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…

LOFmechanismARLOEUF 0.941 OMIM phenotype

Clinical Summary— GBA2

🧬

Gene-Disease Validity (ClinGen)

complex hereditary spastic paraplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

49 unique Pathogenic / Likely Pathogenic· 173 VUS of 411 total submissions

Explore recent and relevant literature in Research Assistant →

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

ClinVar Variant Classifications

411 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28

Likely Pathogenic21

VUS173

Likely Benign123

Benign21

Conflicting32

Pathogenic

Likely Pathogenic

173

VUS

123

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	1	0	0	28
Likely Pathogenic	14	7	0	0	21
VUS	2	161	8	2	173
Likely Benign	0	5	53	65	123
Benign	0	3	16	2	21
Conflicting	—				32
Total	43	177	77	69	398

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

74 pathogenic / likely-pathogenic (of 83) ClinVar copy-number / structural variants overlap GBA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →