Is CACNA1A p.Arg1663Ter (c.4987C>T) pathogenic?

CACNA1A p.Arg1663Ter (c.4987C>T) is classified Pathogenic in CACNA1A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-11-26). Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CACNA1A p.Arg1663Ter (c.4987C>T)?

CACNA1A p.Arg1663Ter (c.4987C>T) is associated with Inborn genetic diseases, episodic ataxia type 2, spinocerebellar ataxia type 6 (ClinVar).

How common is CACNA1A p.Arg1663Ter (c.4987C>T) in the general population?

CACNA1A p.Arg1663Ter (c.4987C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

CACNA1A p.Arg1663Ter

c.4987C>T · rs1555738369 · VCV523785

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 32 of 47
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.91 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2.6, phastCons 1
Overall
CADD	45.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,834 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,620 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.Arg1663Ter
Coding: c.4987C>T
MANE Select: NM_001127222
dbSNP: rs1555738369
Type: single nucleotide variant
Location: chr19:13235694 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: episodic ataxia type 2 spinocerebellar ataxia type 6 developmental and epileptic encephalopathy, 42

Similar variants

CACNA1A p.Arg1663Gln Pathogenic/Likely 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-arg1663ter (accessed [today's date]).

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