Is LARGE1 p.Glu63fs (c.184_187del) pathogenic?

LARGE1 p.Glu63fs (c.184187del) is classified Pathogenic in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-28). Very rare (popmax 0.00133%, afr); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Glu63fs (c.184_187del)?

LARGE1 p.Glu63fs (c.184_187del) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Glu63fs (c.184_187del) in the general population?

LARGE1 p.Glu63fs (c.184_187del) is very rare (popmax 0.00133%, afr) (gnomAD).

LARGE1 p.Glu63fs

c.184_187del · rs2080768582 · VCV2739916

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.1	GERP 2.1, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,938 alleles

Overall 6.23e-05% 1/1,605,970 alleles · very rare exomes 0/1,453,740 · genomes 1/152,230 · 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: LARGE1
Protein: p.Glu63fs
Coding: c.184_187del
MANE Select: NM_133642
dbSNP: rs2080768582
Type: Deletion
Location: chr22:33650588 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB
Residue 63: the 'disordered' region

Full LARGE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

muscular dystrophy-dystroglycanopathy type B6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LARGE1 p.Glu63Gly Uncertain significance ★★ ⚠ same residue
LARGE1 p.Glu63= Likely benign ★ same residue
LARGE1 c.788-5_826del Likely pathogenic ★ same condition
LARGE1 p.Glu207fs Pathogenic ★ same condition
LARGE1 p.Leu567fs Pathogenic ★ same condition
LARGE1 p.Leu604fs Pathogenic ★ same condition
LARGE1 p.Phe162fs Likely pathogenic ★ same condition
LARGE1 p.Phe404fs Pathogenic ★ 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/large1-p-glu63fs (accessed [today's date]).

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