Is CACNB2 p.Pro520= (c.1560T>C) pathogenic?

CACNB2 p.Pro520= (c.1560T>C) is classified Benign/Likely benign in CACNB2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-25). Rare (popmax 0.234%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CACNB2 p.Pro520= (c.1560T>C)?

CACNB2 p.Pro520= (c.1560T>C) is associated with Cardiovascular phenotype, Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Pro520= (c.1560T>C) in the general population?

CACNB2 p.Pro520= (c.1560T>C) is rare (popmax 0.234%, nfe) (gnomAD).

CACNB2 p.Pro520=

c.1560T>C · rs150280879 · VCV136647

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.234%, nfe)

Conditions

Cardiovascular phenotype

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 0.23	GERP -1.5, phastCons 0.95
Overall
CADD	8.359	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.234% European (non-Finnish) · 2,761/1,179,916 alleles

Filtering AF 0.227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.224%

Overall 0.178% 2,875/1,613,808 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.234%	427
Remaining individualsnot grpmax-eligible	0.106%	947
Middle Eastern	0.0495%	2,021
African / African-American	0.036%	2,775
Finnishnot grpmax-eligible	0.0187%	5,335
Admixed American	0.00834%	11,995
South Asian	0.0011%	91,052

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.Pro520=
Coding: c.1560T>C
MANE Select: NM_201596
dbSNP: rs150280879
Type: single nucleotide variant
Location: chr10:18539301 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 520: the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Brugada syndrome 4

Similar variants

CACNB2 p.Pro520Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNB2 p.Pro520Ala 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-pro520 (accessed [today's date]).

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