BCL2 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human BCL2 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene BCL2, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene BCL2, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene BCL2 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene BCL2 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene BCL2, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene BCL2, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene BCL2, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene BCL2 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene BCL2, summarize transcription factor regulatory data. If BCL2 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate BCL2 — names with evidence type (ChIP-seq / predicted / experimentally validated) If BCL2 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene BCL2 protein as a drug target, summarize pharmacology data. If BCL2 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If BCL2 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene BCL2, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene BCL2, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in BCL2: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
BCL2 (HGNC:990; chromosome 18) is the founding member of the BCL-2 anti-apoptotic protein family and a master regulator of cell survival, blocking programmed cell death by sequestering pro-apoptotic BH3-only proteins such as BAX, BAD, BID, and BCL2L11. Its expression is driven by NFKB and STAT3 (activating) and repressed by TP53, placing it at the intersection of oncogenic and tumor-suppressor signaling. BCL2 is one of the most structurally characterized human proteins, with 55 experimental PDB entries, and is targeted by 3,163 molecules in ChEMBL; venetoclax (CHEMBL3137309), a selective BCL2 inhibitor approved for CLL and AML, anchors more than 100 clinical trials. GWAS data link BCL2 variants to hematological traits at extreme significance (eosinophil count p=1e-85; plateletcrit p=4e-76), consistent with its high expression in lymph nodes, bone marrow, and immune cell populations.
BCL2 — Reference
Cross-database identifier and functional mapping reference for BCL2.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:990 |
| Approved Symbol | BCL2 |
| Ensembl Gene ID | ENSG00000171791 |
| NCBI Entrez Gene ID | 596 |
| OMIM ID | 151430 |
| Chromosome | 18 |
| Start Position (GRCh38) | 63,123,346 |
| End Position (GRCh38) | 63,320,128 |
| Strand | − (reverse) |
Transcript identifiers
Ensembl transcripts (9 total)
| Transcript ID | Biotype |
|---|---|
| ENST00000333681 | protein_coding |
| ENST00000398117 | protein_coding |
| ENST00000589955 | protein_coding |
| ENST00000590515 | protein_coding |
| ENST00000677227 | nonsense_mediated_decay |
| ENST00000677635 | protein_coding_CDS_not_defined |
| ENST00000678134 | nonsense_mediated_decay |
| ENST00000678301 | protein_coding |
| ENST00000678349 | nonsense_mediated_decay |
Total: 9 Ensembl transcripts
RefSeq mRNA (human)
| mRNA ID | Status | MANE Select |
|---|---|---|
| NM_000633 | REVIEWED | ✓ Yes |
| NM_000657 | REVIEWED | No |
| NM_001438935 | REVIEWED | No |
Plus 4 predicted variants (XM_011526135, XM_047437733, XM_047437734, XM_054318966)
CCDS IDs
- CCDS11981
- CCDS45882
MANE Select/Canonical transcript exons (ENST00000333681 / NM_000633)
| Exon ID | Start | End | Strand | Total exon count |
|---|---|---|---|---|
| ENSE00001316245 | 63123346 | 63128759 | − | 3 |
| ENSE00001230844 | 63318082 | 63318952 | − | |
| ENSE00002840278 | 63319174 | 63319769 | − |
Protein identifiers
UniProt accessions
- P10415 (reviewed, canonical)
- A0A7I2V3S7 (unreviewed)
- A0A7I2V4W1 (unreviewed)
- A0A7I2V5Q7 (unreviewed)
- A0A7I2V5Q9 (unreviewed)
RefSeq proteins
- NP_000624 (MANE Select)
- NP_000648
- XP_047293689 (predicted protein)
Protein domains and families
InterPro
| ID | Name | Type |
|---|---|---|
| IPR002475 | Bcl2-like | Family |
| IPR003093 | Apoptosis regulator, Bcl-2 protein, BH4 | Domain |
| IPR004725 | Apoptosis regulator, Bcl-2/BclX | Family |
| IPR013278 | Apoptosis regulator, Bcl-2 | Family |
| IPR020717 | Apoptosis regulator, Bcl-2, BH1 motif, conserved site | Conserved site |
| IPR020726 | Apoptosis regulator, Bcl-2, BH2 motif, conserved site | Conserved site |
| IPR020728 | Apoptosis regulator, Bcl-2, BH3 motif, conserved site | Conserved site |
| IPR020731 | Apoptosis regulator, Bcl-2, BH4 motif, conserved site | Conserved site |
| IPR026298 | Bcl-2 family | Family |
| IPR036834 | Bcl-2-like superfamily | Homologous superfamily |
| IPR046371 | Bcl-2, Bcl-2 homology region 1-3 | Domain |
Pfam
| ID | Type |
|---|---|
| PF00452 | Domain |
| PF02180 | Domain |
SMART
| ID | Type |
|---|---|
| SM00265 | Domain |
| SM00337 | Domain |
Antibody availability
No antibody resources found in biobtree annotation for BCL2.
