Is CACNB2 p.Arg511Pro (c.1532G>C) pathogenic?

CACNB2 p.Arg511Pro (c.1532G>C) is classified Uncertain significance in CACNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-13). AlphaMissense: likely benign (0.1026); Very rare (popmax 8.47e-05%, nfe); Associated with Brugada syndrome 4.

What condition is associated with CACNB2 p.Arg511Pro (c.1532G>C)?

CACNB2 p.Arg511Pro (c.1532G>C) is associated with Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Arg511Pro (c.1532G>C) in the general population?

CACNB2 p.Arg511Pro (c.1532G>C) is very rare (popmax 8.47e-05%, 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.Arg511Pro (c.1532G>C)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

CACNB2 p.Arg511Pro

c.1532G>C · VCV4806042

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Brugada syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,944 alleles

Overall 6.84e-05% 1/1,461,838 alleles · very rare

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.Arg511Pro
Coding: c.1532G>C
MANE Select: NM_201596
Type: single nucleotide variant
Location: chr10:18539273 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 511: 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.Arg511Cys Uncertain significance ★★ ⚠ same residue
CACNB2 p.Arg511His Uncertain significance ★★ ⚠ same residue
CACNB2 p.Arg511Ser Uncertain significance ★★ ⚠ 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-arg511pro (accessed [today's date]).

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