Is CACNB2 p.Arg625Pro (c.1874G>C) pathogenic?

CACNB2 p.Arg625Pro (c.1874G>C) is classified Uncertain significance in CACNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-30). AlphaMissense: ambiguous (0.4522); Very rare (popmax 8.48e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CACNB2 p.Arg625Pro (c.1874G>C)?

CACNB2 p.Arg625Pro (c.1874G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is CACNB2 p.Arg625Pro (c.1874G>C) in the general population?

CACNB2 p.Arg625Pro (c.1874G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CACNB2 p.Arg625Pro (c.1874G>C)?

AlphaMissense predicts ambiguous (score 0.4522) — an in-silico prediction, not a clinical call.

CACNB2 p.Arg625Pro

c.1874G>C · rs772911828 · VCV1778591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4522	ambiguous
REVEL	0.495	indeterminate
SaProt	LLR -8.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,862 alleles

Overall 6.84e-05% 1/1,461,678 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.Arg625Pro
Coding: c.1874G>C
MANE Select: NM_201596
dbSNP: rs772911828
Type: single nucleotide variant
Location: chr10:18539615 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 625: 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

Similar variants

CACNB2 p.Arg625Cys Uncertain significance ★★ ⚠ same residue
CACNB2 p.Arg625His Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNB2 p.Arg625= Likely benign ★ same residue
CACNB2 c.1206+5G>A Uncertain significance ★★ same condition
CACNB2 c.1303-3C>T 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-arg625pro (accessed [today's date]).

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