Is CACNA2D1 p.Arg197= (c.591C>T) pathogenic?

CACNA2D1 p.Arg197= (c.591C>T) is classified Likely benign in CACNA2D1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-23). Rare (popmax 0.14%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CACNA2D1 p.Arg197= (c.591C>T)?

CACNA2D1 p.Arg197= (c.591C>T) is associated with Cardiovascular phenotype, Brugada syndrome (ClinVar).

How common is CACNA2D1 p.Arg197= (c.591C>T) in the general population?

CACNA2D1 p.Arg197= (c.591C>T) is rare (popmax 0.14%, eas) (gnomAD).

CACNA2D1 p.Arg197=

c.591C>T · rs749757910 · VCV1656437

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.14%, eas)

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 -0.17	GERP -5, phastCons 0.7
Overall
CADD	10.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.14% East Asian · 63/44,876 alleles

Filtering AF 0.113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.00669% 108/1,613,700 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.14%	712
South Asian	0.0384%	2,603
Admixed American	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0016%	62,462
African / African-American	0.00134%	74,896
European (non-Finnish)	0.000424%	235,954

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: CACNA2D1
Protein: p.Arg197=
Coding: c.591C>T
MANE Select: NM_000722
dbSNP: rs749757910
Type: single nucleotide variant
Location: chr7:82084836 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.97 · 30 PDB
Residue 197: an α-helix

Full CACNA2D1 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

Similar variants

CACNA2D1 p.Arg197Cys Uncertain significance ★ ⚠ same residue
CACNA2D1 p.Arg197His Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNA2D1 c.1662+3G>A Uncertain significance ★★ same condition
CACNA2D1 c.2574+3A>G Uncertain significance ★★ same condition
CACNA2D1 c.3160-1G>A Uncertain significance ★★ same condition
CACNA2D1 p.Ala1022Glu Uncertain significance ★★ ⚠ same condition
CACNA2D1 p.Ala104Thr Uncertain significance ★★ ⚠ same condition
CACNA2D1 p.Ala104Val 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/cacna2d1-p-arg197 (accessed [today's date]).

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