Is CACNB2 p.Ser557Trp (c.1670C>G) pathogenic?

CACNB2 p.Ser557Trp (c.1670C>G) is classified Conflicting classifications of pathogenicity in CACNB2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-27). AlphaMissense: ambiguous (0.3509); Rare (popmax 0.148%, afr); Associated with Cardiovascular phenotype.

What condition is associated with CACNB2 p.Ser557Trp (c.1670C>G)?

CACNB2 p.Ser557Trp (c.1670C>G) is associated with Cardiovascular phenotype, Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Ser557Trp (c.1670C>G) in the general population?

CACNB2 p.Ser557Trp (c.1670C>G) is rare (popmax 0.148%, afr) (gnomAD).

What do computational predictors say about CACNB2 p.Ser557Trp (c.1670C>G)?

AlphaMissense predicts ambiguous (score 0.3509) — an in-silico prediction, not a clinical call.

CACNB2 p.Ser557Trp

c.1670C>G · rs137886839 · VCV264509

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3509 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3509	ambiguous
REVEL	0.327	indeterminate
SaProt	LLR -9.86	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	28.5	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 0.148% African / African-American · 111/75,000 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.00719% 116/1,614,020 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.148%	676
Remaining individualsnot grpmax-eligible	0.0064%	15,624
Admixed American	0.00167%	60,004

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.Ser557Trp
Coding: c.1670C>G
MANE Select: NM_201596
dbSNP: rs137886839
Type: single nucleotide variant
Location: chr10:18539411 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 557: 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.Ser557= Likely benign ★★ same residue
CACNB2 p.Ser557Leu Benign/Likely benign ★★ ⚠ 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-ser557trp (accessed [today's date]).

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