Is CACNB2 p.Thr254= (c.762G>A) pathogenic?

CACNB2 p.Thr254= (c.762G>A) is classified Likely benign in CACNB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-06). Ultra-rare (popmax 0.0164%, mid); Associated with Brugada syndrome 4.

What condition is associated with CACNB2 p.Thr254= (c.762G>A)?

CACNB2 p.Thr254= (c.762G>A) is associated with Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Thr254= (c.762G>A) in the general population?

CACNB2 p.Thr254= (c.762G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Brugada syndrome inherited?

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

CACNB2 p.Thr254=

c.762G>A · rs1212860668 · VCV1087708

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Brugada syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.31, phastCons 1
Overall
CADD	11.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00105% 17/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00401%	24,968
South Asian	0.0022%	45,540
Admixed American	0.00167%	59,982
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000763%	131,113

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.Thr254=
Coding: c.762G>A
MANE Select: NM_201596
dbSNP: rs1212860668
Type: single nucleotide variant
Location: chr10:18514327 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 254: 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.Thr254Met 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
CACNB2 p.Ala139Ser 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-thr254 (accessed [today's date]).

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