Structure
Experimental Structures
NMR (Solution NMR): 7 structures
- 1G5M
- 1GJH
- 1YSW
- 2O21
- 2O22
- 2O2F
- 8U27
X-ray Diffraction: 48 structures
- 2W3L (2.1 Å)
- 2XA0 (2.7 Å)
- 4AQ3 (2.4 Å)
- 4IEH (2.1 Å)
- 4LVT (2.05 Å)
- 4LXD (1.9 Å)
- 4MAN (2.07 Å)
- 5AGW (2.695 Å)
- 5AGX (2.24 Å)
- 5FCG (2.1 Å)
- 5JSN (2.1 Å)
- 5VAU (1.754 Å)
- 5VAX (2.0 Å)
- 5VAY (1.804 Å)
- 6GL8 (1.4 Å)
- 6IWB (2.5 Å)
- 6O0K (1.62 Å)
- 6O0L (2.2 Å)
- 6O0M (1.75 Å)
- 6O0O (1.998 Å)
- 6O0P (1.8 Å)
- 6QG8 (1.9 Å)
- 6QGG (1.5 Å)
- 6QGH (2.0 Å)
- 6QGJ (1.9 Å)
- 6QGK (1.8 Å)
- 7LHB (2.068 Å)
- 7Y90 (2.09 Å)
- 7YA5 (1.85 Å)
- 7YB7 (2.2 Å)
- 8FY1 (2.56 Å)
- 8FY2 (2.98 Å)
- 8HLL (2.62 Å)
- 8HLM (2.522 Å)
- 8HLN (2.354 Å)
- 8HOG (1.8 Å)
- 8HOH (1.9 Å)
- 8HOI (2.25 Å)
- 8HTR (1.6 Å)
- 8HTS (1.25 Å)
- 8IQL (2.9577 Å)
- 8VWX (1.77 Å)
- 8VWZ (2.33 Å)
- 8VXM (2.1 Å)
- 8VXN (2.09 Å)
- 9O14 (1.73 Å)
- 9O15 (1.99 Å)
- 9O16 (1.73 Å)
Total Experimental Structures: 55 PDB entries (7 NMR + 48 X-ray)
Predicted Structures
AlphaFold:
- Model ID: P10415
- pLDDT (global confidence metric): 74.21
- pLDDT classification: 41% very high confidence regions (>90)
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000057329; 12043 | Bcl2 |
| Rat (Rattus norvegicus) | ENSRNOG00000077679; 24224 | Bcl2 |
| Zebrafish (Danio rerio) | ENSDARG00000094704; 570772 | bcl2a |
| Zebrafish (Danio rerio) | ENSDARG00000089109; 100007048 | bcl2b |
| Fruit fly (Drosophila melanogaster) | FBGN0040491; 36251 | Buffy |
| Worm (C. elegans) | WBGENE00000423; 3565776 | ced-9 |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Variants: 31 Total
| Classification | Count |
|---|---|
| Pathogenic | 1 |
| Likely Pathogenic | 2 |
| Uncertain Significance | 6 |
| Likely Benign | 1 |
| Benign | 2 |
| No classification | 19 |
Top 3 Pathogenic/Likely Pathogenic ClinVar Variants
| Variant ID | HGVS Notation | Type | Classification | Gene |
|---|---|---|---|---|
| 253425 | NC_000018.9:g.(?58014591)(68158862_?)del | Copy number loss | Pathogenic | BCL2 |
| 155128 | NC_000018.10:g.(?59909593)(72609801_?)dup | Copy number gain | Likely Pathogenic | BCL2 |
| 3062371 | GRCh37/hg19 18q21.32-22.3(chr18:58508272-70495604)x3 | Copy number gain | Likely Pathogenic | BCL2 |
Note: Pathogenic variants in BCL2 are predominantly large structural variants (CNVs) rather than point mutations; detailed phenotypic associations listed as “See cases” in ClinVar.
