Is CACNA1E p.Ala702Pro (c.2104G>C) pathogenic?

CACNA1E p.Ala702Pro (c.2104G>C) is classified Likely pathogenic in CACNA1E (ClinVar, Single submitter, 1 submitter; last evaluated 2016-04-20). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1.

How common is CACNA1E p.Ala702Pro (c.2104G>C) in the general population?

CACNA1E p.Ala702Pro (c.2104G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1E p.Ala702Pro (c.2104G>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

CACNA1E p.Ala702Pro

c.2104G>C · rs12131800 · VCV427007

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic ✓ concordant with ClinVar · top 1% in CACNA1E
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -12.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 8,069 bp · p 2.6e-26 · regional, not allelic
Overall
CADD	31.0	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: CACNA1E
Protein: p.Ala702Pro
Coding: c.2104G>C
MANE Select: NM_001205293
dbSNP: rs12131800
Type: single nucleotide variant
Location: chr1:181724499 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.56 · 5 PDB
Residue 702: a UniProt-annotated variant site (in dee69); a UniProt-annotated variant site (in dee69; gain-of-function variant affecting channel activity; shifts the voltage dependence of activation toward more negative potentials and slows the fast inactivation time course); an α-helix

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

Similar variants

CACNA1E p.Ala702Thr Pathogenic/Likely pathogenic ★★ same residue
CACNA1E p.Ala702Gly Likely pathogenic ★ same residue
CACNA1E p.Ala702= Uncertain significance ★ same residue
CACNA1E p.Ala702Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CACNA1E p.Ala702Ser Pathogenic same residue
CACNA1E p.Gly348Arg Pathogenic/Likely pathogenic ★★ same type
CACNA1E p.Gly352Arg Pathogenic/Likely pathogenic ★★ same type
CACNA1E p.Ile603Leu 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-ala702pro (accessed [today's date]).

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