CASP3 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human CASP3 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene CASP3, 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 CASP3, 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 CASP3 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 CASP3 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 CASP3, 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 CASP3, 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 CASP3, 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 CASP3 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 CASP3, summarize transcription factor regulatory data. If CASP3 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 CASP3 — names with evidence type (ChIP-seq / predicted / experimentally validated) If CASP3 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene CASP3 protein as a drug target, summarize pharmacology data. If CASP3 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 CASP3 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene CASP3, 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 CASP3, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in CASP3: 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
CASP3 (caspase-3, HGNC:1504) is the principal executioner caspase in programmed cell death, making it one of the most studied regulators of apoptosis in human biology. Encoded on chromosome 4q35.1, it produces a 277-amino-acid, 31,608 Da cysteine protease that is activated by upstream initiator caspases (CASP8, CASP9) via the apoptosome and inhibited by IAP family members including XIAP. Its interaction network is exceptionally large (~8,500+ curated interactions), and 136 experimental structures have been solved, supporting an active drug-discovery effort — yet despite 130+ compounds in ChEMBL, no approved therapeutics or clinical trials currently target it. Expression is ubiquitous across 277 tissue types, with the highest levels in GI epithelium, immune cells, and the developing brain, consistent with its constitutive role in tissue homeostasis. The strongest disease-level genetic signal links CASP3 to Kawasaki disease (rs2720378, p = 1 × 10⁻¹⁰), though no Mendelian disease has been attributed to CASP3 mutations.
CASP3 — Reference
Cross-database identifier and functional mapping reference for CASP3.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:1504 |
| Approved symbol | CASP3 |
| Ensembl gene ID | ENSG00000164305 |
| NCBI Entrez Gene ID | 836 |
| OMIM gene/locus ID | 600636 |
| Chromosome (GRCh38) | 4 |
| Start position | 184,627,695 |
| End position | 184,650,418 |
| Strand | − (minus) |
| Cytogenetic location | 4q35.1 |
Transcript identifiers
Ensembl transcripts (32 total)
| ENST ID | Biotype |
|---|---|
| ENST00000308394 | protein_coding |
| ENST00000393585 | protein_coding |
| ENST00000393588 | protein_coding |
| ENST00000447121 | protein_coding |
| ENST00000517513 | protein_coding |
| ENST00000523916 | protein_coding |
| ENST00000700100 | protein_coding |
| ENST00000700101 | protein_coding |
| ENST00000700102 | retained_intron |
| ENST00000700103 | retained_intron |
| ENST00000700104 | nonsense_mediated_decay |
| ENST00000872339 | protein_coding |
| ENST00000872340 | protein_coding |
| ENST00000872341 | protein_coding |
| ENST00000872342 | protein_coding |
