Is CACNA1A p.Arg869Pro (c.2606G>C) pathogenic?

CACNA1A p.Arg869Pro (c.2606G>C) is classified Uncertain significance in CACNA1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-05). AlphaMissense: likely benign (0.1539); Absent from gnomAD v4.1; Associated with hereditary cerebellar ataxia.

What condition is associated with CACNA1A p.Arg869Pro (c.2606G>C)?

CACNA1A p.Arg869Pro (c.2606G>C) is associated with hereditary cerebellar ataxia (ClinVar).

How common is CACNA1A p.Arg869Pro (c.2606G>C) in the general population?

CACNA1A p.Arg869Pro (c.2606G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1A p.Arg869Pro (c.2606G>C)?

AlphaMissense predicts likely benign (score 0.1539) — an in-silico prediction, not a clinical call.

CACNA1A p.Arg869Pro

c.2606G>C · rs1057518589 · VCV871987

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1539 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary cerebellar ataxia

Computational evidence

Protein change
AlphaMissense	0.1539	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.67	GERP -0.44, phastCons 0.25
Regional constraint	o/e 1.02	unconstrained · MANE · 17 kb · p 0.55 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Arg869Pro
Coding: c.2606G>C
MANE Select: NM_001127222
dbSNP: rs1057518589
Type: single nucleotide variant
Location: chr19:13299027 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 869: the 'disordered' region

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

Disease context

hereditary cerebellar ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNA1A p.Arg869Gln Uncertain significance ★★ ⚠ same residue
CACNA1A c.1082+1G>A Pathogenic ★★ same type
CACNA1A c.1198+1G>A Pathogenic/Likely pathogenic ★★ same type
CACNA1A c.2105-2A>G Likely pathogenic ★★ same type
CACNA1A c.3692+1G>A Pathogenic/Likely pathogenic ★★ same type
CACNA1A c.3822+1G>A Pathogenic ★★ same type
CACNA1A c.3989+1G>A Pathogenic ★★ same type
CACNA1A c.3989+1G>T Pathogenic ★★ same type

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-arg869pro (accessed [today's date]).

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