Is CACNA1E p.Ser2193Phe (c.6578C>T) pathogenic?

CACNA1E p.Ser2193Phe (c.6578C>T) is classified Benign in CACNA1E (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely benign (0.0966); Very rare (popmax 0.00333%, amr).

How common is CACNA1E p.Ser2193Phe (c.6578C>T) in the general population?

CACNA1E p.Ser2193Phe (c.6578C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CACNA1E p.Ser2193Phe (c.6578C>T)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

CACNA1E p.Ser2193Phe

c.6578C>T · rs1025826185 · VCV2982954

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.453	indeterminate
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 13 kb · p 0.062 · regional, not allelic
Overall
CADD	23.6	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 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,613,776 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
European (non-Finnish)	0.00017%	589,946

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.Ser2193Phe
Coding: c.6578C>T
MANE Select: NM_001205293
dbSNP: rs1025826185
Type: single nucleotide variant
Location: chr1:181798470 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.56 · 5 PDB
Residue 2193: a UniProt-annotated variant site (in dee69; uncertain significance)

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

Similar variants

CACNA1E p.Ser2193= 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
CACNA1E p.Phe698Leu 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-ser2193phe (accessed [today's date]).

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