Is CACNA1E p.Arg2154Ser (c.6462A>T) pathogenic?

CACNA1E p.Arg2154Ser (c.6462A>T) is classified Uncertain significance in CACNA1E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-24). AlphaMissense: likely benign (0.3352); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with CACNA1E p.Arg2154Ser (c.6462A>T)?

CACNA1E p.Arg2154Ser (c.6462A>T) is associated with Inborn genetic diseases (ClinVar).

How common is CACNA1E p.Arg2154Ser (c.6462A>T) in the general population?

CACNA1E p.Arg2154Ser (c.6462A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CACNA1E p.Arg2154Ser (c.6462A>T)?

AlphaMissense predicts likely benign (score 0.3352) — an in-silico prediction, not a clinical call.

CACNA1E p.Arg2154Ser

c.6462A>T · rs757207470 · VCV2970603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3352	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -6.74	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 0.96	GERP -3.5, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 13 kb · p 0.062 · regional, not allelic
Overall
CADD	17.32	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 0.00133% African / African-American · 1/74,926 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00048% 7/1,458,750 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00162%	61,654
African / African-Americangrpmax	0.00133%	74,926
European (non-Finnish)	0.000424%	235,861

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg2154Ser
Coding: c.6462A>T
MANE Select: NM_001205293
dbSNP: rs757207470
Type: single nucleotide variant
Location: chr1:181798354 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.56 · 5 PDB
Residue 2154: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNA1E p.Gly352Arg Pathogenic/Likely pathogenic ★★ same condition
CACNA1E p.Ala487Ser Uncertain significance ★★ ⚠ same condition
CACNA1E p.Ala740Val Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg2059Trp Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg2156Cys Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg59Pro Uncertain significance ★★ ⚠ same condition
CACNA1E p.Arg772Gln Uncertain significance ★★ ⚠ same condition
CACNA1E p.Asn381Ser Uncertain significance ★★ ⚠ 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-arg2154ser (accessed [today's date]).

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