Is CACNA1E p.Ser1652Pro (c.4954T>C) pathogenic?

CACNA1E p.Ser1652Pro (c.4954T>C) is classified Uncertain significance in CACNA1E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-21). AlphaMissense: likely pathogenic (0.9814); Absent from gnomAD v4.1.

How common is CACNA1E p.Ser1652Pro (c.4954T>C) in the general population?

CACNA1E p.Ser1652Pro (c.4954T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1E p.Ser1652Pro (c.4954T>C)?

AlphaMissense predicts likely pathogenic (score 0.9814) — an in-silico prediction, not a clinical call.

CACNA1E p.Ser1652Pro

c.4954T>C · rs2529117780 · VCV3027338

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9814 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9814	likely pathogenic
REVEL	0.931	moderately pathogenic-leaning
SaProt	LLR -14.85	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 5.1	GERP 0.87, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 19 kb · p 4e-25 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: CACNA1E
Protein: p.Ser1652Pro
Coding: c.4954T>C
MANE Select: NM_001205293
dbSNP: rs2529117780
Type: single nucleotide variant
Location: chr1:181771365 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.56 · 5 PDB
Residue 1652: a UniProt-annotated variant site (in dee69; uncertain significance); 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 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
CACNA1E p.Phe698Leu Pathogenic/Likely pathogenic ★★ same type
CACNA1E c.3719+1G>A Uncertain significance ★★ 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-ser1652pro (accessed [today's date]).

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