BCL2

Chr 18

BCL2 apoptosis regulator

Also known as: Bcl-2, PPP1R50

NCBI Gene: 596 ENSG00000171791 UniProt: P10415 OMIM: 151430

The BCL2 protein is an integral outer mitochondrial membrane protein that suppresses apoptosis by regulating mitochondrial membrane permeability and inhibiting caspase activity, and also functions as an inhibitor of autophagy. Germline mutations cause autosomal dominant immunodeficiency with polyclonal lymphoproliferation, typically presenting in childhood with recurrent infections, lymphadenopathy, and splenomegaly. The gene shows moderate tolerance to loss-of-function variants (LOEUF 0.71), and while BCL2 translocations are well-known in follicular lymphoma, the germline mutations cause a distinct primary immunodeficiency phenotype.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

2996

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.71

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.71LOEUF

pLI 0.559

Z-score 2.03

OE 0.15 (0.05–0.71)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.40Z-score

OE missense 0.67 (0.56–0.79)

94 obs / 140.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.05–0.71)

0≤0.351.4

Missense OE?0.67 (0.56–0.79)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 1 / 6.7Missense obs/exp: 94 / 140.6Syn Z: -0.28

Background carrier burden — how many people carry a rare variant somewhere in BCL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 390

284 rare PASS variants

Rare truncating (LoF)

1 in 4,500

13 rare PASS variants

Rare synonymous (reference)

1 in 300

180 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BCL2. 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 360	1 in 50,000
South Asian	~43k	1 in 490	≈ 1 in 21,000
Remaining (unassigned)	~30k	1 in 230	none seen
European (Finnish)	~27k	1 in 1,100	≈ 1 in 24,000
Admixed American	~22k	1 in 140	≈ 1 in 5,200
African / African American	~21k	1 in 250	1 in 1,400
East Asian	~20k	1 in 250	≈ 1 in 18,000
Ashkenazi Jewish	~13k	1 in 760	none seen
Middle Eastern	~2,884	1 in 270	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.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

BCL2 · 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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Diffuse Large B Cell LymphomaHigh-grade B-cell LymphomaHigh Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements

Exploring the Clinical Impact of MYC Aberrations and Their Relationship With Microenvironment in Diffuse Large B Cell Lymphoma and High-Grade B Cell Lymphoma

RECRUITING

NCT06588205Fondazione Italiana Linfomi - ETSStarted 2025-05-05

High-grade B-cell LymphomaBurkitt LymphomaLymphoma, B-Cell

Sepantronium Bromide for the Treatment of High-grade B-cell Lymphoma

ACTIVE NOT RECRUITING

NCT05263583Phase PHASE2Cothera Bioscience, IncStarted 2022-12-09

Sepantronium Bromide

Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 PositiveAcute Biphenotypic LeukemiaAcute Lymphoblastic Leukemia

Personalized NK Cell Therapy in CBT

RECRUITING

NCT02727803Phase PHASE2M.D. Anderson Cancer CenterStarted 2016-05-19

Allogeneic Natural Killer Cell Line NK-92Anti-Thymocyte GlobulinBusulfan

Diffuse Large B-Cell Lymphoma Associated With Chronic InflammationEBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise SpecifiedHigh Grade B-Cell Lymphoma, Not Otherwise Specified

Zanubrutinib and CAR T-cell Therapy for the Treatment of Recurrent or Refractory Aggressive B-cell Non-Hodgkin's Lymphoma or Transformed Indolent B-cell Lymphoma

ACTIVE NOT RECRUITING

NCT05202782Phase PHASE2Northwestern UniversityStarted 2022-03-21

Chimeric Antigen Receptor T-Cell TherapyQuality-of-Life AssessmentQuestionnaire Administration

Diffuse Large B-Cell LymphomaDiffuse Large B-Cell Lymphoma, Not Otherwise SpecifiedDouble-Expressor Lymphoma

Testing the Addition of a New Anti-cancer Drug, Venetoclax, to Usual Chemotherapy for High Grade B-cell Lymphomas

ACTIVE NOT RECRUITING

NCT03984448Phase PHASE2, PHASE3National Cancer Institute (NCI)Started 2019-10-22

Biospecimen CollectionBone Marrow BiopsyComputed Tomography

Burkitt LymphomaDouble-Expressor LymphomaHigh Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements

Testing the Safety of Anti-Cancer Drug, CX-5461 (Pidnarulex), in Treating Lymphoma With Specific Changes in the MYC Gene

RECRUITING

NCT07069699Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2027-01-11