Is LGI4 p.Pro350Ser (c.1048C>T) pathogenic?

LGI4 p.Pro350Ser (c.1048C>T) is classified Uncertain significance in LGI4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: likely benign (0.0859); Ultra-rare (popmax 0.017%, mid); Associated with Inborn genetic diseases.

What condition is associated with LGI4 p.Pro350Ser (c.1048C>T)?

LGI4 p.Pro350Ser (c.1048C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LGI4 p.Pro350Ser (c.1048C>T) in the general population?

LGI4 p.Pro350Ser (c.1048C>T) is ultra-rare (popmax 0.017%, mid) (gnomAD).

What do computational predictors say about LGI4 p.Pro350Ser (c.1048C>T)?

AlphaMissense predicts likely benign (score 0.0859) — an in-silico prediction, not a clinical call.

LGI4 p.Pro350Ser

c.1048C>T · VCV3538001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0859 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0859	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -4.5, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 63 bp · p 0.0038 · regional, not allelic
Overall
CADD	17.4	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 0.017% Middle Eastern · 1/5,872 alleles

Overall 0.000194% 3/1,544,122 alleles · ultra-rare exomes 3/1,391,790 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,872
Remaining individualsnot grpmax-eligible	0.00166%	60,178
European (non-Finnish)	8.7e-05%	1,149,622

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.Pro350Ser
Coding: c.1048C>T
MANE Select: NM_139284
Type: single nucleotide variant
Location: chr19:35126521 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.80
Residue 350: a UniProt-annotated variant site (in amc1)

Full LGI4 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

LGI4 p.Asp438Val Uncertain significance ★★ ⚠ same condition
LGI4 p.Leu315Gln Uncertain significance ★★ ⚠ same condition
LGI4 p.Ala242Val Uncertain significance ★ ⚠ same condition
LGI4 p.Ala295Thr Uncertain significance ★ ⚠ same condition
LGI4 p.Ala304Asp Uncertain significance ★ ⚠ same condition
LGI4 p.Ala360Thr Uncertain significance ★ ⚠ same condition
LGI4 p.Ala367Thr Uncertain significance ★ ⚠ same condition
LGI4 p.Ala383Thr 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/lgi4-p-pro350ser (accessed [today's date]).

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