Is LARGE1 p.Ala256fs (c.766dup) pathogenic?

LARGE1 p.Ala256fs (c.766dup) is classified Pathogenic in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Ala256fs (c.766dup)?

LARGE1 p.Ala256fs (c.766dup) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

LARGE1 p.Ala256fs

c.766dup · VCV3663678

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 6 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1

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

Variant & gene context

Gene: LARGE1
Protein: p.Ala256fs
Coding: c.766dup
MANE Select: NM_133642
Type: Duplication
Location: chr22:33564868 (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 256: an α-helix; the 'xylosyltransferase activity' 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.Ala256Ser Uncertain significance ★ ⚠ same residue
LARGE1 p.Leu85_Ala86dup Uncertain significance ★★ same condition
LARGE1 p.Arg53fs Pathogenic ★ same condition
LARGE1 p.Glu61fs Pathogenic ★ same condition
LARGE1 p.Leu514fs Pathogenic ★ same condition
LARGE1 p.Trp316fs Pathogenic ★ same condition
LARGE1 c.1287+2dup Uncertain significance ★ same condition
LARGE1 c.1452-13dup Likely 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/large1-p-ala256fs (accessed [today's date]).

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