Is LGI4 p.Pro404= (c.1212C>T) pathogenic?

LGI4 p.Pro404= (c.1212C>T) is classified Likely benign in LGI4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-23). Ultra-rare (popmax 0.01%, amr).

How common is LGI4 p.Pro404= (c.1212C>T) in the general population?

LGI4 p.Pro404= (c.1212C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

LGI4 p.Pro404=

c.1212C>T · rs754191863 · VCV721517

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.177	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -4.5
Overall
CADD	0.262	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,824 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000434% 7/1,611,530 alleles · ultra-rare exomes 6/1,459,344 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,971
South Asian	0.00111%	90,488

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.Pro404=
Coding: c.1212C>T
MANE Select: NM_139284
dbSNP: rs754191863
Type: single nucleotide variant
Location: chr19:35126357 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.80
Residue 404: a UniProt-annotated variant site (in amc1)

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

Similar variants

LGI4 p.Arg165Cys Uncertain significance ★★ ⚠ same type
LGI4 p.Asp438Val Uncertain significance ★★ ⚠ same type
LGI4 p.Leu211Gln Uncertain significance ★★ ⚠ same type
LGI4 p.Leu315Gln Uncertain significance ★★ ⚠ same type
LGI4 c.1299+221A>G Benign ★★ same type
LGI4 c.1299+52T>C Benign ★★ same type
LGI4 c.1300-134C>T Benign ★★ same type
LGI4 c.1300-151G>C Benign ★★ same type

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-pro404 (accessed [today's date]).

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