Cardiac arrhythmia: genes and variants

Genes linked to Cardiac arrhythmia

• KCNQ1: Potassium voltage-gated channel subfamily KQT member 1

  The protein forms the pore of a voltage-gated potassium channel that helps set electrical activity in heart muscle. Its partnerships with KCNE subunits also support normal function in the inner ear and other tissues, while KCNQ1 variants are linked to long-QT and short-QT syndromes.

  49 disease-causing and 194 uncertain variants in KCNQ1 are linked to Cardiac arrhythmia.

• SCN5A: Sodium channel protein type 5 subunit alpha

  Its rapid inward sodium current drives the upstroke of the cardiac action potential and enables fast electrical conduction through atrial, ventricular, and conduction-system tissue. Pathogenic variants can cause long-QT syndrome type 3, Brugada syndrome, conduction disease, and overlapping arrhythmia phenotypes.

  17 disease-causing and 514 uncertain variants in SCN5A are linked to Cardiac arrhythmia.

• KCNH2: Voltage-gated inwardly rectifying potassium channel KCNH2

  Its unusually rapid inactivation and slow deactivation shape the rapid delayed-rectifier current IKr, a major determinant of ventricular repolarization. Loss-of-function variants can prolong repolarization and cause long-QT syndrome, whereas gain-of-function variants can cause short-QT syndrome.

  15 disease-causing and 384 uncertain variants in KCNH2 are linked to Cardiac arrhythmia.

• CACNA1C: Voltage-dependent L-type calcium channel subunit alpha-1C

  Its opening provides a major source of depolarization-triggered calcium entry in cardiomyocytes, smooth muscle, and neurons, coupling electrical activity to contraction and signaling. Pathogenic variants can cause Timothy syndrome, Brugada or long-QT phenotypes, and several neurodevelopmental disorders.

  2 disease-causing and 0 uncertain variants in CACNA1C are linked to Cardiac arrhythmia.

• KCNJ2: Inward rectifier potassium channel 2

  Its inward-rectifier current stabilizes the resting membrane potential in cardiac and skeletal muscle and contributes to terminal cardiac repolarization. Loss-of-function variants cause Andersen-Tawil syndrome, while gain-of-function variants can cause short-QT syndrome.

  1 disease-causing and 0 uncertain variants in KCNJ2 are linked to Cardiac arrhythmia.

• ASS1: Argininosuccinate synthase

  It catalyzes formation of argininosuccinate from citrulline and aspartate in the urea cycle, enabling nitrogen disposal and arginine synthesis. Biallelic loss-of-function variants cause citrullinemia type I, which can lead to severe hyperammonemia.

  1 disease-causing and 0 uncertain variants in ASS1 are linked to Cardiac arrhythmia.

• 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.

  0 disease-causing and 0 uncertain variants in DSP are linked to Cardiac arrhythmia.

• HCN4: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

  Its hyperpolarization-activated current contributes substantially to spontaneous diastolic depolarization in sinoatrial-node pacemaker cells. Pathogenic variants can cause sinus bradycardia, conduction abnormalities, and in some families left-ventricular noncompaction.

  0 disease-causing and 0 uncertain variants in HCN4 are linked to Cardiac arrhythmia.

• SCN10A: Sodium channel protein type 10 subunit alpha

  The protein forms Nav1.8, a tetrodotoxin-resistant voltage-gated sodium channel found in excitable membranes. It helps generate sensory-neuron electrical signals and is especially important in mechanisms of neuropathic pain and inherited episodic pain.

  0 disease-causing and 0 uncertain variants in SCN10A are linked to Cardiac arrhythmia.

• SCN1A: Sodium channel protein type 1 subunit alpha

  Its sodium current is especially important for reliable firing of inhibitory interneurons and therefore for balancing excitation across neural networks. Loss-of-function variants are the major cause of Dravet syndrome, while other variants cause GEFS+ or familial hemiplegic migraine.

  0 disease-causing and 0 uncertain variants in SCN1A are linked to Cardiac arrhythmia.

• SCN2A: Sodium channel protein type 2 subunit alpha

  The protein forms Nav1.2, a voltage-gated sodium channel that carries sodium current during neuronal action potentials. By shaping neuronal excitability and signal propagation, it supports brain circuits involved in development, learning, and seizure susceptibility.

