Is LARGE1 p.Val474Ile (c.1420G>A) pathogenic?

LARGE1 p.Val474Ile (c.1420G>A) is classified Conflicting classifications of pathogenicity in LARGE1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-05-20). AlphaMissense: likely benign (0.0829); Rare (popmax 0.206%, nfe); Associated with muscular dystrophy-dystroglycanopathy type B6.

How common is LARGE1 p.Val474Ile (c.1420G>A) in the general population?

LARGE1 p.Val474Ile (c.1420G>A) is rare (popmax 0.206%, nfe) (gnomAD).

What do computational predictors say about LARGE1 p.Val474Ile (c.1420G>A)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

LARGE1 p.Val474Ile

Q: What condition is associated with LARGE1 p.Val474Ile (c.1420G>A)?

LARGE1 p.Val474Ile (c.1420G>A) is associated with muscular dystrophy-dystroglycanopathy type B6, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (ClinVar).

c.1420G>A · rs150861748 · VCV95164

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.206%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 0.37, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	21.1	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 0.206% European (non-Finnish) · 2,434/1,179,940 alleles

Filtering AF 0.199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.197%

Overall 0.164% 2,653/1,613,966 alleles · rare exomes 2,477/1,461,710 · genomes 176/152,256 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.206%	485
Remaining individualsnot grpmax-eligible	0.176%	568
Middle Eastern	0.0495%	2,019
Admixed American	0.0467%	2,143
Finnishnot grpmax-eligible	0.0437%	2,286
African / African-American	0.0373%	2,679
South Asian	0.0242%	4,139

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.Val474Ile
Coding: c.1420G>A
MANE Select: NM_133642
dbSNP: rs150861748
Type: single nucleotide variant
Location: chr22:33316116 (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 474: 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 A1 muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

Similar variants

LARGE1 p.Val474Phe 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-val474ile (accessed [today's date]).

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