Brugada syndrome: genes and variants

Genes linked to Brugada syndrome

• 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.

  24 disease-causing and 77 uncertain variants in SCN5A are linked to Brugada syndrome.

• 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.

  9 disease-causing and 815 uncertain variants in HCN4 are linked to Brugada syndrome.

• 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.

  3 disease-causing and 3 uncertain variants in CACNA1C are linked to Brugada syndrome.

• 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.

  1 disease-causing and 5 uncertain variants in ANK2 are linked to Brugada syndrome.

• CACNB2: Voltage-dependent L-type calcium channel subunit beta-2

  It regulates gating and membrane delivery of high-voltage-activated calcium channels, including cardiac Cav1.2. Rare pathogenic variants have been associated with cardiac arrhythmia and neurodevelopmental phenotypes, although variant-specific evidence is important when interpreting causality.

  0 disease-causing and 289 uncertain variants in CACNB2 are linked to Brugada syndrome.

• 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 734 uncertain variants in SCN10A are linked to Brugada syndrome.

Weakly linked (only a few uncertain records): DSP, ANKRD1, COL5A1, GATA4, KCNH2, KCNJ2, MYBPC3 and MYH6.

Where Brugada syndrome variants cluster

• HCN4 Segment H5 (positions 465–486): 6 of 9 disease-causing changes, 36.5× more than its size predicts.
• SCN5A Cytoplasmic (positions 1318–1330): 3 of 24 disease-causing changes, 19.4× more than its size predicts.
• SCN5A IV (positions 1510–1807): 8 of 24 disease-causing changes, 2.3× more than its size predicts.
• SCN5A I (positions 113–420): 6 of 24 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Brugada syndrome

Which prediction tools work for Brugada syndrome

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

• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 96 out of 100
• ESM1b (LLR): 96 out of 100
• EVE: 94 out of 100
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 88 out of 100
• SIFT: 85 out of 100
• CADD: 81 out of 100

Same protein, different disease

• Cardiac arrhythmia is also caused by SCN5A variants; they fall mostly in different places as the Brugada syndrome variants (17 disease-causing).
• Long QT syndrome is also caused by SCN5A variants; they fall mostly in different places as the Brugada syndrome variants (16 disease-causing).
• Progressive familial heart block is also caused by SCN5A variants; they fall mostly in different places as the Brugada syndrome variants (4 disease-causing).
• Atrial fibrillation, familial, 10 is also caused by SCN5A variants; they fall mostly in different places as the Brugada syndrome variants (3 disease-causing).
• Sick sinus syndrome 2, autosomal dominant is also caused by HCN4 variants; they fall mostly in different places as the Brugada syndrome variants (4 disease-causing).
• Long QT syndrome is also caused by CACNA1C variants; they fall mostly in different places as the Brugada syndrome variants (12 disease-causing).
• Timothy syndrome is also caused by CACNA1C variants; they fall mostly in different places as the Brugada syndrome variants (4 disease-causing).
• Long QT syndrome is also caused by ANK2 variants; they fall mostly in different places as the Brugada syndrome variants (3 disease-causing).

Diseases related to Brugada syndrome

• Cardiac arrhythmia, also linked to ANK2, CACNA1C, HCN4, SCN10A and 1 more
• Epilepsy, also linked to CACNA1C, CACNB2, SCN10A and SCN5A
• Long QT syndrome, also linked to ANK2, CACNA1C and SCN5A
• Sick sinus syndrome 2, autosomal dominant, also linked to HCN4 and SCN5A
• Hypertrophic cardiomyopathy, also linked to ANK2
• Amyotrophic lateral sclerosis, also linked to SCN10A
• Dilated cardiomyopathy, also linked to SCN5A
• Primary dilated cardiomyopathy, also linked to SCN5A
• Complex neurodevelopmental disorder, also linked to ANK2
• Epilepsy, idiopathic generalized, susceptibility to, 13, also linked to HCN4
• Atrial fibrillation, familial, 10, also linked to SCN5A
• Diabetes mellitus, also linked to CACNA1C

Frequently asked questions

Which genes are linked to Brugada syndrome?

In CATVariant, Brugada syndrome is linked to 6 analyzed proteins: SCN5A (Sodium channel protein type 5 subunit alpha), HCN4 (Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4), CACNA1C (Voltage-dependent L-type calcium channel subunit alpha-1C), ANK2 (Ankyrin-2), CACNB2 (Voltage-dependent L-type calcium channel subunit beta-2) and SCN10A (Sodium channel protein type 10 subunit alpha).

How many genetic variants are linked to Brugada syndrome?

2,133 variants: 37 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,931 are of uncertain significance or have conflicting reports.

Which uncertain variants in Brugada syndrome 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 Brugada syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 28 disease-causing and 90 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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