Is GLB1 p.Leu166= (c.496C>T) pathogenic?

GLB1 p.Leu166= (c.496C>T) is classified Likely benign in GLB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). Ultra-rare (popmax 0.018%, eas); Associated with GM1 gangliosidosis.

What condition is associated with GLB1 p.Leu166= (c.496C>T)?

GLB1 p.Leu166= (c.496C>T) is associated with GM1 gangliosidosis, mucopolysaccharidosis type 4B (ClinVar).

How common is GLB1 p.Leu166= (c.496C>T) in the general population?

GLB1 p.Leu166= (c.496C>T) is ultra-rare (popmax 0.018%, eas) (gnomAD).

How is GM1 gangliosidosis inherited?

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

GLB1 p.Leu166=

c.496C>T · rs747305905 · VCV1092407

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, eas)

Conditions

GM1 gangliosidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.413	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.8, phastCons 1
Overall
CADD	11.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.018% East Asian · 8/44,394 alleles

Filtering AF 0.00892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00647%

Overall 0.000698% 10/1,433,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.018%	5,549
Remaining individualsnot grpmax-eligible	0.00163%	61,214
European (non-Finnish)	8.6e-05%	1,162,292

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: GLB1
Protein: p.Leu166=
Coding: c.496C>T
MANE Select: NM_000404
dbSNP: rs747305905
Type: single nucleotide variant
Location: chr3:33065519 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.19 · 8 PDB
Residue 166: an α-helix

Full GLB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

GM1 gangliosidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mucopolysaccharidosis type 4B

For GM1 gangliosidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GLB1 p.Leu166del Conflicting classifications of pathogenicity ★ same residue
GLB1 c.1144-2A>G Pathogenic/Likely pathogenic ★★ same condition
GLB1 c.1233+1G>A Pathogenic/Likely pathogenic ★★ same condition
GLB1 c.1347+1G>T Likely pathogenic ★★ same condition
GLB1 c.1479+1G>A Pathogenic ★★ same condition
GLB1 c.1480-2A>G Pathogenic ★★ same condition
GLB1 c.245+1G>A Pathogenic ★★ same condition
GLB1 c.396+2T>C Pathogenic/Likely pathogenic ★★ 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/glb1-p-leu166 (accessed [today's date]).

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