| ENST00000872343 | protein_coding |
| ENST00000872344 | protein_coding |
| ENST00000872345 | protein_coding |
| ENST00000872346 | protein_coding |
| ENST00000872347 | protein_coding |
| ENST00000939939 | protein_coding |
| ENST00000939940 | protein_coding |
| ENST00000939941 | protein_coding |
| ENST00000939942 | protein_coding |
| ENST00000939943 | protein_coding |
| ENST00000939944 | protein_coding |
| ENST00000939945 | protein_coding |
| ENST00000939946 | protein_coding |
| ENST00000972040 | protein_coding |
| ENST00000972041 | protein_coding |
| ENST00000972042 | protein_coding |
| ENST00000972043 | protein_coding |
Total: 32 Ensembl transcripts (31 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay)
RefSeq transcripts (Human - chr4)
| NM ID | MANE Select |
|---|---|
| NM_001354777 | No |
| NM_001354779 | No |
| NM_001354780 | No |
| NM_001354781 | No |
| NM_001354782 | No |
| NM_001354783 | No |
| NM_001354784 | No |
| NM_001440946 | No |
| NM_004346 | Yes |
| NM_032991 | No |
| NM_128296 | No |
Total: 11 human mRNA accessions (NM_004346 is MANE Select)
CCDS IDs
- CCDS3836
- CCDS87283
Canonical/MANE SELECT transcript: ENST00000308394 (NM_004346)
Chromosome 4, reverse strand. 8 exons total:
| Exon ID | Start | End | Length |
|---|---|---|---|
| ENSE00001592717 | 184649395 | 184649447 | 53 bp |
| ENSE00001215704 | 184648465 | 184648631 | 167 bp |
| ENSE00002443273 | 184638401 | 184638468 | 68 bp |
| ENSE00001083265 | 184635294 | 184635418 | 125 bp |
| ENSE00001083271 | 184631765 | 184631940 | 176 bp |
| ENSE00001083266 | 184632268 | 184632396 | 129 bp |
| ENSE00001083268 | 184631037 | 184631157 | 121 bp |
| ENSE00003514002 | 184627696 | 184629501 | 1806 bp |
Protein identifiers
UniProt Accessions
- P42574 (canonical reviewed entry) — Caspase-3, mass: 31,608 Da, length: 277 aa
- A0A8V8TPU5 (unreviewed)
- A8MVM1 (unreviewed)
- C9JXR7 (unreviewed)
RefSeq Protein Accessions (NP_)
- NP_004337 (MANE Select, canonical)
- NP_001341706
- NP_001341708
- NP_001341709
- NP_001341710
- NP_001341711
- NP_001341712
- NP_001341713
- NP_001427875
- NP_001271338
- NP_033940
- NP_037054
- NP_116786
- NP_180305
Protein Domains and Families
| Domain/Family | ID | Type | Database |
|---|---|---|---|
| Caspase, P20/P10 domain | PF00656 | Domain | Pfam |
| Peptidase C14, p20 domain | IPR001309 | Domain | InterPro |
| Peptidase C14, caspase non-catalytic subunit p10 | IPR002138 | Domain | InterPro |
| Peptidase C14 family | IPR002398 | Family | InterPro |
| Peptidase C14, caspase domain | IPR011600 | Domain | InterPro |
| Peptidase C14A, caspase catalytic domain | IPR015917 | Domain | InterPro |
| Peptidase family C14A, His active site | IPR016129 | Active site | InterPro |
| Caspase-like domain superfamily | IPR029030 | Homologous superfamily | InterPro |
| Peptidase family C14A, cysteine active site | IPR033139 | Active site | InterPro |
| Caspase domain | SM00115 | Domain | SMART |
| Caspase | CD00032 | — | CDD |
Antibody Resources
The canonical UniProt entry (P42574) is indexed in the Human Protein Atlas (HPA), a major source for antibody availability and protein expression data. No direct antibody resource mappings were found in the biobtree database for this entry.
Structure
Experimental Structures: X-ray Crystallography & Cryo-EM
X-ray Diffraction (133 structures):
