GBA2

Chr 9AR

glucosylceramidase beta 2

Also known as: AD035, NLGase, SPG46

NCBI Gene: 57704 ENSG00000070610 UniProt: Q9HCG7 OMIM: 609471

The protein is a microsomal beta-glucosidase localized to the endoplasmic reticulum that catalyzes the hydrolysis of bile acid 3-O-glucosides. Biallelic mutations cause spastic paraplegia 46, an autosomal recessive hereditary spastic paraplegia. The pathogenic mechanism involves loss of function of this carbohydrate metabolism enzyme.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a microsomal beta-glucosidase that catalyzes the hydrolysis of bile acid 3-O-glucosides as endogenous compounds. Studies to determine subcellular localization of this protein in the liver indicated that the enzyme was mainly enriched in the microsomal fraction where it appeared to be confined to the endoplasmic reticulum. This putative transmembrane protein is thought to play a role in carbohydrate transport and metabolism. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spastic paraplegia 46, autosomal recessiveMIM #614409

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex hereditary spastic paraplegia · AR · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.94

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.91

OE 0.72 (0.56–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.67Z-score

OE missense 0.80 (0.74–0.87)

440 obs / 550.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.56–0.94)

0≤0.351.4

Missense OE?0.80 (0.74–0.87)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 39 / 54.2Missense obs/exp: 440 / 550.1Syn Z: 0.94

Background carrier burden — how many people carry a rare variant somewhere in GBA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 46

1,245 rare PASS variants

Rare truncating (LoF)

1 in 770

207 rare PASS variants

Rare synonymous (reference)

1 in 150

483 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GBA2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 68	1 in 740
South Asian	~43k	1 in 46	1 in 810
Remaining (unassigned)	~30k	1 in 42	1 in 620
European (Finnish)	~27k	1 in 140	1 in 3,000
Admixed American	~22k	1 in 63	1 in 900
African / African American	~21k	1 in 39	1 in 1,100
East Asian	~20k	1 in 50	1 in 810
Ashkenazi Jewish	~13k	1 in 110	1 in 1,300
Middle Eastern	~2,884	1 in 66	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 17 coding exons well covered in gnomAD exomes; exons 2, 3 marginal. Genomes: all 17.? see exons ↓