Is CACNA1E p.Arg1579Pro (c.4736G>C) pathogenic?

CACNA1E p.Arg1579Pro (c.4736G>C) is classified Likely pathogenic in CACNA1E (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-30). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 69.

What condition is associated with CACNA1E p.Arg1579Pro (c.4736G>C)?

CACNA1E p.Arg1579Pro (c.4736G>C) is associated with developmental and epileptic encephalopathy, 69 (ClinVar).

How common is CACNA1E p.Arg1579Pro (c.4736G>C) in the general population?

CACNA1E p.Arg1579Pro (c.4736G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1E p.Arg1579Pro (c.4736G>C)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

CACNA1E p.Arg1579Pro

c.4736G>C · VCV4687986

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 69

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic ✓ concordant with ClinVar · top 3% in CACNA1E
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -15.56	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 2.1, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 26 kb · p 6e-52 · regional, not allelic
Overall
CADD	33.0	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.Arg1579Pro
Coding: c.4736G>C
MANE Select: NM_001205293
Type: single nucleotide variant
Location: chr1:181763452 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.56 · 5 PDB
Residue 1579: 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

Disease context

developmental and epileptic encephalopathy, 69 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNA1E p.Arg1579Ter Uncertain significance ★ same residue
CACNA1E p.Ala702Thr Pathogenic/Likely pathogenic ★★ same condition
CACNA1E p.Gly348Arg Pathogenic/Likely pathogenic ★★ same condition
CACNA1E p.Gly352Arg Pathogenic/Likely pathogenic ★★ same condition
CACNA1E p.Ile603Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
CACNA1E p.Ile701Val Pathogenic ★★ ⚠ same condition
CACNA1E p.Leu228Pro Pathogenic/Likely pathogenic ★★ same condition
CACNA1E p.Phe698Leu 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/cacna1e-p-arg1579pro (accessed [today's date]).

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