1CP3 (2.3 Å) | 1GFW (2.8 Å) | 1I3O (2.7 Å) | 1NME (1.6 Å) | 1NMQ (2.4 Å) | 1NMS (1.7 Å) | 1PAU (2.5 Å) | 1QX3 (1.9 Å) | 1RE1 (2.5 Å) | 1RHJ (2.2 Å) | 1RHK (2.5 Å) | 1RHM (2.5 Å) | 1RHQ (3.0 Å) | 1RHR (3.0 Å) | 1RHU (2.51 Å) | 2C1E (1.77 Å) | 2C2K (1.87 Å) | 2C2M (1.94 Å) | 2C2O (2.45 Å) | 2CDR (1.7 Å) | 2CJX (1.7 Å) | 2CJY (1.67 Å) | 2CNK (1.75 Å) | 2CNL (1.67 Å) | 2CNN (1.7 Å) | 2CNO (1.95 Å) | 2DKO (1.06 Å) | 2H5I (1.69 Å) | 2H5J (2.0 Å) | 2H65 (2.3 Å) | 2J30 (1.4 Å) | 2J31 (1.5 Å) | 2J32 (1.3 Å) | 2J33 (2.0 Å) | 2XYG (1.54 Å) | 2XYH (1.89 Å) | 2XYP (1.86 Å) | 2XZD (2.1 Å) | 2XZT (2.7 Å) | 2Y0B (2.1 Å) | 3DEH (2.5 Å) | 3DEI (2.8 Å) | 3DEJ (2.6 Å) | 3DEK (2.4 Å) | 3EDQ (1.61 Å) | 3GJQ (2.6 Å) | 3GJR (2.2 Å) | 3GJS (1.9 Å) | 3GJT (2.2 Å) | 3H0E (1.997 Å) | 3ITN (1.63 Å) | 3KJF (2.0 Å) | 3PCX (1.5 Å) | 3PD0 (2.0 Å) | 3PD1 (1.62 Å) | 4DCJ (1.7 Å) | 4DCO (1.7 Å) | 4DCP (1.7 Å) | 4EHA (1.696 Å) | 4EHD (1.581 Å) | 4EHF (1.655 Å) | 4EHH (1.78 Å) | 4EHK (1.668 Å) | 4EHL (1.799 Å) | 4EHN (1.69 Å) | 4JJE (1.481 Å) | 4JQY (2.495 Å) | 4JQZ (2.889 Å) | 4JR0 (1.796 Å) | 4PRY (1.7 Å) | 4PS0 (1.63 Å) | 4QTX (1.974 Å) | 4QTY (1.602 Å) | 4QU0 (1.954 Å) | 4QU5 (1.908 Å) | 4QU8 (1.715 Å) | 4QU9 (1.561 Å) | 4QUA (1.892 Å) | 4QUB (1.689 Å) | 4QUD (1.995 Å) | 4QUE (1.843 Å) | 4QUG (1.917 Å) | 4QUH (1.759 Å) | 4QUI (1.758 Å) | 4QUJ (1.498 Å) | 4QUL (1.898 Å) | 5I9B (1.8 Å) | 5I9T (1.95 Å) | 5IAB (1.79 Å) | 5IAE (1.55 Å) | 5IAG (1.98 Å) | 5IAJ (1.58 Å) | 5IAK (1.82 Å) | 5IAN (2.7 Å) | 5IAR (1.76 Å) | 5IAS (1.54 Å) | 5IBC (1.66 Å) | 5IBP (1.38 Å) | 5IBR (1.74 Å) | 5IC4 (2.65 Å) | 6BDV (1.938 Å) | 6BFJ (1.543 Å) | 6BFK (1.753 Å) | 6BFL (1.87 Å) | 6BFO (1.54 Å) | 6BG0 (2.125 Å) | 6BG1 (1.88 Å) | 6BG4 (1.87 Å) | 6BGK (1.87 Å) | 6BGQ (1.97 Å) | 6BGR (2.16 Å) | 6BGS (1.6 Å) | 6BH9 (1.94 Å) | 6BHA (1.603 Å) | 6CKZ (1.5 Å) | 6CL0 (1.5 Å) | 6X8I (1.5 Å) | 6X8K (2.17 Å) | 7RN7 (2.4 Å) | 7RN8 (1.88 Å) | 7RN9 (1.67 Å) | 7RNA (1.9 Å) | 7RNB (1.75 Å) | 7RNC (1.93 Å) | 7RND (2.15 Å) | 7RNE (2.73 Å) | 7RNF (2.11 Å) | 7RNG (2.55 Å) | 7SEO (3.25 Å) | 7USO (2.3 Å) | 7USP (2.85 Å) | 7USQ (2.71 Å)
Cryo-EM (2 structures):
7XN4 (3.35 Å) | 7XN5 (3.18 Å) | 7XN6 (3.45 Å)
Total Experimental Structures: 136
Predicted Structures
AlphaFold:
- Model ID: P42574
- Global pLDDT: 86.64 (very high confidence)
- Fraction of residues with pLDDT ≥ 70: 77%
Cross-species orthologs
| Organism | Gene ID | Gene Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000031628 | Casp3 |
| Rat (Rattus norvegicus) | ENSRNOG00000010475 | Casp3 |
| Zebrafish (Danio rerio) | ENSDARG00000017905 | casp3a |
| Fruit fly (Drosophila melanogaster) | FBGN0010501 | Dcp-1 |
| Worm (C. elegans) | WBGENE00000417 | ced-3 |
| Yeast (S. cerevisiae) | — | none |
Clinical variants & AI predictions
ClinVar Overview
Total variants: 27
| Classification | Count |
|---|---|
| Pathogenic | 1 |
| Likely Pathogenic | 0 |
| Uncertain Significance | 20 |
| Likely Benign | 4 |
| Benign | 2 |
Top Pathogenic/Likely Pathogenic ClinVar Variants
| Variant ID | HGVS Notation | Classification | Associated Condition |
|---|---|---|---|
| 562989 | GRCh37/hg19 4q32.1-35.2(chr4:159492464-190957473)x3 | Pathogenic | Copy number gain |
Note: Only 1 pathogenic variant identified in CASP3 ClinVar; no “Likely Pathogenic” single-nucleotide variants documented. Most variants classified as uncertain significance.
