Is LARGE1 p.Ala178= (c.534G>A) pathogenic?

LARGE1 p.Ala178= (c.534G>A) is classified Likely benign in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-14). Very rare (popmax 0.00549%, sas); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Ala178= (c.534G>A)?

LARGE1 p.Ala178= (c.534G>A) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Ala178= (c.534G>A) in the general population?

LARGE1 p.Ala178= (c.534G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

LARGE1 p.Ala178=

c.534G>A · rs772655607 · VCV2740422

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

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 -20	GERP -5.5
Overall
CADD	0.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,082 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000558% 9/1,613,932 alleles · very rare exomes 6/1,461,826 · genomes 3/152,106 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00134%	74,892
European (non-Finnish)	0.000169%	589,991

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.Ala178=
Coding: c.534G>A
MANE Select: NM_133642
dbSNP: rs772655607
Type: single nucleotide variant
Location: chr22:33604516 (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 178: 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.Ala178Val Uncertain significance ★ ⚠ same residue
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

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-ala178 (accessed [today's date]).

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