Is CACNB2 p.Arg563Pro (c.1688G>C) pathogenic?

CACNB2 p.Arg563Pro (c.1688G>C) is classified Conflicting classifications of pathogenicity in CACNB2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-26). AlphaMissense: likely pathogenic (0.7124); Ultra-rare (popmax 0.0139%, nfe); Associated with Brugada syndrome 4.

What condition is associated with CACNB2 p.Arg563Pro (c.1688G>C)?

CACNB2 p.Arg563Pro (c.1688G>C) is associated with Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Arg563Pro (c.1688G>C) in the general population?

CACNB2 p.Arg563Pro (c.1688G>C) is ultra-rare (popmax 0.0139%, nfe) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CACNB2 p.Arg563Pro (c.1688G>C)?

AlphaMissense predicts likely pathogenic (score 0.7124) — an in-silico prediction, not a clinical call.

CACNB2 p.Arg563Pro

c.1688G>C · rs766377211 · VCV418104

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Brugada syndrome 4

Computational evidence

Protein change
AlphaMissense	0.7124	likely pathogenic
REVEL	0.489	indeterminate
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0139% European (non-Finnish) · 164/1,179,968 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0115%

Overall 0.0106% 171/1,613,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0139%	7,195
South Asian	0.00769%	13,009

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CACNB2
Protein: p.Arg563Pro
Coding: c.1688G>C
MANE Select: NM_201596
dbSNP: rs766377211
Type: single nucleotide variant
Location: chr10:18539429 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 563: the 'disordered' region

Full CACNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Brugada syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CACNB2 p.Arg563Gly Uncertain significance ★★ ⚠ same residue
CACNB2 p.Arg563Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNB2 p.Arg563= Likely benign ★ same residue
CACNB2 c.1206+5G>A Uncertain significance ★★ same condition
CACNB2 c.1303-3C>T Uncertain significance ★★ same condition
CACNB2 c.1488+6G>A Uncertain significance ★★ same condition
CACNB2 p.Ala105Thr Uncertain significance ★★ ⚠ same condition
CACNB2 p.Ala118Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cacnb2-p-arg563pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown