Is LGI4 p.Pro278= (c.834G>C) pathogenic?

LGI4 p.Pro278= (c.834G>C) is classified Benign in LGI4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-19). Common (popmax 52.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with arthrogryposis multiplex congenita 1, neurogenic, with myelin defect.

What condition is associated with LGI4 p.Pro278= (c.834G>C)?

LGI4 p.Pro278= (c.834G>C) is associated with arthrogryposis multiplex congenita 1, neurogenic, with myelin defect (ClinVar).

LGI4 p.Pro278=

Q: How common is LGI4 p.Pro278= (c.834G>C) in the general population?

LGI4 p.Pro278= (c.834G>C) is common (popmax 52.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.834G>C · rs1687998 · VCV1300107

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 52.1%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

arthrogryposis multiplex congenita 1, neurogenic, with myelin defect

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.029	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.2	GERP -4.2
Overall
CADD	1.362	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 52.1% South Asian · 43,964/84,394 alleles

Filtering AF 51.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 51.5%

Overall 35.9% 553,262/1,541,662 alleles · common exomes 500,699/1,389,554 · genomes 52,563/152,108 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	52.1%	2
Finnishnot grpmax-eligible	40.4%	2
Ashkenazi Jewishnot grpmax-eligible	39%	3
Middle Eastern	37.6%	3
European (non-Finnish)	35.6%	3
Remaining individualsnot grpmax-eligible	35.4%	3
African / African-American	32.2%	3
Amishnot grpmax-eligible	28%	4
Admixed American	26.4%	4
East Asian	23.2%	4

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.Pro278=
Coding: c.834G>C
MANE Select: NM_139284
dbSNP: rs1687998
Type: single nucleotide variant
Location: chr19:35126735 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.80

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-pro278 (accessed [today's date]).

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