Is LARGE1 p.Asp336= (c.1008T>C) pathogenic?

LARGE1 p.Asp336= (c.1008T>C) is classified Benign in LARGE1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 3.73%, eas); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

How common is LARGE1 p.Asp336= (c.1008T>C) in the general population?

LARGE1 p.Asp336= (c.1008T>C) is low-frequency (popmax 3.73%, eas) (gnomAD).

How is Walker-Warburg syndrome inherited?

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

LARGE1 p.Asp336=

Q: What condition is associated with LARGE1 p.Asp336= (c.1008T>C)?

LARGE1 p.Asp336= (c.1008T>C) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

c.1008T>C · rs115076367 · VCV158804

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.73%, eas)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -3.4, phastCons 1
Overall
CADD	9.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.73% East Asian · 1,674/44,862 alleles

Filtering AF 3.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.52%

Overall 0.13% 2,101/1,614,104 alleles · low-frequency exomes 1,799/1,461,818 · genomes 302/152,286 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	3.73%	27
Remaining individualsnot grpmax-eligible	0.365%	274
South Asian	0.0977%	1,023
African / African-American	0.0533%	1,876
Admixed American	0.025%	4,001
Finnishnot grpmax-eligible	0.0125%	8,004
European (non-Finnish)	0.00398%	25,106

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.Asp336=
Coding: c.1008T>C
MANE Select: NM_133642
dbSNP: rs115076367
Type: single nucleotide variant
Location: chr22:33382042 (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 336: an α-helix; the 'xylosyltransferase activity' region

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.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
LARGE1 p.Ala752Gly 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-asp336 (accessed [today's date]).

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