Arrhythmogenic right ventricular dysplasia: genes and variants

Genes linked to Arrhythmogenic right ventricular dysplasia

• DSP: Desmoplakin

  It anchors intermediate filaments to desmosomes, allowing mechanically stressed tissues such as myocardium and epidermis to maintain strong cell-cell adhesion. Pathogenic variants can cause arrhythmogenic or dilated cardiomyopathy and a range of cardiocutaneous disorders.

  6 disease-causing and 1,420 uncertain variants in DSP are linked to Arrhythmogenic right ventricular dysplasia.

• PKP2: Plakophilin-2

  It organizes cardiac desmosomes and helps maintain both mechanical adhesion and electrical coupling between cardiomyocytes. Pathogenic variants are a major cause of arrhythmogenic cardiomyopathy and increase susceptibility to ventricular arrhythmias and sudden cardiac death.

  4 disease-causing and 125 uncertain variants in PKP2 are linked to Arrhythmogenic right ventricular dysplasia.

• RYR2: Ryanodine receptor 2

  It releases calcium from the cardiac sarcoplasmic reticulum in response to trigger calcium entering during each action potential, thereby initiating contraction. Pathogenic variants can destabilize calcium release and are a major cause of catecholaminergic polymorphic ventricular tachycardia.

  3 disease-causing and 22 uncertain variants in RYR2 are linked to Arrhythmogenic right ventricular dysplasia.

• LMNA: Prelamin-A/C

  The gene product produces lamins A and C, structural proteins that form the nuclear lamina beneath the inner nuclear membrane. Lamins help maintain nuclear shape and organize chromatin, and LMNA variants are associated with muscular dystrophy, cardiomyopathy, lipodystrophy, and premature-aging syndromes.

  2 disease-causing and 0 uncertain variants in LMNA are linked to Arrhythmogenic right ventricular dysplasia.

• DSC2: Desmocollin-2

  Its desmosomal adhesion helps cardiomyocytes remain mechanically coupled during repeated contraction. Pathogenic variants can weaken cardiac junctions and contribute to arrhythmogenic cardiomyopathy.

  1 disease-causing and 501 uncertain variants in DSC2 are linked to Arrhythmogenic right ventricular dysplasia.

• JUP: Junction plakoglobin

  It links desmosomal and adherens-junction cadherins to the cytoskeleton and helps maintain mechanical coupling between cardiomyocytes and epithelial cells. Pathogenic variants can cause arrhythmogenic cardiomyopathy and cardiocutaneous syndromes such as Naxos disease.

  0 disease-causing and 514 uncertain variants in JUP are linked to Arrhythmogenic right ventricular dysplasia.

• TMEM43: Transmembrane protein 43

  A multi-pass membrane protein that helps organize protein complexes at the inner nuclear membrane and retain emerin. It also participates in innate-immune signaling and contributes to electrical coupling in the inner ear, with variants linked to cardiomyopathy and auditory neuropathy.

  0 disease-causing and 342 uncertain variants in TMEM43 are linked to Arrhythmogenic right ventricular dysplasia.

Weakly linked (only a few uncertain records): MYH7 and PLN.

Where Arrhythmogenic right ventricular dysplasia variants cluster

• DSP Spectrin 4 (positions 546–627): 3 of 6 disease-causing changes, 17.5× more than its size predicts.

Known disease-causing variants in Arrhythmogenic right ventricular dysplasia

Which prediction tools work for Arrhythmogenic right ventricular dysplasia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• SIFT: 90 out of 100
• MetaLR: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Catecholaminergic polymorphic ventricular tachycardia is also caused by RYR2 variants; they fall mostly in different places as the Arrhythmogenic right ventricular dysplasia variants (58 disease-causing).
• Charcot-Marie-Tooth disease is also caused by LMNA variants; they fall mostly in different places as the Arrhythmogenic right ventricular dysplasia variants (130 disease-causing).
• Dilated cardiomyopathy is also caused by LMNA variants; they fall mostly in different places as the Arrhythmogenic right ventricular dysplasia variants (21 disease-causing).
• Familial partial lipodystrophy, Dunnigan type is also caused by LMNA variants; they fall mostly in different places as the Arrhythmogenic right ventricular dysplasia variants (13 disease-causing).
• Emery-Dreifuss muscular dystrophy is also caused by LMNA variants; they fall mostly in different places as the Arrhythmogenic right ventricular dysplasia variants (12 disease-causing).
• Congenital muscular dystrophy due to LMNA mutation is also caused by LMNA variants; they fall mostly in different places as the Arrhythmogenic right ventricular dysplasia variants (11 disease-causing).

Diseases related to Arrhythmogenic right ventricular dysplasia

• Arrhythmogenic right ventricular cardiomyopathy, also linked to DSC2, DSP, PKP2 and RYR2
• Familial isolated arrhythmogenic right ventricular dysplasia, also linked to DSC2, DSP, PKP2 and TMEM43
• Dilated cardiomyopathy, also linked to DSP and LMNA
• Emery-Dreifuss muscular dystrophy, also linked to LMNA and TMEM43
• Hypertrophic cardiomyopathy, also linked to DSP
• Charcot-Marie-Tooth disease, also linked to LMNA
• Bethlem myopathy, also linked to LMNA
• Cardiac arrhythmia, also linked to DSP
• Catecholaminergic polymorphic ventricular tachycardia, also linked to RYR2
• Primary dilated cardiomyopathy, also linked to LMNA
• Auditory neuropathy, also linked to TMEM43
• Idiopathic pulmonary fibrosis, also linked to DSP

Frequently asked questions

Which genes are linked to Arrhythmogenic right ventricular dysplasia?

In CATVariant, Arrhythmogenic right ventricular dysplasia is linked to 7 analyzed proteins: DSP (Desmoplakin), PKP2 (Plakophilin-2), RYR2 (Ryanodine receptor 2), LMNA (Prelamin-A/C), DSC2 (Desmocollin-2), JUP (Junction plakoglobin) and 1 more.

How many genetic variants are linked to Arrhythmogenic right ventricular dysplasia?

3,137 variants: 16 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2,925 are of uncertain significance or have conflicting reports.

Which uncertain variants in Arrhythmogenic right ventricular dysplasia look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Arrhythmogenic right ventricular dysplasia?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 11 disease-causing and 190 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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