  0 disease-causing and 0 uncertain variants in SCN2A are linked to Cardiac arrhythmia.

• SCN4A: Sodium channel protein type 4 subunit alpha

  Its rapid sodium current initiates and propagates skeletal-muscle action potentials. Gain- and loss-of-function variants cause disorders of muscle excitability including sodium-channel myotonia, paramyotonia congenita, periodic paralysis, and some congenital myopathies.

  0 disease-causing and 0 uncertain variants in SCN4A are linked to Cardiac arrhythmia.

• SCN8A: Sodium channel protein type 8 subunit alpha

  The protein forms Nav1.6, a voltage-gated sodium channel that sets the threshold and propagation of neuronal action potentials. It is widely important for neuronal excitability, and SCN8A variants are associated with developmental and epileptic encephalopathies.

  0 disease-causing and 0 uncertain variants in SCN8A are linked to Cardiac arrhythmia.

• SCN9A: Sodium channel protein type 9 subunit alpha

  The protein forms Nav1.7, a voltage-gated sodium channel that amplifies electrical signals in peripheral sensory neurons. Changes in Nav1.7 activity can produce either excessive pain or congenital insensitivity to pain, making SCN9A central to pain biology.

  0 disease-causing and 0 uncertain variants in SCN9A are linked to Cardiac arrhythmia.

• TTN: Titin

  Its enormous titin polypeptide spans much of the sarcomere and provides passive elasticity, structural alignment, and mechanosensing in striated muscle. Truncating variants are among the most common genetic causes of dilated cardiomyopathy, while other variants cause diverse skeletal and cardiac myopathies.

  0 disease-causing and 0 uncertain variants in TTN are linked to Cardiac arrhythmia.

• ZFHX3: Zinc finger homeobox protein 3

  0 disease-causing and 0 uncertain variants in ZFHX3 are linked to Cardiac arrhythmia.

• ANK2: Ankyrin-2

  It organizes membrane proteins and ion-handling complexes by linking them to the cytoskeleton, with especially important roles in cardiomyocytes and neurons. Pathogenic variants can disrupt cardiac electrical organization and cause ankyrin-B syndrome, including sinus-node dysfunction, arrhythmias, and variable QT abnormalities.

  0 disease-causing and 5 uncertain variants in ANK2 are linked to Cardiac arrhythmia.

Weakly linked (only a few uncertain records): DSC2, JUP, MYH7 and RYR2.

Where Cardiac arrhythmia variants cluster

• KCNQ1 Cytoplasmic (positions 177–192): 8 of 49 disease-causing changes, 6.9× more than its size predicts.
• KCNH2 Segment S5 (positions 548–568): 3 of 15 disease-causing changes, 11.0× more than its size predicts.
• KCNQ1 Segment H5 (positions 300–320): 6 of 49 disease-causing changes, 3.9× more than its size predicts.
• KCNH2 cNMP-binding domain (positions 742–842): 5 of 15 disease-causing changes, 3.8× more than its size predicts.
• KCNQ1 Interaction with KCNE1 C-terminus (positions 535–572): 7 of 49 disease-causing changes, 2.5× more than its size predicts.

Known disease-causing variants in Cardiac arrhythmia

Showing 60 of 85.

