Is LARGE1 p.His139= (c.417C>T) pathogenic?

LARGE1 p.His139= (c.417C>T) is classified Likely benign in LARGE1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0165%, mid); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.His139= (c.417C>T)?

LARGE1 p.His139= (c.417C>T) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.His139= (c.417C>T) in the general population?

LARGE1 p.His139= (c.417C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

LARGE1 p.His139=

c.417C>T · rs115575249 · VCV1161040

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -1	GERP -1.3
Overall
CADD	10.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00397% 64/1,613,688 alleles · ultra-rare exomes 59/1,461,392 · genomes 5/152,296 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Admixed American	0.00667%	15,004
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-American	0.00533%	18,759
East Asian	0.00446%	22,438
European (non-Finnish)	0.0039%	25,644
South Asian	0.0022%	45,534
Finnishnot grpmax-eligible	0.00156%	63,998

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.His139=
Coding: c.417C>T
MANE Select: NM_133642
dbSNP: rs115575249
Type: single nucleotide variant
Location: chr22:33626318 (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 139: a β-strand; 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.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-his139 (accessed [today's date]).

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