Is CACNB2 p.Ser197Phe (c.590C>T) pathogenic?

CACNB2 p.Ser197Phe (c.590C>T) is classified Conflicting classifications of pathogenicity in CACNB2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.2948); Rare (popmax 0.136%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with CACNB2 p.Ser197Phe (c.590C>T)?

CACNB2 p.Ser197Phe (c.590C>T) is associated with Cardiovascular phenotype, cardiomyopathy, Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Ser197Phe (c.590C>T) in the general population?

CACNB2 p.Ser197Phe (c.590C>T) is rare (popmax 0.136%, nfe) (gnomAD).

What do computational predictors say about CACNB2 p.Ser197Phe (c.590C>T)?

AlphaMissense predicts likely benign (score 0.2948) — an in-silico prediction, not a clinical call.

CACNB2 p.Ser197Phe

c.590C>T · rs150528041 · VCV161210

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.2948 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2948	likely benign
REVEL	0.611	indeterminate
SaProt	LLR -13.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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	29.3	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 0.136% European (non-Finnish) · 1,606/1,179,844 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.104% 1,675/1,613,852 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.136%	735
Remaining individualsnot grpmax-eligible	0.08%	1,250
Admixed American	0.0167%	6,001
African / African-American	0.0107%	9,379
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Ser197Phe
Coding: c.590C>T
MANE Select: NM_201596
dbSNP: rs150528041
Type: single nucleotide variant
Location: chr10:18500945 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 197: 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: cardiomyopathy Brugada syndrome 4 Brugada syndrome

Similar variants

CACNB2 p.Ser197Ala 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-ser197phe (accessed [today's date]).

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