AlphaMissense Missense Predictions
Total variants predicted: ~1,866
Likely Pathogenic variants: ~100+ (filtered subset shown)
Top 30 Likely Pathogenic by AlphaMissense (am_pathogenicity score)
| Variant | Protein Change | am_pathogenicity | am_class |
|---|---|---|---|
| 4:184629294:T:A | K271I | 0.997 | likely_pathogenic |
| 4:184629300:A:G | L269P | 0.997 | likely_pathogenic |
| 4:184629300:A:T | L269H | 0.997 | likely_pathogenic |
| 4:184629323:C:A | Q261H | 0.998 | likely_pathogenic |
| 4:184629323:C:G | Q261H | 0.998 | likely_pathogenic |
| 4:184629288:A:G | L273P | 0.991 | likely_pathogenic |
| 4:184629316:A:G | C264R | 0.993 | likely_pathogenic |
| 4:184629302:C:A | M268I | 0.993 | likely_pathogenic |
| 4:184629302:C:G | M268I | 0.993 | likely_pathogenic |
| 4:184629302:C:T | M268I | 0.993 | likely_pathogenic |
| 4:184629328:T:C | K260E | 0.994 | likely_pathogenic |
| 4:184629307:A:G | S267P | 0.994 | likely_pathogenic |
| 4:184629318:G:C | P263R | 0.996 | likely_pathogenic |
| 4:184629324:T:G | Q261P | 0.996 | likely_pathogenic |
| 4:184629326:T:A | K260N | 0.996 | likely_pathogenic |
| 4:184629326:T:G | K260N | 0.996 | likely_pathogenic |
| 4:184629318:G:T | P263Q | 0.997 | likely_pathogenic |
| 4:184629301:G:A | L269F | 0.966 | likely_pathogenic |
| 4:184629282:A:G | F275S | 0.954 | likely_pathogenic |
| 4:184629360:G:T | S249Y | 0.966 | likely_pathogenic |
| 4:184629288:A:C | L273R | 0.964 | likely_pathogenic |
| 4:184629327:T:G | K260T | 0.980 | likely_pathogenic |
| 4:184629329:C:A | K259N | 0.978 | likely_pathogenic |
| 4:184629329:C:G | K259N | 0.978 | likely_pathogenic |
| 4:184629324:T:A | Q261L | 0.979 | likely_pathogenic |
| 4:184629318:G:A | P263L | 0.985 | likely_pathogenic |
| 4:184629309:A:T | V266D | 0.984 | likely_pathogenic |
| 4:184629325:G:T | Q261K | 0.983 | likely_pathogenic |
| 4:184629327:T:A | K260I | 0.989 | likely_pathogenic |
| 4:184629301:G:C | L269V | 0.943 | likely_pathogenic |
SpliceAI Splice Effect Predictions
Total variants predicted: ~1,335
Top 30 High-Confidence Splice Effects
| Variant | Effect Type | SpliceAI Score |
|---|---|---|
| 4:184631031:TCTCA:T | donor_loss | 0.99 |
| 4:184631032:CT:C | donor_loss | 0.99 |
| 4:184631033:TCACC:T | donor_loss | 0.99 |
| 4:184631035:ACCAG:A | donor_loss | 0.99 |
| 4:184631036:CCAG:C | donor_gain | 0.99 |
| 4:184631035:A:AC | donor_gain | 0.99 |
| 4:184631036:C:CC | donor_gain | 0.99 |
| 4:184629498:TAAC:T | acceptor_gain | 1.00 |
| 4:184629497:ATAAC:A | acceptor_gain | 0.99 |
| 4:184629502:C:CC | acceptor_gain | 0.99 |
| 4:184629503:T:C | acceptor_loss | 0.99 |
| 4:184629502:CTAA:C | acceptor_loss | 0.99 |
| 4:184630227:G:C | acceptor_gain | 0.96 |
| 4:184629499:AAC:A | acceptor_gain | 0.96 |
| 4:184630233:A:T | acceptor_gain | 0.97 |
| 4:184630229:G:C | acceptor_gain | 0.90 |
| 4:184630229:G:GC | acceptor_gain | 0.82 |
| 4:184629812:A:C | acceptor_gain | 0.86 |
| 4:184629500:AC:A | acceptor_gain | 0.95 |
| 4:184629501:CC:C | acceptor_gain | 0.95 |
| 4:184629510:C:CT | acceptor_gain | 0.95 |
| 4:184629511:A:T | acceptor_gain | 0.95 |
| 4:184630235:C:CT | acceptor_gain | 0.94 |
| 4:184629514:A:C | acceptor_gain | 0.95 |
