Is LARGE1 p.Ala478Val (c.1433C>T) pathogenic?

LARGE1 p.Ala478Val (c.1433C>T) is classified Uncertain significance in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-02). AlphaMissense: ambiguous (0.528); Very rare (popmax 0.0022%, sas); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Ala478Val (c.1433C>T)?

LARGE1 p.Ala478Val (c.1433C>T) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Ala478Val (c.1433C>T) in the general population?

LARGE1 p.Ala478Val (c.1433C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about LARGE1 p.Ala478Val (c.1433C>T)?

AlphaMissense predicts ambiguous (score 0.528) — an in-silico prediction, not a clinical call.

LARGE1 p.Ala478Val

c.1433C>T · rs2546685386 · VCV2912748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
AlphaMissense	0.528	ambiguous
REVEL	0.245	benign-leaning
SaProt	LLR -13.23	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,040 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,934 alleles · very rare exomes 2/1,461,628 · genomes 0/152,306 · joint denominator

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.Ala478Val
Coding: c.1433C>T
MANE Select: NM_133642
dbSNP: rs2546685386
Type: single nucleotide variant
Location: chr22:33316103 (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 478: 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

Similar variants

LARGE1 p.Ala478Thr Uncertain significance ★★ ⚠ same residue
LARGE1 p.Ala478= Likely benign ★ 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.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-ala478val (accessed [today's date]).

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