GBA1

Chr 1ADMultiAR

glucosylceramidase beta 1

Also known as: GBA, GCB, GLUC

NCBI Gene: 2629 ENSG00000177628 UniProt: P04062 OMIM: 606463

GBA1 encodes glucocerebrosidase, a lysosomal enzyme. Two variants cause Gaucher disease; one variant raises the risk of Parkinson disease and dementia with Lewy bodies, and 5–15% of people with Parkinson disease carry one. Penetrance is low: in UK Biobank, carriers had a 1.7% risk of Parkinson disease by 60 and 10.1% by 70, higher with a high polygenic score.

Risk depends on the variant. Odds ratios are highest for "severe" Gaucher variants such as p.L483P (legacy L444P, 6.4–30.4), intermediate for "mild" ones such as p.N409S (N370S, 2.2–7.8) and lowest for risk-only variants such as p.E365K (E326K, 1.6–5.5); severe-variant Parkinson disease progresses faster, with more cognitive decline. Legacy names count from after the 39-residue signal peptide.

A pseudogene, GBAP1, sits 16 kb away with 96% exonic identity, and recombinant alleles between the two are common. Short-read sequencing and its calling tools miss or miscall them; confirm a clinical result by Sanger or a second method.

GeneReviews OMIM ResearchCurated summary · Tayebi 2025, Brain 2025, Hassanin 2025

Primary Disease Associations & Inheritance

{Lewy body dementia, susceptibility to}MIM #127750

{Parkinson disease, late-onset, susceptibility to}MIM #168600

ADMulti

Gaucher disease, perinatal lethalMIM #608013

Gaucher disease, type IMIM #230800

Gaucher disease, type IIMIM #230900

Gaucher disease, type IIIMIM #231000

Gaucher disease, type IIICMIM #231005

UniProtGaucher disease 1

UniProtGaucher disease 2

UniProtGaucher disease 3

UniProtGaucher disease 3C

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Parkinson disease · AD · ClinGen 2022
Definitive · Gaucher disease · AR · ClinGen 2020
Definitive · Gaucher disease perinatal lethal · AR · Laboratory for Molecular Medicine
Strong · late-onset Parkinson disease · AD · Ambry Genetics

+4 more curated pairs

Two diseases

Two variants: Gaucher disease. One variant: Parkinson disease risk (1.7% by 60, 10.1% by 70 in UK Biobank carriers).Hassanin et al., npj Parkinsons Dis 2025

Variant class

PD odds ratio: severe p.L483P (L444P) 6.4–30.4 · mild p.N409S (N370S) 2.2–7.8 · risk p.E365K (E326K) 1.6–5.5.Brain 2025 (PMC12488979)

Pseudogene

GBAP1 (96% exonic identity) makes recombinant alleles that short-read pipelines miss or miscall. Confirm by Sanger or a second method.Tayebi et al. 2025 (PMC12064688)

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

347

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — GBA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.000

Z-score 2.36

OE 0.51 (0.34–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.17Z-score

OE missense 0.81 (0.73–0.90)

248 obs / 305.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.34–0.80)

0≤0.351.4

Missense OE?0.81 (0.73–0.90)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 14 / 27.3Missense obs/exp: 248 / 305.8Syn Z: -0.40

Background carrier burden — how many people carry a rare variant somewhere in GBA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 83

528 rare PASS variants

Rare truncating (LoF)

1 in 1,300

68 rare PASS variants

Rare synonymous (reference)

1 in 130

251 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GBA1. 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 120	1 in 1,500
South Asian	~43k	1 in 95	1 in 800
Remaining (unassigned)	~30k	1 in 82	1 in 4,300
European (Finnish)	~27k	1 in 280	1 in 1,100
Admixed American	~22k	1 in 110	1 in 900
African / African American	~21k	1 in 75	1 in 1,800
East Asian	~20k	1 in 110	1 in 3,300
Ashkenazi Jewish	~13k	1 in 310	1 in 1,900
Middle Eastern	~2,884	1 in 69	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): 10 of 11 coding exons well covered in gnomAD exomes; exon 11 poorly covered. Genomes: 8 of 11 (exons 5, 10, 11 below).? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

GBA1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — GBA1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Parkinson Disease (PD)Type 1 Gaucher Disease

Parkinson's Disease in Type 1 Gaucher Disease

RECRUITING

NCT07886879Icahn School of Medicine at Mount SinaiStarted 2026-10

Gaucher Disease

Screening for Gaucher Disease and Acid Sphingomyelinase Deficiency

NOT YET RECRUITING

NCT06258577Chung-Hsing WangStarted 2024-05-01

Parkinson Disease

Phase 1/2a Clinical Trial of PR001 (LY3884961) in Patients With Parkinson's Disease With at Least One GBA1 Mutation (PROPEL)

ACTIVE NOT RECRUITING

NCT04127578Phase PHASE1, PHASE2Prevail TherapeuticsStarted 2020-01-03

LY3884961MethylprednisoloneSirolimus

Parkinson Disease

PD Frontline (Part of RAPSODI GD) Remote Assessment of People With Parkinson's

RECRUITING

NCT06151002University College London HospitalsStarted 2020-02-15

Parkinson's Disease

Genotypic Influences on Network Progression in Parkinson's Disease

ACTIVE NOT RECRUITING

NCT04228172Northwell HealthStarted 2020-02-24

DNA/GeneticTestingFDG PET scanMRI scan

Gaucher Disease Type 1

A Clinical Study Evaluating LY-M001 Injection in the Treatment of Adult Patients With Type I Gaucher Disease

RECRUITING

NCT06818838Phase PHASE1, PHASE2Lingyi Biotech Co., Ltd.Started 2024-07-05

LY-M001

Gaucher Disease, Type 2

Phase 1/2 Clinical Trial of PR001 in Infants With Type 2 Gaucher Disease (PROVIDE)

ACTIVE NOT RECRUITING

NCT04411654Phase PHASE1, PHASE2Prevail TherapeuticsStarted 2021-06-29

LY3884961MethylprednisoloneSirolimus

Parkinson's Disease (PD)

A Clinical Study to Evaluate the Safety, Tolerability, and Efficacy of Intracerebral Injection of LY-N001 Injection for the Treatment of Moderate to Advanced Parkinson's Disease With GBA1 Mutations

NOT YET RECRUITING

NCT07685444Phase EARLY_PHASE1Lingyi Biotech Co., Ltd.Started 2026-07-07

LY-N001 Injection

Parkinson's Disease

Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in GBA-PD

ACTIVE NOT RECRUITING

NCT05819359Phase PHASE2Bial R&D Investments, S.A.Started 2023-03-31

BIA 28-6156 10 mgBIA 28-6156 60 mgPlacebo

Parkinson Disease

Chinese PD-GBA Registry

RECRUITING

NCT03523065Xiangya Hospital of Central South UniversityStarted 2017-02-01