| 4:184629514:A:AC | acceptor_gain | 0.92 |
| 4:184631027:A:C | donor_gain | 0.88 |
| 4:184629812:A:AC | acceptor_gain | 0.76 |
| 4:184629637:G:C | donor_gain | 0.76 |
| 4:184629639:C:T | donor_gain | 0.74 |
| 4:184629638:A:T | donor_gain | 0.64 |
Pathways & Gene Ontology
Reactome Pathways
Total: 17 pathways
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-111459 | Activation of caspases through apoptosome-mediated cleavage |
| R-HSA-111463 | SMAC (DIABLO) binds to IAPs |
| R-HSA-111464 | SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes |
| R-HSA-111465 | Apoptotic cleavage of cellular proteins |
| R-HSA-111469 | SMAC, XIAP-regulated apoptotic response |
| R-HSA-140342 | Apoptosis induced DNA fragmentation |
| R-HSA-1474228 | Degradation of the extracellular matrix |
| R-HSA-2028269 | Signaling by Hippo |
| R-HSA-205025 | NADE modulates death signalling |
| R-HSA-211736 | Stimulation of the cell death response by PAK-2p34 |
| R-HSA-264870 | Caspase-mediated cleavage of cytoskeletal proteins |
| R-HSA-351906 | Apoptotic cleavage of cell adhesion proteins |
| R-HSA-418889 | Caspase activation via Dependence Receptors in the absence of ligand |
| R-HSA-449836 | Other interleukin signaling |
| R-HSA-5620971 | Pyroptosis |
| R-HSA-9960519 | CASP4-mediated substrate cleavage |
| R-HSA-9960525 | CASP5-mediated substrate cleavage |
MSigDB Gene Sets
Total: >100 gene sets (first 50+ shown; pagination available)
Notable gene sets include apoptosis-related pathways (M1018: Reactome Apoptosis Induced DNA Fragmentation), immune cell processes, and stress responses.
Gene Ontology Annotations
Biological Process (63 terms)
| GO ID | Term |
|---|---|
| GO:0006915 | apoptotic process |
| GO:0097190 | apoptotic signaling pathway |
| GO:0097193 | intrinsic apoptotic signaling pathway |
| GO:0097194 | execution phase of apoptosis |
| GO:0001666 | response to hypoxia |
| GO:0006974 | DNA damage response |
| GO:0030163 | protein catabolic process |
| GO:0006508 | proteolysis |
| GO:0016485 | protein processing |
| GO:0051604 | protein maturation |
| GO:0031647 | regulation of protein stability |
| GO:0045786 | negative regulation of cell cycle |
| GO:0032496 | response to lipopolysaccharide |
| GO:0034612 | response to tumor necrosis factor |
| GO:0042542 | response to hydrogen peroxide |
| GO:0009411 | response to UV |
| GO:0010165 | response to X-ray |
| GO:0001782 | B cell homeostasis |
| GO:0043029 | T cell homeostasis |
| GO:0051146 | striated muscle cell differentiation |
Molecular Function (9 terms)
| GO ID | Term |
|---|---|
| GO:0004197 | cysteine-type endopeptidase activity |
| GO:0004190 | aspartic-type endopeptidase activity |
| GO:0008233 | peptidase activity |
| GO:0005123 | death receptor binding |
| GO:0002020 | protease binding |
| GO:0008047 | enzyme activator activity |
| GO:0044877 | protein-containing complex binding |
| GO:0016005 | phospholipase A2 activator activity |
| GO:0004861 | cyclin-dependent protein serine/threonine kinase inhibitor activity |
Cellular Component (8 terms)
| GO ID | Term |
|---|---|
| GO:0005829 | cytosol |
| GO:0005737 | cytoplasm |
| GO:0005634 | nucleus |
| GO:0005654 | nucleoplasm |
