Is CACNA1A p.Arg1024Pro (c.3071G>C) pathogenic?

CACNA1A p.Arg1024Pro (c.3071G>C) is classified Uncertain significance in CACNA1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-27). AlphaMissense: likely pathogenic (0.5921); Very rare (popmax 8.75e-05%, nfe); Associated with episodic ataxia type 2.

What condition is associated with CACNA1A p.Arg1024Pro (c.3071G>C)?

CACNA1A p.Arg1024Pro (c.3071G>C) is associated with episodic ataxia type 2, developmental and epileptic encephalopathy, 42 (ClinVar).

How common is CACNA1A p.Arg1024Pro (c.3071G>C) in the general population?

CACNA1A p.Arg1024Pro (c.3071G>C) is very rare (popmax 8.75e-05%, nfe) (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.Arg1024Pro (c.3071G>C)?

AlphaMissense predicts likely pathogenic (score 0.5921) — an in-silico prediction, not a clinical call.

CACNA1A p.Arg1024Pro

c.3071G>C · VCV3748304

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.75e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

episodic ataxia type 2

Computational evidence

Protein change
AlphaMissense	0.5921	likely pathogenic
REVEL	0.498	indeterminate
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.023, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 17 kb · p 0.55 · regional, not allelic
Overall
CADD	22.1	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 8.75e-05% European (non-Finnish) · 1/1,142,926 alleles

Overall 7.19e-05% 1/1,391,056 alleles · very rare

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.Arg1024Pro
Coding: c.3071G>C
MANE Select: NM_001127222
Type: single nucleotide variant
Location: chr19:13298562 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 1024: 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.Arg1024Gln Uncertain significance ★★ ⚠ same residue
CACNA1A p.Arg1024Trp Uncertain significance ★ ⚠ same residue
CACNA1A p.Arg1024= Likely benign ★ 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

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-arg1024pro (accessed [today's date]).

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