AlphaMissense: Missense Pathogenicity Predictions
Total variants with predictions: 100+
Likely Pathogenic predictions: 100+
Top 30 Likely Pathogenic Variants (am_pathogenicity scores)
| Protein Variant | am_pathogenicity | Protein Variant | am_pathogenicity |
|---|---|---|---|
| G233R | 0.999 | Y235D | 0.987 |
| G227R | 0.999 | Y235H | 0.869 |
| G227E | 0.998 | Y235N | 0.932 |
| A228D | 0.998 | Y235S | 0.681 |
| C229R | 0.998 | A234D | 0.987 |
| L232R | 0.981 | A234P | 0.972 |
| L232P | 0.979 | G237D | 0.940 |
| L232Q | 0.978 | G237R | 0.929 |
| L225R | 0.990 | G237V | 0.570 |
| L225P | 0.966 | K239E | 0.766 |
| L225Q | 0.974 | K239M | 0.895 |
| V226E | 0.990 | K239N | 0.910 |
| A228P | 0.986 | K239T | 0.744 |
| L201P | 0.982 | L236P | 0.962 |
| K218N | 0.923 | L236R | 0.841 |
SpliceAI: Splice Effect Predictions
Status: 1,722 splice predictions available in database but detailed scoring data not accessible through current query methods. BCL2 shows substantial spliceai annotation in biobtree but requires direct transcript-level queries for individual delta scores.
Pathways & Gene Ontology
Reactome Pathways (8 total)
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-111447 | Activation of BAD and translocation to mitochondria |
| R-HSA-111453 | BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members |
| R-HSA-6785807 | Interleukin-4 and Interleukin-13 signaling |
| R-HSA-844455 | The NLRP1 inflammasome |
| R-HSA-9018519 | Estrogen-dependent gene expression |
| R-HSA-9634638 | Estrogen-dependent nuclear events downstream of ESR-membrane signaling |
| R-HSA-9818030 | NFE2L2 regulating tumorigenic genes |
| R-HSA-9824594 | Regulation of MITF-M-dependent genes involved in apoptosis |
MSigDB Gene Sets (100+ total)
Sample pathways include KEGG Pathways in Cancer, KEGG Prostate Cancer, Reactome pathways (Innate Immune System, Cytokine Signaling, Inflammasomes, NLR signaling), GO Biological Process sets, and immunology-focused sets (B cell activation, T cell differentiation, apoptotic signaling).
Gene Ontology Annotations
Biological Process: 113 terms
| GO ID | Term |
|---|---|
| GO:0000082 | G1/S transition of mitotic cell cycle |
| GO:0001782 | B cell homeostasis |
| GO:0001783 | B cell apoptotic process |
| GO:0001836 | Release of cytochrome c from mitochondria |
| GO:0006914 | Autophagy |
| GO:0006915 | Apoptotic process |
| GO:0006974 | DNA damage response |
| GO:0008625 | Extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0008630 | Intrinsic apoptotic signaling pathway in response to DNA damage |
| GO:0008631 | Intrinsic apoptotic signaling pathway in response to oxidative stress |
| GO:0010507 | Negative regulation of autophagy |
| GO:0031647 | Regulation of protein stability |
| GO:0043065 | Positive regulation of apoptotic process |
| GO:0043066 | Negative regulation of apoptotic process |
| GO:0043524 | Negative regulation of neuron apoptotic process |
| GO:0046902 | Regulation of mitochondrial membrane permeability |
| GO:0051881 | Regulation of mitochondrial membrane potential |
| GO:0070059 | Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress |
| GO:0097138 | BAD-BCL-2 complex |
| GO:2001243 | Negative regulation of intrinsic apoptotic signaling pathway |
Molecular Function: 11 terms
| GO ID | Term |
|---|---|
| GO:0002020 | Protease binding |
| GO:0015267 | Channel activity |
| GO:0016248 | Channel inhibitor activity |
| GO:0031625 | Ubiquitin protein ligase binding |
| GO:0042802 | Identical protein binding |
| GO:0043565 | Sequence-specific DNA binding |
| GO:0046982 | Protein heterodimerization activity |
| GO:0051434 | BH3 domain binding |
| GO:0051721 | Protein phosphatase 2A binding |
| GO:0060090 | Molecular adaptor activity |
| GO:0140297 | DNA-binding transcription factor binding |
Cellular Component: 14 terms
| GO ID | Term |
|---|---|
| GO:0005634 | Nucleus |
| GO:0005737 | Cytoplasm |
| GO:0005739 | Mitochondrion |
| GO:0005741 | Mitochondrial outer membrane |
