Is LARGE1 p.Ala596= (c.1788G>A) pathogenic?

LARGE1 p.Ala596= (c.1788G>A) is classified Conflicting classifications of pathogenicity in LARGE1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-04-01). Rare (popmax 0.379%, nfe); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Ala596= (c.1788G>A)?

LARGE1 p.Ala596= (c.1788G>A) is associated with muscular dystrophy-dystroglycanopathy type B6, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (ClinVar).

How common is LARGE1 p.Ala596= (c.1788G>A) in the general population?

LARGE1 p.Ala596= (c.1788G>A) is rare (popmax 0.379%, nfe) (gnomAD).

LARGE1 p.Ala596=

c.1788G>A · rs74550830 · VCV167250

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.379%, nfe)

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 -20	GERP -3.7
Overall
CADD	0.046	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.379% European (non-Finnish) · 4,470/1,180,014 alleles

Filtering AF 0.369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.366%

Overall 0.339% 5,479/1,614,108 alleles · rare exomes 5,147/1,461,886 · genomes 332/152,222 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.41%	71
European (non-Finnish)grpmax	0.379%	264
Remaining individualsnot grpmax-eligible	0.299%	334
Finnishnot grpmax-eligible	0.259%	386
South Asian	0.187%	536
Amishnot grpmax-eligible	0.11%	910
African / African-American	0.0586%	1,705
Admixed American	0.0333%	3,001
Middle Eastern	0.0165%	6,062
East Asian	0.00446%	22,443

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala596=
Coding: c.1788G>A
MANE Select: NM_133642
dbSNP: rs74550830
Type: single nucleotide variant
Location: chr22:33283291 (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 596: the 'glucuronyltransferase activity' region; a β-strand

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

Also linked: muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

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-ala596 (accessed [today's date]).

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