Is CACNA1E p.Ala2222Pro (c.6664G>C) pathogenic?

CACNA1E p.Ala2222Pro (c.6664G>C) is classified Uncertain significance in CACNA1E (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely benign (0.058); Very rare (popmax 0.000254%, nfe).

How common is CACNA1E p.Ala2222Pro (c.6664G>C) in the general population?

CACNA1E p.Ala2222Pro (c.6664G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CACNA1E p.Ala2222Pro (c.6664G>C)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

CACNA1E p.Ala2222Pro

c.6664G>C · rs369634310 · VCV1488805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -5.50	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 -1.3	GERP -3.4
Regional constraint	o/e 0.92	unconstrained · MANE · 13 kb · p 0.062 · regional, not allelic
Overall
CADD	0.016	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,896 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,440 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: CACNA1E
Protein: p.Ala2222Pro
Coding: c.6664G>C
MANE Select: NM_001205293
dbSNP: rs369634310
Type: single nucleotide variant
Location: chr1:181798556 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.56 · 5 PDB
Residue 2222: a UniProt-annotated variant site (in dee69; uncertain significance); the 'disordered' region

Full CACNA1E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACNA1E p.Ala2222Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNA1E p.Ala2222Ser Likely benign ★ same residue
CACNA1E p.Ala702Thr Pathogenic/Likely pathogenic ★★ same type
CACNA1E p.Gly348Arg Pathogenic/Likely pathogenic ★★ same type
CACNA1E p.Gly352Arg Pathogenic/Likely pathogenic ★★ same type
CACNA1E p.Ile603Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
CACNA1E p.Ile701Val Pathogenic ★★ ⚠ same type
CACNA1E p.Leu228Pro Pathogenic/Likely 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/cacna1e-p-ala2222pro (accessed [today's date]).

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