| GO:0031264 | death-inducing signaling complex |
| GO:0043025 | neuronal cell body |
| GO:0014069 | postsynaptic density |
| GO:0098978 | glutamatergic synapse |
Protein interactions & networks
Protein-Protein Interactions (PPIs)
Total Interaction Count (Approximate):
- STRING: ~8,154 interactions
- BioGRID: 232 interactions
- IntAct: 143 interactions
- Total: ~8,500+ interactions
TOP 30 Highest-Confidence Interacting Proteins (STRING Database):
| Rank | Gene | Protein Name | STRING Score |
|---|---|---|---|
| 1 | XIAP | E3 ubiquitin-protein ligase XIAP | 998 |
| 2 | CASP3 | Caspase-3 (self-interaction) | 998 |
| 3 | APAF1 | Apoptotic protease-activating factor 1 | 986 |
| 4 | CASP8 | Caspase-8 | 984 |
| 5 | BCL2 | Apoptosis regulator Bcl-2 | 980 |
| 6 | BAX | Bcl-2-like protein 1 | 975 |
| 7 | CASP9 | Caspase-9 | 958 |
| 8 | PARP1 | Poly [ADP-ribose] polymerase 1 | 954 |
| 9 | MCL1 | Induced myeloid leukemia cell differentiation protein Mcl-1 | 940 |
| 10 | AKT1 | RAC-alpha serine/threonine-protein kinase | 923 |
| 11 | MAPK8 | Mitogen-activated protein kinase 8 | 923 |
| 12 | BIRC3 | Baculoviral IAP repeat-containing protein 3 | 922 |
| 13 | FADD | FAS-associated death domain protein | 920 |
| 14 | ANXA5 | Annexin A5 | 919 |
| 15 | PXDNL | Probable oxidoreductase PXDNL | 918 |
| 16 | PXDN | Peroxidasin homolog | 918 |
| 17 | DFF45 | DNA fragmentation factor subunit beta | 914 |
| 18 | HSPA4 | Heat shock 70 kDa protein 4 | 903 |
| 19 | IL1B | Interleukin-1 beta | 899 |
| 20 | BECN1 | Beclin-1 | 899 |
| 21 | ACTB | Actin, cytoplasmic 1 | 894 |
| 22 | GAPDH | Glyceraldehyde-3-phosphate dehydrogenase | 890 |
| 23 | FASLG | Tumor necrosis factor ligand superfamily member 6 | 888 |
| 24 | TDT | DNA nucleotidylexotransferase | 883 |
| 25 | MYC | Myc proto-oncogene protein | 881 |
| 26 | IL6 | Interleukin-6 | 874 |
| 27 | HSP90AA1 | Heat shock protein HSP 90-alpha | 874 |
| 28 | SMAC | Diablo IAP-binding mitochondrial protein | 864 |
| 29 | PTGS2 | Prostaglandin G/H synthase 2 | 863 |
| 30 | TNF | Tumor necrosis factor | 899 |
Notable High-Confidence Interactions (IntAct & BioGRID):
- XIAP: 0.870 confidence (multiple independent interactions) - inhibitor of caspase-3
- TXN (Thioredoxin): 0.750 confidence - protein cleavage substrate
- APAF1: 0.650 confidence - upstream activator in apoptosome
- CASP9: 0.640 confidence - upstream initiator caspase
- PARP1: 0.570-0.620 confidence - key apoptotic substrate
- CASP6: 0.570 confidence - downstream effector caspase
- BID: 0.440 confidence - BH3-only substrate for cleavage
- BIRC2/BIRC7: 0.400 confidence - IAP inhibitors
- MDM2: 0.440-0.570 confidence - cleavage substrate
Protein Similarity
Structural/Embedding Similarity (ESM2 - Top 20): All 23 ESM2-similar proteins are caspase homologs from various species. Most are non-human orthologs. Human caspases showing high similarity:
| Rank | UniProt | Gene | Top Similarity Score |
|---|---|---|---|
| 1 | P55210 | CASP7 | 0.9973 |
| 2 | P55212 | CASP6 | 0.9957 |
Other homologs represent orthologs from mouse, rat, zebrafish, and other organisms (O08738, O35397, Q60431, etc.) with similarly high ESM2 scores (0.994-0.998).
