Is CACNA1A p.Pro2144= (c.6432G>A) pathogenic?

CACNA1A p.Pro2144= (c.6432G>A) is classified Likely benign in CACNA1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-25). Very rare (popmax 0.00296%, afr); Associated with episodic ataxia type 2.

What condition is associated with CACNA1A p.Pro2144= (c.6432G>A)?

CACNA1A p.Pro2144= (c.6432G>A) is associated with episodic ataxia type 2, developmental and epileptic encephalopathy, 42 (ClinVar).

How common is CACNA1A p.Pro2144= (c.6432G>A) in the general population?

CACNA1A p.Pro2144= (c.6432G>A) is very rare (popmax 0.00296%, afr) (gnomAD).

How is Familial paroxysmal ataxia inherited?

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

CACNA1A p.Pro2144=

c.6432G>A · VCV3256962

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00296%, afr)

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 -20	GERP -4.1
Overall
CADD	0.076	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00296% African / African-American · 2/67,648 alleles

Filtering AF 0.000491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000184%

Overall 0.000562% 7/1,246,262 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00482%	20,750
African / African-Americangrpmax	0.00296%	33,824
European (non-Finnish)	0.000373%	268,217

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2144=
Coding: c.6432G>A
MANE Select: NM_001127222
Type: single nucleotide variant
Location: chr19:13209406 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 2144: a UniProt-annotated variant site (in ea2 and sca6); the 'disordered' region

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.Pro2144Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNA1A p.Pro2144Gln 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

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-pro2144 (accessed [today's date]).

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