Is CACNA1D p.Val259Asp (c.776T>A) pathogenic?

CACNA1D p.Val259Asp (c.776T>A) is classified Pathogenic in CACNA1D (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-15). AlphaMissense: likely pathogenic (0.9893); Absent from gnomAD v4.1.

How common is CACNA1D p.Val259Asp (c.776T>A) in the general population?

CACNA1D p.Val259Asp (c.776T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1D p.Val259Asp (c.776T>A)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

CACNA1D p.Val259Asp

c.776T>A · rs2473017875 · VCV2580195

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic ✓ concordant with ClinVar
REVEL	0.989	strongly pathogenic-leaning
SaProt	LLR -14.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 201 kb · p 1.3e-24 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CACNA1D
Protein: p.Val259Asp
Coding: c.776T>A
MANE Select: NM_001128840
dbSNP: rs2473017875
Type: single nucleotide variant
Location: chr3:53665669 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.60 · 6 PDB
Residue 259: an α-helix

Full CACNA1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNA1D p.Ser652Leu Pathogenic/Likely pathogenic ★★ same type
CACNA1D c.1892+3A>G Uncertain significance ★★ same type
CACNA1D c.2406+3A>G Uncertain significance ★★ same type
CACNA1D c.2474-1G>A Uncertain significance ★★ same type
CACNA1D c.2474-2A>C Uncertain significance ★★ same type
CACNA1D c.2751+2T>C Uncertain significance ★★ same type
CACNA1D c.3314+1G>A Uncertain significance ★★ same type
CACNA1D c.3314+1G>C Uncertain significance ★★ same type

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/cacna1d-p-val259asp (accessed [today's date]).

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