Is LARGE1 p.Tyr516= (c.1548C>T) pathogenic?

LARGE1 p.Tyr516= (c.1548C>T) is classified Benign/Likely benign in LARGE1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). Common (popmax 8.51%, 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.

LARGE1 p.Tyr516=

Q: What condition is associated with LARGE1 p.Tyr516= (c.1548C>T)?

LARGE1 p.Tyr516= (c.1548C>T) 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.Tyr516= (c.1548C>T) in the general population?

LARGE1 p.Tyr516= (c.1548C>T) is common (popmax 8.51%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1548C>T · rs34292743 · VCV95166

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 8.51%, afr) — too common for a highly-penetrant pathogenic allele

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 -3.3	GERP -2.8
Overall
CADD	1.304	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51% African / African-American · 6,387/75,068 alleles

Filtering AF 8.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.26%

Overall 0.452% 7,298/1,614,248 alleles · common exomes 3,636/1,461,876 · genomes 3,662/152,372 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.51%	12
Remaining individualsnot grpmax-eligible	0.517%	194
Admixed American	0.493%	203
Middle Eastern	0.462%	216
East Asian	0.0512%	1,952
European (non-Finnish)	0.0187%	5,340
South Asian	0.0143%	7,007
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
Finnishnot grpmax-eligible	0.00468%	21,349

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.Tyr516=
Coding: c.1548C>T
MANE Select: NM_133642
dbSNP: rs34292743
Type: single nucleotide variant
Location: chr22:33304411 (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 516: the 'glucuronyltransferase activity' region; an α-helix

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-tyr516 (accessed [today's date]).

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