Is LGI1 p.Pro522= (c.1566A>C) pathogenic?

LGI1 p.Pro522= (c.1566A>C) is classified Likely benign in LGI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-27). Very rare (popmax 0.00203%, nfe); Associated with autosomal dominant epilepsy with auditory features.

What condition is associated with LGI1 p.Pro522= (c.1566A>C)?

LGI1 p.Pro522= (c.1566A>C) is associated with autosomal dominant epilepsy with auditory features (ClinVar).

How common is LGI1 p.Pro522= (c.1566A>C) in the general population?

LGI1 p.Pro522= (c.1566A>C) is very rare (popmax 0.00203%, nfe) (gnomAD).

How is Epilepsy with auditory features inherited?

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

LGI1 p.Pro522=

c.1566A>C · rs771120986 · VCV1112667

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

autosomal dominant epilepsy with auditory features

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -5.7, phastCons 0.86
Overall
CADD	3.977	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,980 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00155% 25/1,613,960 alleles · very rare exomes 25/1,461,622 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,166
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Pro522=
Coding: c.1566A>C
MANE Select: NM_005097
dbSNP: rs771120986
Type: single nucleotide variant
Location: chr10:93797695 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.81 · 9 PDB
Residue 522: a UniProt-annotated variant site (in dee121; likely pathogenic; loss of protein secretion); a β-strand

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-pro522 (accessed [today's date]).

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