Is CACNA2D1 p.Pro773Ser (c.2317C>T) pathogenic?

CACNA2D1 p.Pro773Ser (c.2317C>T) is classified Uncertain significance in CACNA2D1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-09). AlphaMissense: likely benign (0.0686); Very rare (popmax 0.000614%, nfe); Associated with Brugada syndrome.

What condition is associated with CACNA2D1 p.Pro773Ser (c.2317C>T)?

CACNA2D1 p.Pro773Ser (c.2317C>T) is associated with Brugada syndrome (ClinVar).

How common is CACNA2D1 p.Pro773Ser (c.2317C>T) in the general population?

CACNA2D1 p.Pro773Ser (c.2317C>T) is very rare (popmax 0.000614%, nfe) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CACNA2D1 p.Pro773Ser (c.2317C>T)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

CACNA2D1 p.Pro773Ser

c.2317C>T · rs1268971839 · VCV947893

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000614%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Brugada syndrome

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 0.94, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 110 kb · p 2.7e-23 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P785S vs ClinVar P773S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000614% European (non-Finnish) · 7/1,139,622 alleles

Filtering AF 0.000255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000164%

Overall 0.000495% 7/1,415,188 alleles · very rare

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.Pro773Ser
Coding: c.2317C>T
MANE Select: NM_000722
dbSNP: rs1268971839
Type: single nucleotide variant
Location: chr7:81968965 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.97 · 30 PDB
Residue 773: a β-strand; a disulfide bond

Full CACNA2D1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Brugada syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CACNA2D1 p.Pro773Leu 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-pro773ser (accessed [today's date]).

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