Is CACNB2 p.Pro9Leu (c.26C>T) pathogenic?

CACNB2 p.Pro9Leu (c.26C>T) is classified Uncertain significance in CACNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-08). Very rare (popmax 0.000169%, nfe); Associated with Brugada syndrome 4.

What condition is associated with CACNB2 p.Pro9Leu (c.26C>T)?

CACNB2 p.Pro9Leu (c.26C>T) is associated with Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Pro9Leu (c.26C>T) in the general population?

CACNB2 p.Pro9Leu (c.26C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Brugada syndrome inherited?

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

CACNB2 p.Pro9Leu

c.26C>T · rs1409641626 · VCV2199783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Brugada syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.187	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	17.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,852 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.Pro9Leu
Coding: c.26C>T
MANE Select: NM_201596 · reported on NM_201590
dbSNP: rs1409641626
Type: single nucleotide variant
Location: chr10:18340952 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB

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.Pro9Ala Uncertain significance ★★ same residue
CACNB2 p.Pro9= Likely benign ★ same residue
CACNB2 p.Pro9Thr 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-pro9leu (accessed [today's date]).

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