Is CACNA2D1 p.Ser277= (c.831C>T) pathogenic?

CACNA2D1 p.Ser277= (c.831C>T) is classified Likely benign in CACNA2D1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-16). Ultra-rare (popmax 0.0275%, sas); Associated with Cardiovascular phenotype.

What condition is associated with CACNA2D1 p.Ser277= (c.831C>T)?

CACNA2D1 p.Ser277= (c.831C>T) is associated with Cardiovascular phenotype, Brugada syndrome (ClinVar).

How common is CACNA2D1 p.Ser277= (c.831C>T) in the general population?

CACNA2D1 p.Ser277= (c.831C>T) is ultra-rare (popmax 0.0275%, sas) (gnomAD).

CACNA2D1 p.Ser277=

c.831C>T · rs144936173 · VCV1299931

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, sas)

Conditions

Cardiovascular phenotype

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 -13	GERP -4.7
Overall
CADD	0.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0275% South Asian · 25/90,970 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.0041% 66/1,609,368 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0275%	3,639
Middle Eastern	0.0165%	6,058
African / African-American	0.00404%	24,773
Remaining individualsnot grpmax-eligible	0.00321%	31,155
Finnishnot grpmax-eligible	0.00317%	31,592
European (non-Finnish)	0.0028%	35,700

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.Ser277=
Coding: c.831C>T
MANE Select: NM_000722
dbSNP: rs144936173
Type: single nucleotide variant
Location: chr7:82060476 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.97 · 30 PDB
Residue 277: the vwfa domain; an α-helix

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-ser277 (accessed [today's date]).

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