| GO:0005783 | Endoplasmic reticulum |
| GO:0005789 | Endoplasmic reticulum membrane |
| GO:0005829 | Cytosol |
| GO:0016020 | Membrane |
| GO:0031965 | Nuclear membrane |
| GO:0032991 | Protein-containing complex |
| GO:0043209 | Myelin sheath |
| GO:0046930 | Pore complex |
| GO:0097138 | BAD-BCL-2 complex |
| GO:0097148 | BCL-2 complex |
Protein interactions & networks
Protein-protein Interactions
Interaction count summary:
- STRING: 7,722 interactions (100 shown; ~7,722 total)
- BioGRID: 402 interactions
- IntAct: 217 interactions with confidence scores
- SIGNOR: 85 interactions
- MINT: 1 interaction
- DIP: 1 interaction
Top 30 highest-confidence interacting proteins:
| Rank | Protein | Gene | Confidence/Score | Interaction Type | Database |
|---|---|---|---|---|---|
| 1 | BAX | BAX | 0.950 | Colocalization/Physical association | IntAct |
| 2 | BECN1 | BECN1 | 0.950 | Association/Physical association | IntAct |
| 3 | BCL2L11 | BCL2L11 | 0.930 | Direct interaction | IntAct |
| 4 | BID | BID | 0.870 | Direct interaction/Physical association | IntAct |
| 5 | BIK | BIK | 0.860 | Direct interaction/Physical association | IntAct |
| 6 | BAD | BAD | 0.850 | Physical association | IntAct |
| 7 | BBC3 (PUMA) | BBC3 | 0.820 | Direct interaction/Association | IntAct |
| 8 | NLRP1 | NLRP1 | 0.750 | Physical association/Association | IntAct |
| 9 | NR4A1 | NR4A1 | 0.670 | Direct interaction/Physical association | IntAct |
| 10 | TP53BP2 | TP53BP2 | 0.650 | Direct interaction | IntAct |
| 11 | BMF | BMF | 0.620 | Direct interaction | IntAct |
| 12 | BAK1 | BAK1 | 0.610 | Direct interaction | IntAct |
| 13 | SOD1 | SOD1 | 0.560 | Physical association | IntAct |
| 14 | APP | APP | 0.560 | Physical association | IntAct |
| 15 | PMAIP1 | PMAIP1 | 0.520 | Physical association | IntAct |
| 16 | ITPR1 | ITPR1 | 0.520 | Physical association | IntAct |
| 17 | SPNS1 | SPNS1 | 0.460 | Physical association | IntAct |
| 18 | BCL2L1 | BCL2L1 | 0.440 | Direct interaction | IntAct |
| 19 | VDAC1 | VDAC1 | 0.400 | Physical association | IntAct |
| 20 | BBC3 | BBC3 | 0.400 | Physical association | IntAct |
| 21 | NR4A3 | NR4A3 | 0.400 | Physical association | IntAct |
| 22 | SIVA1 | SIVA1 | 0.400 | Physical association | IntAct |
| 23 | VRK2 | VRK2 | 0.370 | Physical association | IntAct |
| 24 | CASP8 | CASP8 | 0.370 | Physical association | IntAct |
| 25 | BCL2L12 | BCL2L12 | 0.370 | Physical association | IntAct |
| 26 | RTL10 | RTL10 | 0.350 | Association | IntAct |
| 27 | Q00987 | Undefined | 953 | - | STRING |
| 28 | Q16611 | Undefined | 969 | - | STRING |
| 29 | O95140 | Undefined | 943 | - | STRING |
| 30 | Q92934 | BAK | 926 | - | STRING |
Protein Similarity
Structural/Embedding Similarity (ESM2) — Top 20:
| Rank | Protein ID | Top Similarity | Avg Similarity |
|---|---|---|---|
| 1 | O35425 | 1.0000 | 0.9500 |
| 2 | Q792S6 | 1.0000 | 0.9500 |
| 3 | Q6R755 | 0.9998 | 0.9673 |
| 4 | Q9JJV8 | 0.9998 | 0.9668 |
| 5 | P49950 | 0.9993 | 0.9670 |
| 6 | Q9UMX3 | 0.9991 | 0.9468 |
| 7 | P10417 | 0.9992 | 0.9668 |
| 8 | Q86TM6 | 0.9995 | 0.9627 |
| 9 | Q9DBY1 | 0.9995 | 0.9632 |
| 10 | Q2NL34 | 0.9979 | 0.9606 |
| 11 | O02718 | 0.9978 | 0.9666 |
| 12 | P10415 | 0.9978 | 0.9667 |
| 13 | Q00709 | 0.9967 | 0.9669 |
| 14 | Q96D05 | 0.9987 | 0.9478 |
| 15 | Q9D882 | 0.9987 | 0.9469 |
| 16 | Q16611 | 0.9905 | 0.9719 |
| 17 | Q9I8I2 | 0.9845 | 0.9569 |
| 18-20 | 17 total proteins | - | - |
Sequence Homology (DIAMOND) — Top 20:
| Rank | Protein ID | Identity % | Bitscore | Gene/Description |
|---|---|---|---|---|
| 1 | Q1RMX3 | 100.00 | 389 | BCL2-like (apoptosis inhibitor) |
| 2 | Q45T69 | 100.00 | 389 | BCL2-like (apoptosis inhibitor) |
| 3 | P53563 | 99.60 | 465 | BCL2-related protein |
| 4 | Q64373 | 99.60 | 466 | BCL2-related protein |
| 5 | P70345 | 99.00 | 387 | BCL2-like protein |
| 6 | Q07813 | 99.00 | 382 | BCL2-like protein |
| 7 | Q63690 | 99.00 | 382 | BCL2-like protein |
| 8 | Q92843 | 99.50 | 388 | BCL2-like protein |
| 9 | Q07818 | 98.90 | 365 | BCL2-like protein |
