Is LARGE1 p.Ser471Arg (c.1413C>A) pathogenic?

LARGE1 p.Ser471Arg (c.1413C>A) is classified Uncertain significance in LARGE1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-06-27). AlphaMissense: likely benign (0.1353); Ultra-rare (popmax 0.0661%, mid); Associated with muscular dystrophy-dystroglycanopathy type B6.

How common is LARGE1 p.Ser471Arg (c.1413C>A) in the general population?

LARGE1 p.Ser471Arg (c.1413C>A) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

What do computational predictors say about LARGE1 p.Ser471Arg (c.1413C>A)?

AlphaMissense predicts likely benign (score 0.1353) — an in-silico prediction, not a clinical call.

LARGE1 p.Ser471Arg

Q: What condition is associated with LARGE1 p.Ser471Arg (c.1413C>A)?

LARGE1 p.Ser471Arg (c.1413C>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.1413C>A · rs376160270 · VCV579774

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1353 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
AlphaMissense	0.1353	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.67, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	16.51	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0661% Middle Eastern · 4/6,056 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00273% 44/1,614,070 alleles · ultra-rare exomes 38/1,461,776 · genomes 6/152,294 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,514
African / African-American	0.0426%	2,345
South Asian	0.0022%	45,534
Remaining individualsnot grpmax-eligible	0.0016%	62,494
European (non-Finnish)	0.000424%	235,995

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.Ser471Arg
Coding: c.1413C>A
MANE Select: NM_133642
dbSNP: rs376160270
Type: single nucleotide variant
Location: chr22:33316123 (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 471: 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.Ser471Gly 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-ser471arg (accessed [today's date]).

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