Is CACNA1A p.Ser515= (c.1545C>T) pathogenic?

CACNA1A p.Ser515= (c.1545C>T) is classified Likely benign in CACNA1A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Rare (popmax 0.114%, eas); Associated with episodic ataxia type 2.

What condition is associated with CACNA1A p.Ser515= (c.1545C>T)?

CACNA1A p.Ser515= (c.1545C>T) is associated with episodic ataxia type 2, developmental and epileptic encephalopathy, 42 (ClinVar).

How common is CACNA1A p.Ser515= (c.1545C>T) in the general population?

CACNA1A p.Ser515= (c.1545C>T) is rare (popmax 0.114%, eas) (gnomAD).

How is Familial paroxysmal ataxia inherited?

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

CACNA1A p.Ser515=

c.1545C>T · rs372275167 · VCV542846

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.114%, eas)

Conditions

episodic ataxia type 2

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 0.087	GERP -5.3, phastCons 0.66
Overall
CADD	11.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.114% East Asian · 51/44,636 alleles

Filtering AF 0.0892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0803%

Overall 0.00735% 118/1,605,124 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.114%	875
African / African-American	0.0334%	2,996
Middle Eastern	0.0166%	6,022
Admixed American	0.0117%	8,542
Remaining individualsnot grpmax-eligible	0.00806%	12,413
European (non-Finnish)	0.00239%	41,882
South Asian	0.0011%	90,728

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.Ser515=
Coding: c.1545C>T
MANE Select: NM_001127222
dbSNP: rs372275167
Type: single nucleotide variant
Location: chr19:13317122 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 515: an α-helix

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 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
CACNA1A c.3990-2A>G 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/cacna1a-p-ser515 (accessed [today's date]).

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