Is LARGE1 p.Arg650Gln (c.1949G>A) pathogenic?

LARGE1 p.Arg650Gln (c.1949G>A) is classified Benign/Likely benign in LARGE1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0763); Common (popmax 6.04%, afr) — too common for a highly-penetrant pathogenic allele; Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

How is Walker-Warburg syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LARGE1 p.Arg650Gln (c.1949G>A)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

LARGE1 p.Arg650Gln

Q: What condition is associated with LARGE1 p.Arg650Gln (c.1949G>A)?

LARGE1 p.Arg650Gln (c.1949G>A) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

Q: How common is LARGE1 p.Arg650Gln (c.1949G>A) in the general population?

LARGE1 p.Arg650Gln (c.1949G>A) is common (popmax 6.04%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1949G>A · rs73399520 · VCV95170

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.04%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.15	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 0.12	GERP -1.1, phastCons 0.61
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	19.49	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 6.04% African / African-American · 4,530/75,054 alleles

Filtering AF 5.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.83%

Overall 0.322% 5,205/1,614,220 alleles · common exomes 2,574/1,461,882 · genomes 2,631/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.04%	17
Admixed American	0.536%	186
Remaining individualsnot grpmax-eligible	0.421%	238
Middle Eastern	0.297%	337
South Asian	0.0253%	3,960
East Asian	0.0111%	8,978
European (non-Finnish)	0.00373%	26,819

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.Arg650Gln
Coding: c.1949G>A
MANE Select: NM_133642
dbSNP: rs73399520
Type: single nucleotide variant
Location: chr22:33277184 (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 650: 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 (congenital with brain and eye anomalies), type A6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy type B6

For Walker-Warburg syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (United Kingdom)

Similar variants

LARGE1 p.Arg650Trp Uncertain significance ★ ⚠ same residue
LARGE1 p.Arg650= 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.Ala478Thr 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-arg650gln (accessed [today's date]).

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