Is CACNA1A p.Ala2Val (c.5C>T) pathogenic?

CACNA1A p.Ala2Val (c.5C>T) is classified Conflicting classifications of pathogenicity in CACNA1A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-12). AlphaMissense: ambiguous (0.4098); Ultra-rare (popmax 0.0297%, afr); Associated with episodic ataxia type 2.

What condition is associated with CACNA1A p.Ala2Val (c.5C>T)?

CACNA1A p.Ala2Val (c.5C>T) is associated with episodic ataxia type 2, developmental and epileptic encephalopathy, 42 (ClinVar).

How common is CACNA1A p.Ala2Val (c.5C>T) in the general population?

CACNA1A p.Ala2Val (c.5C>T) is ultra-rare (popmax 0.0297%, afr) (gnomAD).

How is Familial paroxysmal ataxia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CACNA1A p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.4098) — an in-silico prediction, not a clinical call.

CACNA1A p.Ala2Val

c.5C>T · rs927310190 · VCV422504

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, afr)

Conditions

episodic ataxia type 2

Computational evidence

Protein change
AlphaMissense	0.4098	ambiguous
REVEL	0.612	indeterminate
SaProt	LLR -7.70	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP -0.14, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 139 bp · p 0.22 · regional, not allelic
Overall
CADD	27.5	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

Grpmax group 0.0297% African / African-American · 21/70,598 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00176% 26/1,481,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0297%	3,362
Admixed American	0.0074%	13,522
Remaining individualsnot grpmax-eligible	0.00174%	57,310
South Asian	0.00138%	72,364

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: CACNA1A
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_001127222
dbSNP: rs927310190
Type: single nucleotide variant
Location: chr19:13506220 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB

Full CACNA1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

episodic ataxia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 42

For Familial paroxysmal ataxia (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

CACNA1A p.Ala2Ser Uncertain significance ★ ⚠ same residue
CACNA1A c.1082+1G>A Pathogenic ★★ same condition
CACNA1A c.1198+1G>A Pathogenic/Likely pathogenic ★★ same condition
CACNA1A c.2105-2A>G Likely pathogenic ★★ same condition
CACNA1A c.3692+1G>A Pathogenic/Likely pathogenic ★★ same condition
CACNA1A c.3822+1G>A Pathogenic ★★ same condition
CACNA1A c.3989+1G>A Pathogenic ★★ same condition
CACNA1A c.3989+1G>T 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/cacna1a-p-ala2val (accessed [today's date]).

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