Is CACNB2 p.Ser565Pro (c.1693T>C) pathogenic?

CACNB2 p.Ser565Pro (c.1693T>C) is classified Uncertain significance in CACNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-03). AlphaMissense: likely benign (0.2611); Absent from gnomAD v4.1; Associated with Brugada syndrome 4.

What condition is associated with CACNB2 p.Ser565Pro (c.1693T>C)?

CACNB2 p.Ser565Pro (c.1693T>C) is associated with Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Ser565Pro (c.1693T>C) in the general population?

CACNB2 p.Ser565Pro (c.1693T>C) is absent from gnomAD v4.1 (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.Ser565Pro (c.1693T>C)?

AlphaMissense predicts likely benign (score 0.2611) — an in-silico prediction, not a clinical call.

CACNB2 p.Ser565Pro

c.1693T>C · rs2494914116 · VCV1718765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2611 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Brugada syndrome 4

Computational evidence

Protein change
AlphaMissense	0.2611	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CACNB2
Protein: p.Ser565Pro
Coding: c.1693T>C
MANE Select: NM_201596
dbSNP: rs2494914116
Type: single nucleotide variant
Location: chr10:18539434 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 565: 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.Ser565= Likely benign ★★ same residue
CACNB2 p.Ser565Phe 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
CACNB2 p.Ala128Val 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-ser565pro (accessed [today's date]).

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