Is CACNA2D1 p.Ala545= (c.1635A>G) pathogenic?

CACNA2D1 p.Ala545= (c.1635A>G) is classified Likely benign in CACNA2D1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-17). Ultra-rare (popmax 0.033%, mid); Associated with Cardiovascular phenotype.

What condition is associated with CACNA2D1 p.Ala545= (c.1635A>G)?

CACNA2D1 p.Ala545= (c.1635A>G) is associated with Cardiovascular phenotype, Brugada syndrome (ClinVar).

How common is CACNA2D1 p.Ala545= (c.1635A>G) in the general population?

CACNA2D1 p.Ala545= (c.1635A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

CACNA2D1 p.Ala545=

c.1635A>G · rs540691116 · VCV1776910

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.101	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.99	GERP -3.6, phastCons 0.004
Overall
CADD	5.468	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,066 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00106% 17/1,606,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,033
South Asian	0.0022%	45,474
Remaining individualsnot grpmax-eligible	0.00161%	62,242
European (non-Finnish)	0.00102%	97,822

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.Ala545=
Coding: c.1635A>G
MANE Select: NM_000722
dbSNP: rs540691116
Type: single nucleotide variant
Location: chr7:81997206 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.97 · 30 PDB
Residue 545: a disulfide bond; the cache domain

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 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
CACNA2D1 p.Ala30Pro Uncertain significance ★★ ⚠ same condition
CACNA2D1 p.Ala321Thr 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-ala545 (accessed [today's date]).

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