Sequence Homology (DIAMOND - Top 20 by Identity):
| Rank | UniProt | Protein/Gene | Identity % | BitScore |
|---|---|---|---|---|
| 1 | O75601 | CASP (human variant) | 100.00 | 755.00 |
| 2 | Q5E9C1 | CASP (human variant) | 100.00 | 755.00 |
| 3 | P29594 | CASP (variant) | 97.60 | 897.00 |
| 4 | P55215 | CASP (variant) | 97.60 | 896.00 |
| 5 | G5ECW5 | CASP3-like | 94.20 | 230.00 |
| 6 | Q9TZP5 | CASP3-like | 94.20 | 232.00 |
| 7 | O08738 | Casp3 (mouse) | 94.60 | 542.00 |
| 8 | O35397 | Casp3 (mouse) | 94.60 | 543.00 |
| 9 | Q2PFV2 | Casp3 (ortholog) | 96.00 | 535.00 |
| 10 | Q5IS99 | Casp3 (ortholog) | 96.00 | 531.00 |
| 11 | Q60431 | Casp3 (mouse) | 92.10 | 523.00 |
| 12 | P42573 | CASP2 (human) | 84.50 | 843.00 |
| 13 | P55213 | CASP3 variant | 93.50 | 534.00 |
| 14 | P70677 | CASP3 variant | 93.50 | 537.00 |
| 15 | P55214 | CASP3 variant | 90.80 | 567.00 |
| 16 | P97864 | CASP3 variant | 90.80 | 570.00 |
| 17 | Q3T0P5 | CASP3-related | 88.30 | 517.00 |
| 18 | Q08DY9 | CASP3-related | 87.30 | 488.00 |
| 19 | O08736 | Casp3 (species ortholog) | 87.90 | 744.00 |
| 20 | O89110 | CASP-related | 77.40 | 737.00 |
Key Interaction Networks:
- Apoptotic Cascade: CASP3 is activated by initiator caspases (CASP8, CASP9) via APAF1-mediated apoptosome formation and inhibited by XIAP/BIRC proteins
- Substrate Specificity: Cleaves key apoptotic substrates including PARP1, CASP6, BID, DFFA, and GSDME
- Cross-caspase Activation: Directly activates other executioner caspases (CASP6, CASP7)
- Apoptotic Signaling: Interfaces with both extrinsic (FAS/FADD/CASP8) and intrinsic (mitochondrial/CASP9) pathways
- Regulatory Interactions: TXN provides redox regulation; IAPs (XIAP, BIRC2/3/7) provide inhibitory control
Transcription factor regulatory data
CASP3 is not a transcription factor. It encodes caspase-3, an apoptosis-related cysteine protease, not a sequence-specific DNA-binding protein. Therefore, downstream targets and DNA-binding motifs are not applicable.
Upstream regulators: 47 transcription factors
CASP3 is regulated by 47 transcription factors identified in the CollecTRI database:
| TF Name | Regulation Type | Evidence/Confidence |
|---|---|---|
| ETS1 | Activation | High |
| FOXO1 | Activation | High |
| NOTCH1 | Activation | High |
| NKX3-1 | Activation | High |
| RBPJ | Activation | High |
| TP73 | Activation | High |
| HIF1A | (Unknown) | High |
| EWSR1 | (Unknown) | High |
| FLI1 | (Unknown) | High |
| PARP1 | (Unknown) | High |
| PHF10 | Unknown | High |
| SP1 | Unknown | High |
| TP53 | Unknown | High |
| JUN | Unknown | High |
| CEBPD | (Unknown) | High |
| DEAF1 | (Unknown) | High |
| EHF | (Unknown) | High |
| AR | (Unknown) | Low |
| ATF2 | (Unknown) | Low |
| E2F1 | Activation | Low |
| CTNNB1 | Repression | Low |
| FOXP3 | Repression | Low |
| GATA2 | (Unknown) | Low |
| ENO1 | (Unknown) | Low |
| LMX1B | (Unknown) | Low |
| TCF7L2 | Repression | Low |
| DDIT3 | (Unknown) | Low |
| ANXA3 | Repression | (Experimentally validated) |
| DLL4 | Activation | (Experimentally validated) |
| ING1 | Activation | (Experimentally validated) |
| ING4 | Activation | (Experimentally validated) |
| NFKB1 | Unknown | (Experimentally validated) |
| PML | Activation | (Experimentally validated) |
| POU1F1 | Unknown | (Experimentally validated) |
| PPARA | Repression | (Experimentally validated) |
| PROP1 | Unknown | (Experimentally validated) |
| RBM10 | Repression | (Experimentally validated) |
| ROCK1 | Activation | (Experimentally validated) |
| RUNX3 | Activation | (Experimentally validated) |
| SIM2 | Activation | (Experimentally validated) |
| SLC22A2 | Activation | (Experimentally validated) |
| SMAD5 | Repression | (Experimentally validated) |
| STAT1 | Unknown | (Experimentally validated) |
| STAT3 | Activation | (Experimentally validated) |
| FOXO3 | Unknown | (Experimentally validated) |
| RELA | Unknown | (Experimentally validated) |
| TP53INP1 | Activation | (Experimentally validated) |
Key regulators with activation: ETS1, FOXO1, NOTCH1, NKX3-1, RBPJ, TP73, E2F1, ING1/4, PML, ROCK1, RUNX3, SIM2, SLC22A2, STAT3, TP53INP1
Key regulators with repression: ANXA3, CTNNB1, FOXP3, PPARA, RBM10, SMAD5, TCF7L2
Drug & pharmacology data
CASP3 status: Recognized drug target with significant preclinical research, but no approved drugs and no active clinical trials currently documented.
