	SCN10A, SCN5A
Cardiac conduction	2	72.5×	9e-04	SCN10A, SCN5A
Developmental Biology	3	14.5×	9e-04	ACVR2B, SCN10A, SCN5A
Muscle contraction	2	51.4×	0.001	SCN10A, SCN5A
Axon guidance	2	30.1×	0.003	SCN10A, SCN5A
Nervous system development	2	28.6×	0.003	SCN10A, SCN5A
Regulation of signaling by NODAL	1	317.2×	0.005	ACVR2B
Signaling by Activin	1	253.8×	0.006	ACVR2B
Signaling by NODAL	1	165.5×	0.008	ACVR2B
Signaling by BMP	1	119.0×	0.010	ACVR2B
Signaling by TGFB family members	1	38.5×	0.028	ACVR2B
Signal Transduction	1	3.4×	0.267	ACVR2B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bundle of His cell action potential	2	4213.0×	4e-06	SCN10A, SCN5A
odontogenesis of dentin-containing tooth	3	225.7×	6e-06	ACVR2B, SCN10A, SCN5A
AV node cell action potential	2	2106.5×	7e-06	SCN10A, SCN5A
regulation of atrial cardiac muscle cell membrane depolarization	2	936.2×	3e-05	SCN10A, SCN5A
membrane depolarization during action potential	2	842.6×	3e-05	SCN10A, SCN5A
cardiac muscle cell action potential involved in contraction	2	351.1×	2e-04	SCN10A, SCN5A
regulation of heart rate	2	234.1×	3e-04	SCN10A, SCN5A
sodium ion transmembrane transport	2	101.5×	0.001	SCN10A, SCN5A
AV node cell to bundle of His cell communication	1	2106.5×	0.004	SCN5A
membrane depolarization during Purkinje myocyte cell action potential	1	1404.3×	0.005	SCN5A
membrane depolarization during bundle of His cell action potential	1	1404.3×	0.005	SCN5A
membrane depolarization during atrial cardiac muscle cell action potential	1	1404.3×	0.005	SCN5A
venous blood vessel development	1	842.6×	0.006	ACVR2B
membrane depolarization during AV node cell action potential	1	842.6×	0.006	SCN5A
membrane depolarization during SA node cell action potential	1	842.6×	0.006	SCN5A
positive regulation of activin receptor signaling pathway	1	702.2×	0.006	ACVR2B
detection of mechanical stimulus involved in sensory perception	1	702.2×	0.006	PIEZO2
regulation of ventricular cardiac muscle cell membrane depolarization	1	702.2×	0.006	SCN5A
SA node cell action potential	1	702.2×	0.006	SCN5A
cardiac ventricle development	1	601.9×	0.006	SCN5A
response to denervation involved in regulation of muscle adaptation	1	601.9×	0.006	SCN5A
regulation of atrial cardiac muscle cell membrane repolarization	1	601.9×	0.006	SCN5A
lymphatic endothelial cell differentiation	1	601.9×	0.006	ACVR2B
trophoblast cell migration	1	601.9×	0.006	ACVR2B
negative regulation of adipose tissue development	1	601.9×	0.006	ACVR2B
brainstem development	1	526.6×	0.006	SCN5A
positive regulation of action potential	1	526.6×	0.006	SCN5A
embryonic foregut morphogenesis	1	421.3×	0.007	ACVR2B
retina vasculature development in camera-type eye	1	421.3×	0.007	ACVR2B
atrial cardiac muscle cell action potential	1	421.3×	0.007	SCN5A

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 2

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
ACVR2B	AXITINIB
SCN10A	IMIPRAMINE
SCN5A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
SCN10A	21	4
ACVR2B	12	4
PIEZO2	0	0
ACVR2B-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AXITINIB	4	ACVR2B
PAZOPANIB	4	ACVR2B
DASATINIB	4	ACVR2B, SCN5A
IMIPRAMINE	4	SCN10A, SCN5A
SERTINDOLE	4	SCN10A, SCN5A
PIMOZIDE	4	SCN10A, SCN5A
NIFEDIPINE	4	SCN10A, SCN5A
DILTIAZEM	4	SCN10A, SCN5A
MIBEFRADIL	4	SCN10A, SCN5A
HALOPERIDOL	4	SCN10A, SCN5A
MEXILETINE	4	SCN10A, SCN5A
AMITRIPTYLINE	4	SCN10A, SCN5A
AMIODARONE	4	SCN10A, SCN5A
CHLORPROMAZINE	4	SCN10A, SCN5A
LAMOTRIGINE	4	SCN10A, SCN5A
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
FEDRATINIB	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
SCN10A	144	Binding:124, Functional:16, ADMET:4
ACVR2B	104	Binding:104

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ACVR2B	104
SCN10A	144
SCN5A	594

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
AXITINIB	4	ACVR2B
PAZOPANIB	4	ACVR2B
DASATINIB	4	ACVR2B, SCN5A
IMIPRAMINE	4	SCN10A, SCN5A
SERTINDOLE	4	SCN10A, SCN5A
PIMOZIDE	4	SCN10A, SCN5A
NIFEDIPINE	4	SCN10A, SCN5A
DILTIAZEM	4	SCN10A, SCN5A
MIBEFRADIL	4	SCN10A, SCN5A
HALOPERIDOL	4	SCN10A, SCN5A
MEXILETINE	4	SCN10A, SCN5A
AMITRIPTYLINE	4	SCN10A, SCN5A
AMIODARONE	4	SCN10A, SCN5A
CHLORPROMAZINE	4	SCN10A, SCN5A
LAMOTRIGINE	4	SCN10A, SCN5A
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
FEDRATINIB	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	ACVR2B, SCN10A, SCN5A
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	2	PIEZO2, ACVR2B-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIEZO2	0	—
ACVR2B-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.