Is LARGE1 p.Leu412= (c.1234C>T) pathogenic?

LARGE1 p.Leu412= (c.1234C>T) is classified Conflicting classifications of pathogenicity in LARGE1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0717%, amr); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Leu412= (c.1234C>T)?

LARGE1 p.Leu412= (c.1234C>T) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Leu412= (c.1234C>T) in the general population?

LARGE1 p.Leu412= (c.1234C>T) is ultra-rare (popmax 0.0717%, amr) (gnomAD).

LARGE1 p.Leu412=

c.1234C>T · rs748508322 · VCV193883

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0717%, amr)

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.021, phastCons 1
Overall
CADD	2.136	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0717% Admixed American · 43/59,996 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.00285% 46/1,614,024 alleles · ultra-rare exomes 43/1,461,884 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0717%	1,395
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Leu412=
Coding: c.1234C>T
MANE Select: NM_133642
dbSNP: rs748508322
Type: single nucleotide variant
Location: chr22:33337699 (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 412: the 'xylosyltransferase activity' region; an α-helix

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.Arg95Ter Pathogenic ★★ same condition
LARGE1 p.Glu509Lys Pathogenic/Likely pathogenic ★★ same condition
LARGE1 c.*155C>T Uncertain significance ★★ same condition
LARGE1 p.Ala149Ser Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala252Val Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala478Thr Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala635Thr Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala752Gly 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/large1-p-leu412 (accessed [today's date]).

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