Is LGI4 p.Arg258Pro (c.773G>C) pathogenic?

LGI4 p.Arg258Pro (c.773G>C) is classified Pathogenic in LGI4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-07-30). AlphaMissense: ambiguous (0.5546); Very rare (popmax 0.00333%, amr); Associated with arthrogryposis multiplex congenita 1, neurogenic, with myelin defect.

What condition is associated with LGI4 p.Arg258Pro (c.773G>C)?

LGI4 p.Arg258Pro (c.773G>C) is associated with arthrogryposis multiplex congenita 1, neurogenic, with myelin defect (ClinVar).

How common is LGI4 p.Arg258Pro (c.773G>C) in the general population?

LGI4 p.Arg258Pro (c.773G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about LGI4 p.Arg258Pro (c.773G>C)?

AlphaMissense predicts ambiguous (score 0.5546) — an in-silico prediction, not a clinical call.

LGI4 p.Arg258Pro

c.773G>C · rs755500591 · VCV424870

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5546 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

arthrogryposis multiplex congenita 1, neurogenic, with myelin defect

Computational evidence

Protein change
AlphaMissense	0.5546	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -14.77	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP -2.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 8,105 bp · p 0.22 · regional, not allelic
Overall
CADD	20.2	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 · 2/60,014 alleles

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

Overall 0.000124% 2/1,612,422 alleles · very rare exomes 2/1,460,110 · genomes 0/152,312 · joint denominator

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: LGI4
Protein: p.Arg258Pro
Coding: c.773G>C
MANE Select: NM_139284
dbSNP: rs755500591
Type: single nucleotide variant
Location: chr19:35126873 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.80
Residue 258: a UniProt-annotated variant site (in amc1)

Full LGI4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arthrogryposis multiplex congenita 1, neurogenic, with myelin defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LGI4 p.Arg165Cys Uncertain significance ★★ ⚠ same condition
LGI4 p.Leu211Gln Uncertain significance ★★ ⚠ same condition
LGI4 c.459-33G>A Benign ★★ same condition
LGI4 c.*10C>T Benign ★★ same condition
LGI4 c.*11G>A Benign ★★ same condition
LGI4 p.Gln465= Benign ★★ same condition
LGI4 p.His152= Benign ★★ same condition
LGI4 p.Leu466= Benign ★★ 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/lgi4-p-arg258pro (accessed [today's date]).

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