Is LARGE1 p.Tyr693= (c.2079T>C) pathogenic?

LARGE1 p.Tyr693= (c.2079T>C) is classified Likely benign in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). Very rare (popmax 0.00133%, afr); Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Tyr693= (c.2079T>C)?

LARGE1 p.Tyr693= (c.2079T>C) is associated with muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

How common is LARGE1 p.Tyr693= (c.2079T>C) in the general population?

LARGE1 p.Tyr693= (c.2079T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

LARGE1 p.Tyr693=

c.2079T>C · rs996290544 · VCV1638648

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

muscular dystrophy-dystroglycanopathy type B6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.2	GERP -4.5
Overall
CADD	0.174	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,114 alleles · very rare exomes 3/1,461,850 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,034
European (non-Finnish)	0.000169%	589,991

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.Tyr693=
Coding: c.2079T>C
MANE Select: NM_133642
dbSNP: rs996290544
Type: single nucleotide variant
Location: chr22:33274619 (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 693: the 'glucuronyltransferase activity' 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.Tyr693Cys 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-tyr693 (accessed [today's date]).

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