Is CACNA1C p.Pro44Ala (c.130C>G) pathogenic?

CACNA1C p.Pro44Ala (c.130C>G) is classified Uncertain significance in CACNA1C (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). Very rare (popmax 0.000683%, nfe); Associated with Brugada syndrome.

What condition is associated with CACNA1C p.Pro44Ala (c.130C>G)?

CACNA1C p.Pro44Ala (c.130C>G) is associated with Brugada syndrome, long QT syndrome (ClinVar).

How common is CACNA1C p.Pro44Ala (c.130C>G) in the general population?

CACNA1C p.Pro44Ala (c.130C>G) is very rare (popmax 0.000683%, nfe) (gnomAD).

How is Brugada syndrome inherited?

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

CACNA1C p.Pro44Ala

c.130C>G · rs1057518456 · VCV373514

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000683%, nfe)

Conditions

Brugada syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.327	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 62 kb · p 0.13 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000683% European (non-Finnish) · 8/1,172,142 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000502% 8/1,594,066 alleles · very rare exomes 6/1,441,832 · genomes 2/152,234 · joint denominator

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: CACNA1C
Protein: p.Pro44Ala
Coding: c.130C>G
MANE Select: NM_000719
dbSNP: rs1057518456
Type: single nucleotide variant
Location: chr12:2115304 (GRCh38)
Gene constraint: LOEUF 0.186 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.73 · 33 PDB

Full CACNA1C 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

Also linked: long QT syndrome

For Brugada syndrome (Orphanet):

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

Similar variants

CACNA1C p.Pro44= Likely benign ★★ same residue
CACNA1C p.Arg518Cys Pathogenic/Likely pathogenic ★★ same condition
CACNA1C p.Arg518His Pathogenic/Likely pathogenic ★★ same condition
CACNA1C p.Arg858His Pathogenic/Likely pathogenic ★★ same condition
CACNA1C p.Arg860Gly Likely pathogenic ★★ same condition
CACNA1C p.Arg860Ter Pathogenic ★★ same condition
CACNA1C p.Glu1115Lys Pathogenic/Likely pathogenic ★★ same condition
CACNA1C p.Gly1378Arg Pathogenic/Likely pathogenic ★★ 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/cacna1c-p-pro44ala (accessed [today's date]).

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