Is CACNA1A p.Arg1663Gln (c.4988G>A) pathogenic?

CACNA1A p.Arg1663Gln (c.4988G>A) is classified Pathogenic/Likely pathogenic in CACNA1A (ClinVar, Multiple submitters, 20 submitters; last evaluated 2025-11-14). AlphaMissense: likely pathogenic (0.9898); Absent from gnomAD v4.1; Associated with spinocerebellar ataxia type 6.

What condition is associated with CACNA1A p.Arg1663Gln (c.4988G>A)?

CACNA1A p.Arg1663Gln (c.4988G>A) is associated with spinocerebellar ataxia type 6, episodic ataxia type 2, developmental and epileptic encephalopathy, 42 (ClinVar).

How common is CACNA1A p.Arg1663Gln (c.4988G>A) in the general population?

CACNA1A p.Arg1663Gln (c.4988G>A) is absent from gnomAD v4.1 (gnomAD).

How is Spinocerebellar ataxia type 6 inherited?

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

What do computational predictors say about CACNA1A p.Arg1663Gln (c.4988G>A)?

AlphaMissense predicts likely pathogenic (score 0.9898) — an in-silico prediction, not a clinical call.

CACNA1A p.Arg1663Gln

c.4988G>A · rs121908247 · VCV68432

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.9898 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia type 6

Computational evidence

Protein change
AlphaMissense	0.9898	likely pathogenic ✓ concordant with ClinVar
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -15.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.49	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 20 kb · p 1.8e-20 · regional, not allelic
Overall
CADD	35.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CACNA1A
Protein: p.Arg1663Gln
Coding: c.4988G>A
MANE Select: NM_001127222
dbSNP: rs121908247
Type: single nucleotide variant
Location: chr19:13235693 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 1663: a UniProt-annotated variant site (in ea2 and sca6); a UniProt-annotated variant site (in sca6; pathogenic; also found in patients with global developmental delay and congenital ataxia; loss of function observed in the drosophila homolog); an α-helix

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

Disease context

spinocerebellar ataxia type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: episodic ataxia type 2 developmental and epileptic encephalopathy, 42 mega-cisterna magna migraine, familial hemiplegic, 1

For Spinocerebellar ataxia type 6 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Elderly
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CACNA1A p.Arg1663Ter Pathogenic ★★ 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-arg1663gln (accessed [today's date]).

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