| 10 | O77737 | 97.90 | 459 | BCL2-like protein |
| 11 | Q07817 | 97.90 | 460 | BCL2-like protein |
| 12 | Q6R755 | 97.90 | 478 | BCL2-like protein |
| 13 | Q9JJV8 | 97.90 | 478 | BCL2-like protein |
| 14 | O02703 | 97.40 | 378 | BCL2-like protein |
| 15 | Q07812 | 97.40 | 378 | BCL2-like protein |
| 16 | P10417 | 96.60 | 473 | BCL2-like protein |
| 17 | P49950 | 96.60 | 469 | BCL2-like protein |
| 18 | Q16548 | 96.40 | 278 | BCL2-like protein |
| 19 | P10415 | 90.40 | 427 | BCL2 (self) |
| 20 | O02718 | 87.40 | 412 | BCL2-like protein |
Network Summary: BCL2 forms a tightly interconnected apoptosis regulation network centered on direct interactions with pro-apoptotic BH3-only proteins (BID, BAD, BIK, BBC3, BMF, BAK1, BCL2L11) and anti-apoptotic partners (BCL2L1). Key scaffolding interactions include BECN1 (autophagy-apoptosis crosstalk), ITPR1 (calcium signaling), and NLRP1 (inflammasome). ESM2 embeddings identify highly structurally similar BCL2-family proteins, while sequence homology reveals ~87-100% identity across vertebrate BCL2 orthologs.
Now let me compile the comprehensive summary. Based on my research:
BCL2 is NOT a transcription factor — it has no downstream targets in curated databases, so I’ll skip the downstream targets and motif sections.
Transcription factor regulatory data
BCL2 Status: Not a transcription factor
Upstream Regulators of BCL2
BCL2 is regulated by at least 50 transcription factors. Here are the top 30 with highest evidence support:
| TF | Regulation | Evidence (xref count) | Sources |
|---|---|---|---|
| TP53 | Repression | 45 | TRRUST, TFactS, GOA, SIGNOR, NTNU Curated, DoRothEA_A (predicted), ExTRI |
| NFKB | Activation | 39 | ExTRI, TRRUST, TFactS, IntAct, GEREDB, NTNU Curated, DoRothEA_A (predicted) |
| STAT3 | Activation | 32 | GEREDB, NTNU Curated, DoRothEA_A (predicted), ExTRI, TRRUST, TFactS |
| NFKB1 | Activation | 26 | ExTRI, TRRUST, TFactS, NTNU Curated, DoRothEA_A (predicted) |
| CREB1 | Activation | 23 | ExTRI, HTRI, TRRUST, SIGNOR, NTNU Curated, Pavlidis2021, DoRothEA_A (predicted) |
| NKX3-1 | Repression | 23 | ExTRI, GOA, GEREDB |
| MYC | Unknown | 14 | ExTRI, HTRI, TRRUST, TFactS, DoRothEA_A (predicted) |
| MYB | Activation | 14 | TRRUST, NTNU Curated, DoRothEA_A (predicted), ExTRI |
| ESR1 | Activation | 13 | DoRothEA_A (predicted), ExTRI, HTRI, TRRUST |
| GLI1 | Activation | 12 | DoRothEA_A (predicted), ExTRI, TRRUST, TFactS, NTNU Curated, Pavlidis2021 |
| CEBPA | Repression | 11 | TRRUST, TFactS, IntAct, NTNU Curated, DoRothEA_A (predicted), ExTRI |
| GATA4 | Unknown | 10 | ExTRI, GEREDB |
| AP1 | Activation | 10 | ExTRI, GEREDB, NTNU Curated |
| MITF | Activation | 10 | ExTRI, TFactS, SIGNOR, GEREDB, DoRothEA_A (predicted) |
| PPARG | Activation | 10 | HTRI, TRRUST, GEREDB, NTNU Curated, DoRothEA_A (predicted), ExTRI |
| TCF3 | Unknown | 10 | Multiple sources |
| WT1 | Unknown | 10 | Multiple sources |
| E2F1 | Activation | 9 | ExTRI, HTRI, TRRUST, TFactS, NTNU Curated, DoRothEA_A (predicted) |
| CEBPB | Unknown | 9 | ExTRI, GEREDB |
| ZBTB17 | Unknown | 9 | Multiple sources |
| TFAP2A | Repression | 9 | DoRothEA_A (predicted), ExTRI, HTRI, TRRUST |
| BCL6 | Unknown | 8 | ExTRI |
| NOTCH1 | Activation | 8 | SIGNOR, TFactS |
| STAT5A | Unknown | 8 | Multiple sources |
| STAT5B | Unknown | 8 | Multiple sources |
| HIF1A | Unknown | 8 | ExTRI (Low confidence) |
| MYBL1 | Unknown | 8 | Multiple sources |
| MYBL2 | Unknown | 8 | Multiple sources |
| EGR1 | Unknown | 7 | ExTRI, NTNU Curated, DoRothEA_A (predicted) |
| GLI3 | Unknown | 7 | Multiple sources |
Evidence types identified:
- Experimentally validated: ChIP-seq, HTRI, TRRUST, TFactS, IntAct, SIGNOR, GEREDB, GOA, NTNU Curated, Pavlidis2021, ExTRI
- Predicted: DoRothEA_A
Total upstream regulators: 50+ transcription factors regulate BCL2 expression, with TP53 having the strongest repressive effect and NFKB/STAT3 having strong activating effects, reflecting BCL2’s central role in apoptosis regulation.
