Is CACNB2 p.Pro9Ala (c.25C>G) pathogenic?

CACNB2 p.Pro9Ala (c.25C>G) is classified Uncertain significance in CACNB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-08). Very rare (popmax 0.00746%, nfe); Associated with hypertrophic cardiomyopathy.

What condition is associated with CACNB2 p.Pro9Ala (c.25C>G)?

CACNB2 p.Pro9Ala (c.25C>G) is associated with hypertrophic cardiomyopathy, Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Pro9Ala (c.25C>G) in the general population?

CACNB2 p.Pro9Ala (c.25C>G) is very rare (popmax 0.00746%, nfe) (gnomAD).

CACNB2 p.Pro9Ala

c.25C>G · rs761564584 · VCV1793643

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.114	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	10.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00746% European (non-Finnish) · 88/1,180,020 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00595% 96/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)grpmax	0.00746%	13,409
African / African-American	0.004%	24,970

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro9Ala
Coding: c.25C>G
MANE Select: NM_201596 · reported on NM_201590
dbSNP: rs761564584
Type: single nucleotide variant
Location: chr10:18340951 (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

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Brugada syndrome 4

Similar variants

CACNB2 p.Pro9Leu 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-pro9ala (accessed [today's date]).

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