Is LARGE1 p.Arg9Gln (c.26G>A) pathogenic?

LARGE1 p.Arg9Gln (c.26G>A) is classified Uncertain significance in LARGE1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-12-17). AlphaMissense: likely benign (0.1632); Ultra-rare (popmax 0.0823%, mid); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

How common is LARGE1 p.Arg9Gln (c.26G>A) in the general population?

LARGE1 p.Arg9Gln (c.26G>A) is ultra-rare (popmax 0.0823%, mid) (gnomAD).

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.Arg9Gln (c.26G>A)?

AlphaMissense predicts likely benign (score 0.1632) — an in-silico prediction, not a clinical call.

LARGE1 p.Arg9Gln

Q: What condition is associated with LARGE1 p.Arg9Gln (c.26G>A)?

LARGE1 p.Arg9Gln (c.26G>A) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

c.26G>A · rs763697782 · VCV341439

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1632 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0823%, mid)

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	0.1632	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -8.94	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 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 111 kb · p 0.14 · regional, not allelic
Overall
CADD	24.5	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 0.0823% Middle Eastern · 5/6,076 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00266% 43/1,613,824 alleles · ultra-rare exomes 37/1,461,814 · genomes 6/152,010 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0823%	1,215
African / African-American	0.00534%	18,724
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
South Asian	0.00329%	30,361
European (non-Finnish)	0.00237%	42,142
Admixed American	0.00167%	59,968
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Arg9Gln
Coding: c.26G>A
MANE Select: NM_133642
dbSNP: rs763697782
Type: single nucleotide variant
Location: chr22:33761451 (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 (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.Arg9= Likely benign ★ same residue
LARGE1 p.Arg9Trp 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

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-arg9gln (accessed [today's date]).

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