Arrhythmogenic right ventricular dysplasia 5

Summary

Arrhythmogenic right ventricular dysplasia 5 (MONDO:0011459) is a disease caused by TMEM43 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TMEM43 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 895

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic right ventricular dysplasia 5
Mondo ID	MONDO:0011459
MeSH	C565776
OMIM	604400
DOID	DOID:0110074
UMLS	C1858379
MedGen	346805
GARD	0024800
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy 5 · arrhythmogenic right ventricular cardiomyopathy caused by mutation in TMEM43 · arrhythmogenic right ventricular dysplasia 5 · arrhythmogenic right ventricular dysplasia type 5 · arrhythmogenic right ventricular dysplasia, familial, 5 · arrhythmogenic right ventricular dysplasia, familial, type 5 · ARVC5 · ARVD5 · TMEM43 arrhythmogenic right ventricular cardiomyopathy

Data availability: 895 ClinVar variants · 4 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › familial cardiomyopathy › familial isolated arrhythmogenic right ventricular dysplasia › arrhythmogenic right ventricular dysplasia 5

Related subtypes (15): arrhythmogenic right ventricular dysplasia 13, arrhythmogenic right ventricular dysplasia 1, arrhythmogenic right ventricular dysplasia 3, arrhythmogenic right ventricular dysplasia 4, arrhythmogenic right ventricular dysplasia 6, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 8, arrhythmogenic right ventricular dysplasia 9, arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular dysplasia 11, arrhythmogenic right ventricular dysplasia 12, familial isolated arrhythmogenic ventricular dysplasia, left dominant form, familial isolated arrhythmogenic ventricular dysplasia, biventricular form, familial isolated arrhythmogenic ventricular dysplasia, right dominant form, arrhythmogenic right ventricular dysplasia, familial, 14

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

600 retrieved; paginated sample, class counts are floors:

309 uncertain significance, 198 likely benign, 60 conflicting classifications of pathogenicity, 26 benign/likely benign, 6 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1701917	NM_024334.3(TMEM43):c.393-2A>G	TMEM43	Likely pathogenic	criteria provided, single submitter
1005419	NM_024334.3(TMEM43):c.326A>G (p.His109Arg)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022952	NM_024334.3(TMEM43):c.443A>G (p.Asn148Ser)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024402	NM_024334.3(TMEM43):c.346C>T (p.Arg116Trp)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1057804	NM_024334.3(TMEM43):c.956T>C (p.Met319Thr)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1406293	NM_024334.3(TMEM43):c.392+16_392+32del	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1408369	NM_024334.3(TMEM43):c.905G>A (p.Arg302Lys)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165451	NM_024334.3(TMEM43):c.323T>C (p.Val108Ala)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1780356	NM_024334.3(TMEM43):c.17C>G (p.Ser6Cys)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178138	NM_024334.3(TMEM43):c.280G>A (p.Ala94Thr)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178140	NM_024334.3(TMEM43):c.484G>A (p.Asp162Asn)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179489	NM_024334.3(TMEM43):c.428C>T (p.Thr143Met)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180542	NM_024334.3(TMEM43):c.644A>C (p.His215Pro)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180543	NM_024334.3(TMEM43):c.658C>T (p.Arg220Cys)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180544	NM_024334.3(TMEM43):c.796C>T (p.Arg266Trp)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1911204	NM_024334.3(TMEM43):c.1097C>T (p.Ala366Val)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191780	NM_024334.3(TMEM43):c.121A>G (p.Met41Val)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191781	NM_024334.3(TMEM43):c.164G>A (p.Gly55Asp)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191782	NM_024334.3(TMEM43):c.206C>T (p.Ser69Leu)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191784	NM_024334.3(TMEM43):c.296A>G (p.Lys99Arg)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202114	NM_024334.3(TMEM43):c.1141G>A (p.Gly381Ser)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202115	NM_024334.3(TMEM43):c.98C>T (p.Ser33Leu)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202116	NM_024334.3(TMEM43):c.601G>A (p.Asp201Asn)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202117	NM_024334.3(TMEM43):c.659G>A (p.Arg220His)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202118	NM_024334.3(TMEM43):c.661C>T (p.Arg221Cys)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202119	NM_024334.3(TMEM43):c.718C>T (p.Arg240Cys)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202121	NM_024334.3(TMEM43):c.859C>T (p.His287Tyr)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202122	NM_024334.3(TMEM43):c.1100G>A (p.Gly367Asp)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202124	NM_024334.3(TMEM43):c.214G>A (p.Val72Met)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202127	NM_024334.3(TMEM43):c.286C>G (p.Arg96Gly)	TMEM43	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
TMEM43	Definitive	Autosomal dominant	arrhythmogenic right ventricular dysplasia 5	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM43	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TMEM43	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TMEM43	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TMEM43	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy

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
TMEM43	HGNC:28472	ENSG00000170876	Q9BTV4	Transmembrane protein 43	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM43	Transmembrane protein 43	May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM43	Other/Unknown	no		TMEM43_fam

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
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM43	287	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM43	1,864

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM43	Q9BTV4	89.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of cell communication by electrical coupling	1	8426.0×	9e-04	TMEM43
nuclear membrane organization	1	2407.4×	0.001	TMEM43
metal ion transport	1	1872.4×	0.001	TMEM43
sodium ion transport	1	271.8×	0.007	TMEM43
potassium ion transport	1	191.5×	0.007	TMEM43
memory	1	183.2×	0.007	TMEM43
lipid metabolic process	1	91.6×	0.012	TMEM43
innate immune response	1	33.6×	0.030	TMEM43

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
TMEM43	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TMEM43	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TMEM43

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)
TMEM43	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.