Uncertain variants in Cardiac arrhythmia that look disease-causing

Which prediction tools work for Cardiac arrhythmia

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

• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 94 out of 100
• ESM1b (LLR): 93 out of 100
• EVE: 92 out of 100
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 91 out of 100
• AlphaGenome (regulatory): 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 85 out of 100
• phyloP: 73 out of 100
• DMS / MaveDB: 62 out of 100
• AlphaGenome (splicing): 51 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Long QT syndrome is also caused by KCNQ1 variants; they fall partly in the same places as the Cardiac arrhythmia variants (175 disease-causing).
• Atrial fibrillation, familial, 10 is also caused by KCNQ1 variants; they fall partly in the same places as the Cardiac arrhythmia variants (8 disease-causing).
• Short QT syndrome type 3 is also caused by KCNQ1 variants; they fall in the same places as the Cardiac arrhythmia variants (4 disease-causing).
• Brugada syndrome is also caused by SCN5A variants; they fall mostly in different places as the Cardiac arrhythmia variants (24 disease-causing).
• Long QT syndrome is also caused by SCN5A variants; they fall mostly in different places as the Cardiac arrhythmia variants (16 disease-causing).
• Dilated cardiomyopathy is also caused by SCN5A variants; they fall mostly in different places as the Cardiac arrhythmia variants (4 disease-causing).
• Progressive familial heart block is also caused by SCN5A variants; they fall mostly in different places as the Cardiac arrhythmia variants (4 disease-causing).
• Long QT syndrome is also caused by KCNH2 variants; they fall mostly in different places as the Cardiac arrhythmia variants (114 disease-causing).
• Short QT syndrome type 3 is also caused by KCNH2 variants; they fall mostly in different places as the Cardiac arrhythmia variants (4 disease-causing).
• Long QT syndrome is also caused by CACNA1C variants; they fall mostly in different places as the Cardiac arrhythmia variants (12 disease-causing).
• Timothy syndrome is also caused by CACNA1C variants; they fall mostly in different places as the Cardiac arrhythmia variants (4 disease-causing).
• Brugada syndrome is also caused by CACNA1C variants; they fall mostly in different places as the Cardiac arrhythmia variants (3 disease-causing).
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures is also caused by CACNA1C variants; they fall mostly in different places as the Cardiac arrhythmia variants (3 disease-causing).
• Andersen Tawil syndrome is also caused by KCNJ2 variants; they fall mostly in different places as the Cardiac arrhythmia variants (34 disease-causing).
• Short QT syndrome type 3 is also caused by KCNJ2 variants; they fall mostly in different places as the Cardiac arrhythmia variants (28 disease-causing).
• Citrullinemia is also caused by ASS1 variants; they fall mostly in different places as the Cardiac arrhythmia variants (69 disease-causing).

Diseases related to Cardiac arrhythmia

• Epilepsy, also linked to CACNA1C, KCNQ1, SCN10A, SCN1A and 5 more
• Long QT syndrome, also linked to ANK2, CACNA1C, KCNH2, KCNJ2 and 2 more
• Amyotrophic lateral sclerosis, also linked to SCN10A, SCN1A, SCN2A, SCN4A and 2 more
• Brugada syndrome, also linked to ANK2, CACNA1C, HCN4, SCN10A and 1 more
• Focal epilepsy, also linked to SCN10A, SCN1A, SCN2A, SCN4A and 1 more
• Lennox-Gastaut syndrome, also linked to SCN10A, SCN1A, SCN2A, SCN8A and 1 more
• Hypertrophic cardiomyopathy, also linked to ANK2, DSP and TTN
• Dilated cardiomyopathy, also linked to DSP, SCN5A and TTN
• Complex neurodevelopmental disorder, also linked to ANK2, SCN2A and SCN8A
• Short QT syndrome type 3, also linked to KCNH2, KCNJ2 and KCNQ1
• Atrial fibrillation, familial, 10, also linked to KCNJ2, KCNQ1 and SCN5A
• Genetic developmental and epileptic encephalopathy, also linked to SCN1A, SCN2A and SCN8A

Frequently asked questions

Which genes are linked to Cardiac arrhythmia?

In CATVariant, Cardiac arrhythmia is linked to 17 analyzed proteins: KCNQ1 (Potassium voltage-gated channel subfamily KQT member 1), SCN5A (Sodium channel protein type 5 subunit alpha), KCNH2 (Voltage-gated inwardly rectifying potassium channel KCNH2), CACNA1C (Voltage-dependent L-type calcium channel subunit alpha-1C), KCNJ2 (Inward rectifier potassium channel 2), ASS1 (Argininosuccinate synthase) and 11 more.

How many genetic variants are linked to Cardiac arrhythmia?

1,224 variants: 85 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,102 are of uncertain significance or have conflicting reports.

Which uncertain variants in Cardiac arrhythmia look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SCN5A R893C and KCNQ1 A300S. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Cardiac arrhythmia?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 74 disease-causing and 157 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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