Arrhythmogenic right ventricular dysplasia, familial, 14

Summary

Arrhythmogenic right ventricular dysplasia, familial, 14 (MONDO:0030062) is a disease caused by CDH2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CDH2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic right ventricular dysplasia, familial, 14
Mondo ID	MONDO:0030062
OMIM	618920
DOID	DOID:0080959
UMLS	C5394505
MedGen	1712001
GARD	0025519
Is cancer (heuristic)	no

Also known as: Arrhythmogenic Right Ventricular Cardiomyopathy 14 · ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 14 · arrhythmogenic right ventricular dysplasia, familial, 14 · ARVD14

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records.

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, familial, 14

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 5, 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

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

13 retrieved; paginated sample, class counts are floors:

4 conflicting classifications of pathogenicity, 4 uncertain significance, 2 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1685257	NM_001792.5(CDH2):c.1344+1G>A	CDH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075674	NM_001792.5(CDH2):c.1159-1G>A	CDH2	Pathogenic	criteria provided, single submitter
929497	NM_001792.5(CDH2):c.686A>C (p.Gln229Pro)	CDH2	Pathogenic	no assertion criteria provided
1415384	NM_001792.5(CDH2):c.1306G>A (p.Asp436Asn)	CDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1514978	NM_001792.5(CDH2):c.1100C>T (p.Thr367Met)	CDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679772	NM_001792.5(CDH2):c.14C>T (p.Ala5Val)	CDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
929498	NM_001792.5(CDH2):c.1219G>A (p.Asp407Asn)	CDH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1776237	NM_001792.5(CDH2):c.1604C>G (p.Thr535Ser)	CDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1927969	NM_001792.5(CDH2):c.1133A>G (p.Asn378Ser)	CDH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
4074731	NM_001792.5(CDH2):c.2459A>G (p.Tyr820Cys)	CDH2	Uncertain significance	criteria provided, single submitter
3779498	NM_020317.5(RSRP1):c.520+152_520+153insC	RSRP1	Uncertain significance	criteria provided, single submitter
789103	NM_001792.5(CDH2):c.885C>T (p.Asp295=)	CDH2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
789104	NM_001792.5(CDH2):c.702+6A>T	CDH2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
CDH2	Strong	Autosomal dominant	arrhythmogenic right ventricular dysplasia, familial, 14	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDH2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDH2	HGNC:1759	ENSG00000170558	P19022	Cadherin-2	gencc,clinvar
RSRP1	HGNC:25234	ENSG00000117616	Q9BUV0	Arginine/serine-rich protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDH2	Cadherin-2	Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell.
RSRP1	Arginine/serine-rich protein 1	Probably acts as a spliceosomal factor that contributes to spliceosome assembly and regulates the isoform switching of proteins such as PARP6.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDH2	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
RSRP1	Other/Unknown	no		RSRP1

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	1
stromal cell of endometrium	1
ventricular zone	1
germinal epithelium of ovary	1
monocyte	1
pylorus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDH2	233	ubiquitous	marker	heart right ventricle, ventricular zone, stromal cell of endometrium
RSRP1	305	ubiquitous	marker	germinal epithelium of ovary, pylorus, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH2	5,623
RSRP1	798

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDH2	P19022	79.68
RSRP1	Q9BUV0	51.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	878.5×	0.012	CDH2
Myogenesis	1	380.7×	0.012	CDH2
Adherens junctions interactions	1	248.3×	0.012	CDH2
Cell-cell junction organization	1	248.3×	0.012	CDH2
Cell junction organization	1	187.2×	0.012	CDH2
MITF-M-dependent gene expression	1	181.3×	0.012	CDH2
Cell-Cell communication	1	137.6×	0.013	CDH2
MITF-M-regulated melanocyte development	1	114.2×	0.014	CDH2
Post-translational protein phosphorylation	1	100.2×	0.014	CDH2
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.015	CDH2
Post-translational protein modification	1	19.2×	0.062	CDH2
Developmental Biology	1	14.5×	0.075	CDH2
Metabolism of proteins	1	12.4×	0.081	CDH2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mesenchymal cell migration	1	4213.0×	0.003	CDH2
positive regulation of synaptic vesicle clustering	1	4213.0×	0.003	CDH2
regulation of oligodendrocyte progenitor proliferation	1	2808.7×	0.003	CDH2
neuroligin clustering involved in postsynaptic membrane assembly	1	2808.7×	0.003	CDH2
regulation of postsynaptic density protein 95 clustering	1	2106.5×	0.003	CDH2
detection of muscle stretch	1	1203.7×	0.004	CDH2
radial glial cell differentiation	1	766.0×	0.005	CDH2
neuroepithelial cell differentiation	1	766.0×	0.005	CDH2
synaptic vesicle clustering	1	702.2×	0.005	CDH2
type B pancreatic cell development	1	648.1×	0.005	CDH2
striated muscle cell differentiation	1	495.6×	0.006	CDH2
glial cell differentiation	1	443.5×	0.006	CDH2
neural crest cell development	1	401.2×	0.006	CDH2
blood vessel morphogenesis	1	401.2×	0.006	CDH2
brain morphogenesis	1	366.4×	0.006	CDH2
homeostasis of number of cells	1	337.0×	0.006	CDH2
neuronal stem cell population maintenance	1	337.0×	0.006	CDH2
spliceosomal complex assembly	1	300.9×	0.006	RSRP1
adherens junction organization	1	255.3×	0.007	CDH2
calcium-dependent cell-cell adhesion	1	240.7×	0.007	CDH2
cell-cell junction assembly	1	221.7×	0.007	CDH2
cell-cell adhesion mediated by cadherin	1	205.5×	0.007	CDH2
heterophilic cell-cell adhesion	1	168.5×	0.008	CDH2
synapse assembly	1	115.4×	0.012	CDH2
cerebral cortex development	1	102.8×	0.012	CDH2
cell morphogenesis	1	78.8×	0.016	CDH2
homophilic cell-cell adhesion	1	70.2×	0.017	CDH2
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.019	CDH2
cell-cell adhesion	1	50.8×	0.022	CDH2
positive regulation of MAPK cascade	1	40.3×	0.026	CDH2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDH2	0	0
RSRP1	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
CDH2	4	Binding:3, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CDH2, RSRP1

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)
CDH2	4	—
RSRP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.