Is LARGE1 p.Gln82Arg (c.245A>G) pathogenic?

LARGE1 p.Gln82Arg (c.245A>G) is classified Uncertain significance in LARGE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-10). AlphaMissense: likely benign (0.1331); Very rare (popmax 0.000847%, nfe); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Gln82Arg (c.245A>G)?

LARGE1 p.Gln82Arg (c.245A>G) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Gln82Arg (c.245A>G) in the general population?

LARGE1 p.Gln82Arg (c.245A>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about LARGE1 p.Gln82Arg (c.245A>G)?

AlphaMissense predicts likely benign (score 0.1331) — an in-silico prediction, not a clinical call.

LARGE1 p.Gln82Arg

c.245A>G · rs774035009 · VCV1211127

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
AlphaMissense	0.1331	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.14	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 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 111 kb · p 0.14 · regional, not allelic
Overall
CADD	24.2	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 0.000847% European (non-Finnish) · 10/1,179,984 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000745% 12/1,611,770 alleles · very rare exomes 11/1,459,512 · genomes 1/152,258 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00162%	61,814
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)grpmax	0.000847%	117,998

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln82Arg
Coding: c.245A>G
MANE Select: NM_133642
dbSNP: rs774035009
Type: single nucleotide variant
Location: chr22:33650530 (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 82: the 'disordered' 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.Gln82His 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-gln82arg (accessed [today's date]).

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