Brugada syndrome 4

Summary

Brugada syndrome 4 (MONDO:0012743) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 674

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Brugada syndrome 4
Mondo ID	MONDO:0012743
MeSH	C567508
OMIM	611876
DOID	DOID:0110221
UMLS	C2678477
MedGen	395632
GARD	0010362
Is cancer (heuristic)	no

Also known as: BRGDA4 · Brugada syndrome 4 · Brugada syndrome caused by mutation in CACNB2 · Brugada syndrome type 4 · CACNB2 Brugada syndrome

Data availability: 674 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › Brugada syndrome › Brugada syndrome 4

Related subtypes (8): Brugada syndrome 1, Brugada syndrome 2, Brugada syndrome 3, Brugada syndrome 5, Brugada syndrome 6, Brugada syndrome 7, Brugada syndrome 8, Brugada syndrome 9

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:

277 uncertain significance, 246 likely benign, 36 conflicting classifications of pathogenicity, 24 benign/likely benign, 15 benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
156228	NM_201590.3(CACNB2):c.32C>T (p.Thr11Ile)	CACNB2	Pathogenic	no assertion criteria provided
3774534	NM_201596.3(CACNB2):c.804+162G>T	CACNB2	Likely pathogenic	criteria provided, single submitter
1025487	NM_201596.3(CACNB2):c.673A>G (p.Ile225Val)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1398592	NM_201596.3(CACNB2):c.358C>T (p.Arg120Trp)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446276	NM_201596.3(CACNB2):c.1459C>G (p.Leu487Val)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161209	NM_201596.3(CACNB2):c.380C>T (p.Ala127Val)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161210	NM_201596.3(CACNB2):c.590C>T (p.Ser197Phe)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161211	NM_201596.3(CACNB2):c.641G>C (p.Ser214Thr)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161212	NM_201596.3(CACNB2):c.1511C>T (p.Thr504Ile)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161213	NM_201596.3(CACNB2):c.1776C>A (p.Asp592Glu)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1739779	NM_201596.3(CACNB2):c.594T>C (p.Ser198=)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1771658	NM_201596.3(CACNB2):c.1559C>T (p.Pro520Leu)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180291	NM_201596.3(CACNB2):c.1206+3A>T	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190717	NM_201596.3(CACNB2):c.1702G>A (p.Val568Ile)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190727	NM_201596.3(CACNB2):c.1522G>A (p.Ala508Thr)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190729	NM_201596.3(CACNB2):c.1592G>A (p.Arg531His)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190731	NM_201596.3(CACNB2):c.1696G>A (p.Ala566Thr)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190736	NM_201596.3(CACNB2):c.1816C>T (p.Arg606Trp)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191435	NM_201596.3(CACNB2):c.1206+4_1206+7dup	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216845	NM_201596.3(CACNB2):c.1432C>T (p.Arg478Cys)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222521	NM_201596.3(CACNB2):c.334-8C>T	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264509	NM_201596.3(CACNB2):c.1670C>G (p.Ser557Trp)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299567	NM_201596.3(CACNB2):c.1936C>T (p.Arg646Trp)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3484145	NM_201596.3(CACNB2):c.1469C>A (p.Thr490Asn)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
375853	NM_201596.3(CACNB2):c.1591C>T (p.Arg531Cys)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383672	NM_201596.3(CACNB2):c.102G>T (p.Ala34=)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
402473	NM_201596.3(CACNB2):c.804+146G>T	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
402474	NM_201596.3(CACNB2):c.1357C>T (p.Leu453Phe)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411701	NM_201596.3(CACNB2):c.1025T>C (p.Ile342Thr)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411704	NM_201596.3(CACNB2):c.1076A>G (p.Glu359Gly)	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CACNB2	Limited	Unknown	Brugada syndrome 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNB2	Orphanet:130	Brugada syndrome

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
CACNB2	HGNC:1402	ENSG00000165995	Q08289	Voltage-dependent L-type calcium channel subunit beta-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNB2	Voltage-dependent L-type calcium channel subunit beta-2	Beta subunit of voltage-dependent calcium channels which contributes to the function of the calcium channel by increasing peak calcium current.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNB2	Scaffold/PPI	no		VDCC_L_bsu, SH3_domain, VDCC_L_b2su

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
adrenal tissue	1
buccal mucosa cell	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNB2	237	broad	marker	adrenal tissue, mucosa of stomach, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNB2	1,425

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNB2	Q08289	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 1 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
Presynaptic depolarization and calcium channel opening	1	951.7×	0.010	CACNB2
Phase 2 - plateau phase	1	761.3×	0.010	CACNB2
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.010	CACNB2
Adrenaline,noradrenaline inhibits insulin secretion	1	393.8×	0.010	CACNB2
Phase 0 - rapid depolarisation	1	346.1×	0.010	CACNB2
Sensory processing of sound	1	308.6×	0.010	CACNB2
NCAM signaling for neurite out-growth	1	271.9×	0.010	CACNB2
Cellular responses to mechanical stimuli	1	259.6×	0.010	CACNB2
NCAM1 interactions	1	248.3×	0.010	CACNB2
Regulation of insulin secretion	1	219.6×	0.010	CACNB2
Integration of energy metabolism	1	175.7×	0.011	CACNB2
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.011	CACNB2
Cardiac conduction	1	108.8×	0.016	CACNB2
Sensory Perception	1	95.2×	0.017	CACNB2
Muscle contraction	1	77.2×	0.018	CACNB2
Transmission across Chemical Synapses	1	76.1×	0.018	CACNB2
Axon guidance	1	45.1×	0.027	CACNB2
Neuronal System	1	44.3×	0.027	CACNB2
Nervous system development	1	42.9×	0.027	CACNB2
Cellular responses to stimuli	1	31.5×	0.035	CACNB2
Developmental Biology	1	14.5×	0.072	CACNB2
Metabolism	1	11.6×	0.086	CACNB2

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 calcium ion transmembrane transport via high voltage-gated calcium channel	1	8426.0×	0.001	CACNB2
membrane depolarization during atrial cardiac muscle cell action potential	1	5617.3×	0.001	CACNB2
membrane depolarization during AV node cell action potential	1	3370.4×	0.001	CACNB2
positive regulation of muscle contraction	1	2407.4×	0.001	CACNB2
calcium ion import	1	802.5×	0.003	CACNB2
positive regulation of calcium ion transport	1	581.1×	0.004	CACNB2
neuromuscular junction development	1	526.6×	0.004	CACNB2
regulation of heart rate by cardiac conduction	1	374.5×	0.004	CACNB2
calcium ion transmembrane transport	1	210.7×	0.007	CACNB2
calcium ion transport	1	181.2×	0.007	CACNB2
protein localization to plasma membrane	1	108.7×	0.011	CACNB2
visual perception	1	79.5×	0.013	CACNB2
chemical synaptic transmission	1	77.3×	0.013	CACNB2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CACNB2	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNB2	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNB2
TACRINE	4	CACNB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNB2	22	Binding:20, ADMET:1, Toxicity: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

2 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.

Compound	Max phase	Cohort target (bioactivity)
NIMODIPINE	4	CACNB2
TACRINE	4	CACNB2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNB2
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.