Is LARGE1 p.Ser609= (c.1827A>G) pathogenic?

LARGE1 p.Ser609= (c.1827A>G) is classified Benign in LARGE1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 6.06%, afr) — too common for a highly-penetrant pathogenic allele; Associated with muscular dystrophy-dystroglycanopathy type B6.

What condition is associated with LARGE1 p.Ser609= (c.1827A>G)?

LARGE1 p.Ser609= (c.1827A>G) is associated with muscular dystrophy-dystroglycanopathy type B6, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (ClinVar).

LARGE1 p.Ser609=

Q: How common is LARGE1 p.Ser609= (c.1827A>G) in the general population?

LARGE1 p.Ser609= (c.1827A>G) is common (popmax 6.06%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1827A>G · rs11913417 · VCV95169

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 6.06%, afr) — too common for a highly-penetrant pathogenic allele

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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8	GERP -4
Overall
CADD	0.152	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.06% African / African-American · 4,547/75,024 alleles

Filtering AF 5.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.85%

Overall 0.976% 15,756/1,614,120 alleles · common exomes 12,357/1,461,886 · genomes 3,399/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.06%	16
South Asian	5.76%	17
Middle Eastern	3.88%	26
Ashkenazi Jewishnot grpmax-eligible	2.91%	34
Amishnot grpmax-eligible	2.41%	41
Remaining individualsnot grpmax-eligible	1.54%	65
Admixed American	1.1%	91
European (non-Finnish)	0.264%	379
East Asian	0.174%	575
Finnishnot grpmax-eligible	0.0531%	1,883

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.Ser609=
Coding: c.1827A>G
MANE Select: NM_133642
dbSNP: rs11913417
Type: single nucleotide variant
Location: chr22:33283252 (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 609: 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

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

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-ser609 (accessed [today's date]).

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