Drug & pharmacology data
Summary
BCL2 is a well-established drug target in clinical use with 3,163 molecules in ChEMBL targeting the BCL2 protein (CHEMBL4860).
Targeting Molecules
- Total in ChEMBL/DrugBank: 3,163 molecules
- Approved/Advanced clinical candidates: ~30-50 compounds with development phase ≥1
TOP Approved & Clinical BCL2 Inhibitors
| Molecule ID | Name | Mechanism | Highest Phase |
|---|---|---|---|
| CHEMBL3137309 | Venetoclax (ABT-199, GDC-0199, RG7601) | BCL2 selective inhibitor | 4 (Approved) |
| CHEMBL443684 | Navitoclax (ABT-263) | BCL2/BCL-XL/BCL-W inhibitor | 3 |
| CHEMBL408194 | Obatoclax (GX15-070) | Pan-BCL2 family inhibitor | 3 |
| CHEMBL4446378 | Tapotoclax (AMG 176) | MCL1 inhibitor (BCL2 family) | 1 |
| CHEMBL3793424 | A-1331852 | BCL2 selective inhibitor | Pre-clinical |
| CHEMBL3342332 | A-1155463 | BCL2 selective inhibitor | Pre-clinical |
Venetoclax (approved 2016 for CLL; 2021 for AML) is the primary BCL2 inhibitor in clinical practice.
Clinical Trials (Sample of TOP 20 for Venetoclax)
Phase 4 Active Trials:
| Trial ID | Phase | Status | Intervention | Indication |
|---|---|---|---|---|
| NCT04790045 | 4 | Recruiting | Venetoclax-based regimens | CLL |
| NCT05144243 | 4 | Active, not recruiting | Venetoclax + azacitidine | AML (treatment-naive) |
| NCT06571825 | 4 | Recruiting | RIC allo-HSCT vs. venetoclax consolidation | Elderly AML post-CR |
| NCT07044687 | 4 | Recruiting | Venetoclax + azacitidine | AML (ineligible for intensive) |
Phase 3 Completed/Active Trials:
| Trial ID | Phase | Status | Intervention | Indication |
|---|---|---|---|---|
| NCT02005471 | 3 | Completed | Venetoclax + rituximab vs. bendamustine + rituximab | Relapsed/refractory CLL |
| NCT02242942 | 3 | Completed | Obinutuzumab + venetoclax vs. obinutuzumab + chlorambucil | Treatment-naive CLL |
| NCT02756611 | 3 | Completed | Venetoclax monotherapy | Relapsed/refractory CLL |
| NCT02950051 | 3 | Completed | Rituximab + venetoclax vs. standard chemoimmunotherapy | Untreated CLL (no del17p) |
| NCT02993523 | 3 | Active, not recruiting | Venetoclax + azacitidine vs. azacitidine alone | AML (ineligible for standard induction) |
| NCT03069352 | 3 | Completed | Venetoclax + low-dose cytarabine vs. cytarabine alone | Untreated AML (ineligible for intensive) |
| NCT03112174 | 3 | Completed | Ibrutinib + venetoclax | Mantle cell lymphoma |
| NCT05197192 | 3 | Recruiting | Acalabrutinib + obinutuzumab + venetoclax vs. obinutuzumab + venetoclax | Untreated high-risk CLL |
Total venetoclax clinical trials: 100+ (613 trial connections recorded)
Pharmacogenomics & Drug Interactions
Known Drug-Gene Interactions:
CYP3A4 Metabolism (Primary): Venetoclax is extensively metabolized by CYP3A4
- CYP3A4 Inhibitors (strong): Increase venetoclax exposure → requires dose reduction
- Examples: Ketoconazole, ritonavir, clarithromycin, erythromycin
- CYP3A4 Inducers (strong): Decrease venetoclax exposure → may reduce efficacy
- Examples: Rifampin, phenytoin, St. John’s Wort
- CYP3A4 Inhibitors (strong): Increase venetoclax exposure → requires dose reduction
P-glycoprotein (MDR1/ABCB1) Interactions: Venetoclax is a P-gp substrate; strong inhibitors can increase exposure
Dosing Guidelines:
- Standard dosing (CYP3A4 normal): 400 mg daily for CLL; 100-600 mg daily for AML (in combination)
- With strong CYP3A4 inhibitors: Reduce to 100 mg daily (or 50% of standard dose)
- With moderate CYP3A4 inhibitors: Reduce to 200 mg daily
- Avoid strong CYP3A4 inducers or increase venetoclax dose if co-administration necessary
Other Noted Interactions:
- P-glycoprotein inhibitors may increase venetoclax levels
- Grapefruit juice: Avoid (potent CYP3A4 inhibitor)
- Warfarin: Monitor INR closely (venetoclax may increase effect)
Pharmacogenomics Status: No FDA-approved genetic testing recommended for BCL2 inhibitor selection; however, CYP3A4 phenotyping may guide dosing adjustments in patients with strong drug interactions.
