BAP1

Chr 3AD

BRCA1 associated deubiquitinase 1

Also known as: HUCEP-13, KURIS, TPDS1, UBM2, UCHL2, UVM2, hucep-6

NCBI Gene: 8314ENSG00000163930UniProt: Q96QZ7

This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

Primary Disease Associations & Inheritance

{Uveal melanoma, susceptibility to, 2}MIM #606661
AD
Kury-Isidor syndromeMIM #619762
AD
Tumor predisposition syndrome 1MIM #614327
AD
568
ClinVar variants
81
Pathogenic / LP
0.99
pLI score· haploinsufficient
12
Active trials
Clinical Summary— BAP1
🧬
Gene-Disease Validity (ClinGen)
BAP1-related tumor predisposition syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
81 Pathogenic / Likely Pathogenic· 286 VUS of 568 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.28LOEUF
pLI 0.994
Z-score 4.68
OE 0.12 (0.06–0.28)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.64Z-score
OE missense 0.64 (0.58–0.71)
277 obs / 431.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.06–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.58–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 4 / 33.1Missense obs/exp: 277 / 431.6Syn Z: 0.18

ClinVar Variant Classifications

568 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59
Likely Pathogenic22
VUS286
Likely Benign179
Benign15
Conflicting7
59
Pathogenic
22
Likely Pathogenic
286
VUS
179
Likely Benign
15
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
42
3
14
0
59
Likely Pathogenic
17
3
2
0
22
VUS
6
243
33
4
286
Likely Benign
0
2
99
78
179
Benign
0
6
8
1
15
Conflicting
—7
Total6525715683568

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

View in ClinVar →

Protein Context — Lollipop Plot

BAP1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

BAP1-related neurodevelopmental syndrome

moderate
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗

BAP1-related tumor predisposition syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
EyeSkinCancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Uveal melanoma, susceptibility to, 2}

MIM #606661

Molecular basis of disorder known

Autosomal dominant

Kury-Isidor syndrome

MIM #619762

Molecular basis of disorder known

Autosomal dominant

Tumor predisposition syndrome 1

MIM #614327

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — BAP1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Germline mutations predisposing to melanoma.
Toussi A et al.·J Cutan Pathol
2020Review
Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.
Walpole S et al.·J Natl Cancer Inst
2018Review
Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma.
Robertson AG et al.·Cancer Cell
2017
An overview of BAP1 biological functions and current therapeutics.
Elsayed AM et al.·Biochim Biophys Acta Rev Cancer
2025Review
Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention.
Lowery MA et al.·Clin Cancer Res
2018
Histologic and Genetic Features of 51 Melanocytic Neoplasms With Protein Kinase C Fusion Genes.
de la Fouchardière A et al.·Mod Pathol
2023
Saturation genome editing of BAP1 functionally classifies somatic and germline variants.
Waters AJ et al.·Nat Genet
2024Functional
Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.
Küry S et al.·Am J Hum Genet
2022
Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.
Bakouny Z et al.·Nat Commun
2021Clinical trial
SPP1+ Neutrophils Mediate Resistance to Immune Checkpoint Blockade in BAP1-Inactivated Tumors.
Shi J et al.·Cancer Res
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Single-cell epigenetic profiling reveals a tumor-intrinsic interferon response program in ccRCC tied to poor prognosis and BAP1 loss.
Camp SY et al.·Sci Adv
2026🔓 Open Access
Hepatocyte-targeted Bap1 reduction in the liver primes an inflammatory transcriptional response.
Nenad WC et al.·G3 (Bethesda)
2026
Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant.
Ragnarsson KA et al.·Fam Cancer
2026🔓 Open AccessCohort
Functional characterization of BAP1 mutations in genome edited cholangiocarcinoma organoids: Role in cell death and drug responses.
Mi W et al.·iScience
2026🔓 Open AccessFunctional
PD-L1 and BAP1 as Prognostic Biomarkers in Malignant Pleural Mesothelioma.
Gajić M et al.·Cells
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
MesotheliomaFamilies

Long Term Follow-up of Mesothelioma Patients and Their Family Members With Germline Mutations in BAP1 and Other Genes

RECRUITING
NCT03830229National Cancer Institute (NCI)Started 2019-03-13
Uveal Melanoma

Identification of New Candidate Genes for Hereditary Predisposition to Uveal Melanoma

ACTIVE NOT RECRUITING
NCT06550674Phase NACentre Jean PerrinStarted 2024-10-29
Constitutional exome analysis
Renal Cell CarcinomaMetastatic Renal Cell CarcinomaKidney Cancer

Study of Olaparib in Metastatic Renal Cell Carcinoma Patients With DNA Repair Gene Mutations

RECRUITING
NCT03786796Phase PHASE2Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsStarted 2019-06-03
Olaparib
Mesothelioma

New Preclinical and Clinical Approaches to Mesothelioma

RECRUITING
NCT06536179Marco Emilio BianchiStarted 2024-07-25
Metastatic Uveal MelanomaUveal Melanoma, MetastaticUveal Melanoma, Recurrent

Evaluation of the Safety, Efficacy, and Pharmacokinetics of NBM-BMX in Patients With Metastatic Uveal Melanoma

RECRUITING
NCT07136181Phase PHASE1, PHASE2Novelwise Pharmaceutical CorporationStarted 2025-11-20
NBM-BMX Capsule are proprietary products developed by Novelwise Pharmaceutical Corporation (Novelwise) for treatment of patients suffering from cancers.
Acute LeukemiaAdenomatous PolyposisAdrenocortical Carcinoma

Familial Investigations of Childhood Cancer Predisposition

RECRUITING
NCT03050268St. Jude Children's Research HospitalStarted 2017-04-06
Gastric CancerGastroEsophageal Cancer

Study of SBRT/Olaparib Followed by Pembrolizumab/Olaparib in Gastric Cancers

ACTIVE NOT RECRUITING
NCT05379972Phase PHASE2University of Colorado, DenverStarted 2023-01-12
PembrolizumabOlaparibStereotactic Body Radiation Therapy
Solid Tumor MalignanciesClear Cell Endometrial CarcinomaOvarian Cancer

Efficacy and Safety of the Valemetostat in Patients With Selected Solid Tumors.

NOT YET RECRUITING
NCT07303387Phase PHASE2Gustave Roussy, Cancer Campus, Grand ParisStarted 2026-02-28
Valemetostat Tosylate
Familial CancerBRCA1-Associated Protein-1 (BAP1) MutationsTumor Predisposition Syndrome (TPDS)

Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients With BAP1 Tumor Predisposition Syndrome

RECRUITING
NCT04431024National Cancer Institute (NCI)Started 2021-03-30
Advanced Solid TumorDiffuse Large B Cell LymphomaLymphoma, T-Cell

A Study of Tulmimetostat DZR123 (CPI-0209) in Patients With Advanced Solid Tumors and Lymphomas

RECRUITING
NCT04104776Phase PHASE1, PHASE2Novartis PharmaceuticalsStarted 2019-09-18
TulmimetostatEnzalutamide
Malignant Solid Neoplasms

Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment

RECRUITING
NCT02029001Phase PHASE2Centre Leon BerardStarted 2014-03
Nilotinib (400 mg BID)Everolimus (10 mg QD)Sorafenib (400 mg BID)
Mesothelioma, Malignant Pleural

Genetic Susceptibility in MAlignant Pleural Mesothelioma: Clinical Implication of GermliNE VariaTionS

RECRUITING
NCT06886672Fondazione IRCCS Policlinico San Matteo di PaviaStarted 2023-06-15

External Resources

Links to major genomics databases and tools