Is LARGE1 p.Val40Ala (c.119T>C) pathogenic?

LARGE1 p.Val40Ala (c.119T>C) is classified Uncertain significance in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely benign (0.099); Ultra-rare (popmax 0.0259%, nfe); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Val40Ala (c.119T>C)?

LARGE1 p.Val40Ala (c.119T>C) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Val40Ala (c.119T>C) in the general population?

LARGE1 p.Val40Ala (c.119T>C) is ultra-rare (popmax 0.0259%, nfe) (gnomAD).

What do computational predictors say about LARGE1 p.Val40Ala (c.119T>C)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

LARGE1 p.Val40Ala

c.119T>C · rs148383806 · VCV843053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0259%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -5.89	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 9.3	GERP 2.1, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 111 kb · p 0.14 · regional, not allelic
Overall
CADD	20.9	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 0.0259% European (non-Finnish) · 306/1,179,948 alleles

Filtering AF 0.0235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0226%

Overall 0.0199% 319/1,600,778 alleles · ultra-rare exomes 309/1,448,572 · genomes 10/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0259%	3,856
African / African-American	0.00801%	12,482
Remaining individualsnot grpmax-eligible	0.00642%	15,573
South Asian	0.0033%	30,343

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.Val40Ala
Coding: c.119T>C
MANE Select: NM_133642
dbSNP: rs148383806
Type: single nucleotide variant
Location: chr22:33650656 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB

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.Val40Leu Uncertain significance ★★ ⚠ same residue
LARGE1 p.Val40Met Uncertain significance ★★ ⚠ same residue
LARGE1 p.Val40= 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

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-val40ala (accessed [today's date]).

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