Is CACNA2D3 p.Asp697= (c.2091C>T) pathogenic?

CACNA2D3 p.Asp697= (c.2091C>T) is classified Likely benign in CACNA2D3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-27). Ultra-rare (popmax 0.0165%, mid); Associated with CACNA2D3-related disorder.

What condition is associated with CACNA2D3 p.Asp697= (c.2091C>T)?

CACNA2D3 p.Asp697= (c.2091C>T) is associated with CACNA2D3-related disorder (ClinVar).

How common is CACNA2D3 p.Asp697= (c.2091C>T) in the general population?

CACNA2D3 p.Asp697= (c.2091C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

CACNA2D3 p.Asp697=

c.2091C>T · rs377667754 · VCV3053454

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

CACNA2D3-related disorder

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 -0.047	GERP -4.2, phastCons 0.89
Overall
CADD	9.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00582% 94/1,613,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.0147%	6,820
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)	0.00619%	16,162
South Asian	0.0022%	45,537
Admixed American	0.00167%	60,006

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: CACNA2D3
Protein: p.Asp697=
Coding: c.2091C>T
MANE Select: NM_018398
dbSNP: rs377667754
Type: single nucleotide variant
Location: chr3:54887993 (GRCh38)
Gene constraint: LOEUF 0.454 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.30
Residue 697: a disulfide bond

Full CACNA2D3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CACNA2D3-related disorder

Similar variants

CACNA2D3 p.Ala702Thr Uncertain significance ★ ⚠ same condition
CACNA2D3 p.His624Asn Uncertain significance ★ ⚠ same condition
CACNA2D3 p.Leu938Phe Uncertain significance ★ ⚠ same condition
CACNA2D3 p.Lys983Arg Uncertain significance ★ ⚠ same condition
CACNA2D3 p.Met481Lys Uncertain significance ★ ⚠ same condition
CACNA2D3 p.Ala16Val Uncertain significance ⚠ same condition
CACNA2D3 p.Asn347Ser Uncertain significance ⚠ same condition
CACNA2D3 p.His765Tyr 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/cacna2d3-p-asp697 (accessed [today's date]).

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