Is CACNA1A p.Pro2001Ser (c.6001C>T) pathogenic?

CACNA1A p.Pro2001Ser (c.6001C>T) is classified Conflicting classifications of pathogenicity in CACNA1A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-06-02). AlphaMissense: likely benign (0.0829); Ultra-rare (popmax 0.0191%, mid); Associated with spinocerebellar ataxia type 6.

What condition is associated with CACNA1A p.Pro2001Ser (c.6001C>T)?

CACNA1A p.Pro2001Ser (c.6001C>T) is associated with spinocerebellar ataxia type 6, episodic ataxia type 2, developmental and epileptic encephalopathy, 42 (ClinVar).

How common is CACNA1A p.Pro2001Ser (c.6001C>T) in the general population?

CACNA1A p.Pro2001Ser (c.6001C>T) is ultra-rare (popmax 0.0191%, mid) (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.Pro2001Ser (c.6001C>T)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

CACNA1A p.Pro2001Ser

c.6001C>T · rs751947412 · VCV451126

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0191%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia type 6

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2.5, phastCons 0.99
Regional constraint	o/e 1.07	unconstrained · MANE · 6,952 bp · p 0.039 · regional, not allelic
Overall
CADD	17.33	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 0.0191% Middle Eastern · 1/5,244 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00377% 57/1,512,542 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0191%	5,244
Admixed American	0.0113%	8,861
African / African-American	0.00559%	17,905
Remaining individualsnot grpmax-eligible	0.00517%	19,326
European (non-Finnish)	0.0038%	26,310
East Asian	0.00229%	43,714

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.Pro2001Ser
Coding: c.6001C>T
MANE Select: NM_001127222
dbSNP: rs751947412
Type: single nucleotide variant
Location: chr19:13212680 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.34 · 4 PDB
Residue 2001: 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

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

For Spinocerebellar ataxia type 6 (Orphanet):

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

Similar variants

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
CACNA1A c.3990-2A>G Pathogenic/Likely 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-pro2001ser (accessed [today's date]).

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