Is LARGE1 p.Ser111= (c.333C>T) pathogenic?

LARGE1 p.Ser111= (c.333C>T) is classified Likely benign in LARGE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-08). Ultra-rare (popmax 0.0183%, amr); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Ser111= (c.333C>T)?

LARGE1 p.Ser111= (c.333C>T) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Ser111= (c.333C>T) in the general population?

LARGE1 p.Ser111= (c.333C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

LARGE1 p.Ser111=

c.333C>T · rs746767821 · VCV383718

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP -0.84, phastCons 1
Overall
CADD	14.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,010 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000805% 13/1,613,978 alleles · ultra-rare exomes 12/1,461,748 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,180,062

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.Ser111=
Coding: c.333C>T
MANE Select: NM_133642
dbSNP: rs746767821
Type: single nucleotide variant
Location: chr22:33650442 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB

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-ser111 (accessed [today's date]).

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