Is CACNA2D1 p.Ile714= (c.2142C>T) pathogenic?

CACNA2D1 p.Ile714= (c.2142C>T) is classified Conflicting classifications of pathogenicity in CACNA2D1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-03). Very rare (popmax 0.00837%, amr); Associated with Cardiovascular phenotype.

What condition is associated with CACNA2D1 p.Ile714= (c.2142C>T)?

CACNA2D1 p.Ile714= (c.2142C>T) is associated with Cardiovascular phenotype, Brugada syndrome (ClinVar).

How common is CACNA2D1 p.Ile714= (c.2142C>T) in the general population?

CACNA2D1 p.Ile714= (c.2142C>T) is very rare (popmax 0.00837%, amr) (gnomAD).

CACNA2D1 p.Ile714=

c.2142C>T · rs745501384 · VCV1498569

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00837%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.6, phastCons 1
Overall
CADD	14.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00837% Admixed American · 5/59,720 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00115% 18/1,568,798 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00837%	11,944
Remaining individualsnot grpmax-eligible	0.00493%	20,300
African / African-American	0.00135%	73,826
European (non-Finnish)	0.00079%	126,619

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.Ile714=
Coding: c.2142C>T
MANE Select: NM_000722
dbSNP: rs745501384
Type: single nucleotide variant
Location: chr7:81970737 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.97 · 30 PDB
Residue 714: an α-helix; a disulfide bond

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.Ile714Met Uncertain significance ★★ ⚠ 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
CACNA2D1 p.Ala30Pro 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-ile714 (accessed [today's date]).

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