Based on the biobtree data, here’s a comprehensive summary of BCL2 expression profiles:
Expression profiles
Tissue Expression
BCL2 shows ubiquitous expression across human tissues with high average expression (76.98 score). Below are the top tissues:
| Tissue | Expression Score | Quality |
|---|---|---|
| Dorsal motor nucleus of vagus nerve | 96.44 | Gold |
| Superficial temporal artery | 90.51 | Gold |
| Calcaneal tendon | 90.50 | Gold |
| Cortical plate (brain) | 90.44 | Gold |
| Colonic epithelium | 89.85 | Gold |
| Inferior olivary complex (brain) | 89.77 | Gold |
| Cranial nerve II (optic nerve) | 89.75 | Gold |
| Trigeminal ganglion | 88.60 | Gold |
| Medial globus pallidus (brain) | 88.33 | Gold |
| Tendon | 88.33 | Gold |
| Lateral globus pallidus (brain) | 88.12 | Gold |
| Globus pallidus | 87.91 | Gold |
| Epididymal caput | 87.69 | Gold |
| Seminal vesicle | 87.61 | Gold |
| Tendon of biceps brachii | 87.48 | Gold |
| Nasopharyngeal epithelium | 87.32 | Gold |
| Lymph node | 87.28 | Gold |
| Bone marrow cell | 87.22 | Gold |
| Germinal epithelium of ovary | 87.17 | Gold |
| Thoracic mammary gland | 86.98 | Gold |
| Mammary gland | 86.89 | Gold |
| Sural nerve | 86.88 | Gold |
| Dorsal root ganglion | 86.80 | Gold |
| Thyroid gland | 86.64 | Gold |
| Decidua | 86.31 | Gold |
| Thyroid gland (left lobe) | 86.04 | Gold |
| Granulocyte | 86.00 | Gold |
| Tibial nerve | 85.86 | Gold |
| Nephron tubule | 85.71 | Gold |
| Renal medulla | 85.47 | Gold |
Pattern: BCL2 is highly and broadly expressed across nervous tissues (brain, spinal cord, nerves), connective tissues (tendons, ligaments), immune tissues (lymph nodes, bone marrow), and endocrine tissues (thyroid, reproductive organs). Expression is particularly enriched in neural and sensory tissues.
Single-Cell Expression Datasets
BCL2 is cataloged in 3 major single-cell RNA-seq atlases:
GTEx snRNAseq atlas (E-ANND-2) — 209,126 cells
- Covers multiple tissues: breast, lung, heart, esophagus, prostate, skin, skeletal muscle
- Cell types include: epithelial cells (basal, luminal, ciliated), immune cells (T, B, NK cells, macrophages, dendritic cells), myocytes (cardiac, skeletal, smooth muscle), fibroblasts, endothelial cells, Schwann cells
10x single-cell T cell atlas (E-CURD-85) — 111,869 cells
- T cells from blood, synovial fluid, and synovial tissue in psoriatic arthritis patients
- Relevant for immune/inflammatory contexts
Breast cancer single-cell dataset (E-GEOD-75688) — 549 cells
- Primary breast cancer cells and lymph node metastases
- Covers 4 breast cancer subtypes (luminal A, luminal B, HER2, triple negative)
Cell Type Pattern: BCL2 expression is notably present in immune cell populations (particularly T cells, B cells, macrophages) and epithelial cell types, consistent with its critical role in lymphoid tissues and apoptosis regulation in proliferative tissues.
