Is LGI1 p.Ser463Phe (c.1388C>T) pathogenic?

LGI1 p.Ser463Phe (c.1388C>T) is classified Uncertain significance in LGI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-06). AlphaMissense: likely benign (0.1369); Ultra-rare (popmax 0.011%, sas); Associated with autosomal dominant epilepsy with auditory features.

What condition is associated with LGI1 p.Ser463Phe (c.1388C>T)?

LGI1 p.Ser463Phe (c.1388C>T) is associated with autosomal dominant epilepsy with auditory features (ClinVar).

How common is LGI1 p.Ser463Phe (c.1388C>T) in the general population?

LGI1 p.Ser463Phe (c.1388C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

How is Epilepsy with auditory features inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LGI1 p.Ser463Phe (c.1388C>T)?

AlphaMissense predicts likely benign (score 0.1369) — an in-silico prediction, not a clinical call.

LGI1 p.Ser463Phe

c.1388C>T · rs766323679 · VCV2902550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal dominant epilepsy with auditory features

Computational evidence

Protein change
AlphaMissense	0.1369	likely benign
REVEL	0.616	indeterminate
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 5,041 bp · p 7.5e-14 · regional, not allelic
Overall
CADD	25.6	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 0.011% South Asian · 10/91,084 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000805% 13/1,614,156 alleles · ultra-rare exomes 13/1,461,872 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000169%	590,012

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: LGI1
Protein: p.Ser463Phe
Coding: c.1388C>T
MANE Select: NM_005097
dbSNP: rs766323679
Type: single nucleotide variant
Location: chr10:93797517 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.81 · 9 PDB
Residue 463: a UniProt-annotated variant site (in dee121; likely pathogenic; loss of protein secretion)

Full LGI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant epilepsy with auditory features — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epilepsy with auditory features (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

LGI1 c.504-1G>T Likely pathogenic ★★ same condition
LGI1 p.Arg136Trp Pathogenic/Likely pathogenic ★★ same condition
LGI1 p.Arg330Ter Pathogenic ★★ same condition
LGI1 p.Arg474Gln Likely pathogenic ★★ ⚠ same condition
LGI1 p.Ser473Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
LGI1 p.Ala227Val Uncertain significance ★★ ⚠ same condition
LGI1 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
LGI1 p.Ala354Ser 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/lgi1-p-ser463phe (accessed [today's date]).

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