Disease associations
Mendelian / monogenic disease
BCL2 is associated with one rare monogenic disorder:
| Disease | Disease ID | Inheritance | Evidence |
|---|---|---|---|
| Multiple congenital anomalies-hypotonia-seizures syndrome | MONDO:0013563 (Orphanet:280633) | — | ClinVar variants |
Note: The clinvar mapping suggests BCL2 variants are associated with this rare syndromic condition. Limited curated gene-disease associations available in GenCC for BCL2.
Phenotype associations
17 HPO clinical phenotypes associated with BCL2 mutations/expression:
| Phenotype | HPO ID |
|---|---|
| Lymphoma | HP:0002665 |
| Lymphadenopathy | HP:0002716 |
| Splenomegaly | HP:0001744 |
| Mediastinal lymphadenopathy | HP:0100721 |
| Mediastinal mass | HP:0033823 |
| Pleural effusion | HP:0002202 |
| Ascites | HP:0001541 |
| Fever | HP:0001945 |
| Night sweats | HP:0030166 |
| Fatigue | HP:0012378 |
| Weight loss | HP:0001824 |
| Lymphedema | HP:0001004 |
| Hypercalcemia | HP:0003072 |
| Increased LDH | HP:0025435 |
| Abnormal peritoneum morphology | HP:0002585 |
| Meningitis | HP:0001287 |
| Skin nodule | HP:0200036 |
Complex disease / GWAS associations
108 genome-wide associations identified. Top 30 by statistical significance:
| Trait | Variant ID | P-value | Gene/Region |
|---|---|---|---|
| Eosinophil count | GCST90002381_607 | 1e-85 | BCL2 |
| White blood cell count (basophil) | GCST004618_21 | 1e-51 | BCL2 |
| Mean corpuscular hemoglobin | GCST090002390_163 | 1e-51 | BCL2 |
| Basophil percentage of white cells | GCST004631_15 | 1e-46 | BCL2 |
| Mean reticulocyte volume | GCST90002396_283 | 1e-43 | BCL2 |
| Basophil percentage of granulocytes | GCST004634_21 | 2e-40 | BCL2 |
| Mean corpuscular volume | GCST090002392_535 | 3e-48 | BCL2 |
| Monocyte count | GCST90002393_342 | 4e-67 | BCL2 |
| Plateletcrit | GCST90002400_702 | 4e-76 | BCL2 |
| Mean platelet volume | GCST90002395_697 | 4e-35 | BCL2 |
| Sum eosinophil basophil counts | GCST004624_16 | 3e-37 | BCL2 |
| Red blood cell count | GCST90002403_389 | 1e-36 | BCL2 |
| Plateletcrit | GCST004607_161 | 9e-31 | BCL2 |
| Non-albumin protein levels | GCST005990_22 | 9e-30 | BCL2 |
| Monocyte count | GCST90002393_341 | 1e-29 | BCL2 |
| Monocyte percentage of white cells | GCST90002394_274 | 1e-28 | BCL2 |
| Neutrophil percentage of granulocytes | GCST004623_138 | 4e-27 | BCL2 |
| Eosinophil count | GCST004606_52 | 7e-25 | BCL2 |
| Waist-to-hip ratio adjusted for BMI | GCST90020025_965 | 1e-24 | BCL2 |
| Mean corpuscular hemoglobin | GCST004630_201 | 9e-25 | BCL2 |
| Platelet count | GCST90002402_632 | 4e-25 | BCL2 |
| Mosaic loss of chromosome Y | GCST009067_5 | 1e-33 | BCL2 |
| Mosaic loss of chromosome Y | GCST009375_1 | 1e-33 | BCL2 |
| Mean corpuscular volume | GCST004602_205 | 8e-21 | BCL2 |
| White blood cell count | GCST90002407_343 | 4e-21 | BCL2 |
| Eosinophil percentage of white cells | GCST90002382_269 | 2e-66 | BCL2 |
| Eosinophil percentage of white cells | GCST90002382_268 | 6e-22 | BCL2 |
| Serum total protein levels | GCST005989_31 | 2e-14 | BCL2 |
| Waist-hip index | GCST90020027_1509 | 5e-25 | BCL2 |
| Monocyte count | GCST004625_177 | 3e-20 | BCL2 |
Key disease associations: Chronic lymphocytic leukemia (GCST002073 studies, p<1e-10), follicular lymphoma (GCST002643_5, p=8e-10), multiple sclerosis (GCST009597_39, p=4e-07), type 2 diabetes (GCST004894_58, p=4e-08), prostate cancer (GCST006085_131, p=1e-08), adolescent idiopathic scoliosis (GCST003128_2, p=2e-12).
Phenotype pattern: BCL2 GWAS associations are predominantly hematological traits (blood cell counts, morphology, and derivatives), reflecting its central role in lymphocyte development and apoptosis.