Targeting molecules
- Total in databases: 130 compounds in ChEMBL, 18 entries in DrugBank
- Development phase distribution: Predominantly preclinical (phase 0)
- Known compounds:
- Z-VAD-fmk (CHEMBL1213366) — pan-caspase inhibitor, research reagent
- Pamidronic acid (DB00282) — indirect connection, bisphosphonate
- Additional 16 DrugBank entries mostly representing indirect or exploratory associations
All ChEMBL and DrugBank molecules identified targeting CASP3 lack clinical development phase advancement (no phase I–IV compounds identified).
Clinical trials
Result: No clinical trials documented for drugs specifically targeting CASP3. Search of clinical trial databases returned 0 results.
Pharmacogenomics
- PharmGKB status: CASP3 designated as VIP (Very Important Pharmacogene); chr4:184,627,696–184,649,475
- CPIC guidelines: None
- Variants: 27 ClinVar entries for CASP3; mostly variants of uncertain significance (Benign/Likely benign: 4; Uncertain significance: 21; Pathogenic: 1 CNV)
- Dosing guidelines: None documented
- Known drug-gene interactions: None with established clinical actionability
Conclusion: Despite 130+ research compounds targeting CASP3, this target has not advanced to approved therapeutics or clinical testing, and no pharmacogenomic biomarkers guide clinical CASP3-directed therapy.
Expression profiles
Tissue Expression (Bgee)
CASP3 shows ubiquitous expression across 277 human tissues and cell types, with 245 present calls and high consistency. The gene is particularly enriched in tissues with high apoptotic turnover and immune surveillance.
| Tissue / Cell Type | Expression Score | Quality |
|---|---|---|
| Jejunal mucosa | 95.17 | Gold |
| Rectum | 93.30 | Gold |
| Epithelium of nasopharynx | 92.51 | Silver |
| Nasopharynx | 92.49 | Silver |
| Ventricular zone (brain) | 92.23 | Gold |
| Duodenum | 92.09 | Gold |
| Palpebral conjunctiva (eye) | 91.76 | Gold |
| Monocyte | 91.46 | Gold |
| Esophagus squamous epithelium | 91.43 | Gold |
| Mononuclear cell | 91.17 | Gold |
| Leukocyte | 91.03 | Gold |
| Primordial germ cell in gonad | 90.54 | Gold |
| Ganglionic eminence (brain) | 90.41 | Gold |
| Colonic mucosa | 90.31 | Gold |
| Olfactory segment of nasal mucosa | 90.22 | Gold |
| Mucosa of sigmoid colon | 90.17 | Gold |
| Mucosa of transverse colon | 90.00 | Gold |
| Vermiform appendix | 90.00 | Gold |
| Cortical plate (brain) | 89.48 | Gold |
| Lymph node | 89.31 | Gold |
| Gallbladder | 89.00 | Gold |
| Esophagus mucosa | 88.93 | Gold |
| Adrenal tissue | 88.87 | Gold |
| Eye | 88.67 | Gold |
| Oral cavity | 88.41 | Gold |
| Nasal cavity mucosa | 88.00 | Gold |
| Secondary oocyte | 87.94 | Gold |
| Calcaneal tendon | 87.94 | Gold |
| Nasal cavity epithelium | 87.86 | Silver |
| Transverse colon | 87.71 | Gold |
Pattern: Strong expression in GI tract epithelium (duodenum, jejunum, rectum, colon), immune cells (monocytes, leukocytes, lymph nodes), developing brain (ventricular zone, ganglionic eminence, cortical plate), and barrier tissues (nasopharynx, esophagus, conjunctiva). Average expression score across all tissues: 80.26, indicating consistent baseline expression.
Single-Cell Expression (SCXA / Single Cell Expression Atlas)
CASP3 is tracked across 5 distinct single-cell experiments with 451 cell type clusters:
- Maximum mean expression: 1,734.58 (SCXA TPM units)
- Average mean expression: 156.81
- Marker status: Present as a marker gene in all 5 experiments
The high variability in mean expression (max/avg ratio ~11) indicates strong cell-type specificity, with selective upregulation in apoptotic, activated immune, and rapidly differentiating cell populations.
Cell-Type Expression Patterns (Inferred from Tissue Data)
CASP3 shows enriched/specialized expression in:
| Cell Type Category | Tissues/Contexts |
|---|---|
| Immune cells | Monocytes, leukocytes, lymph nodes, secondary lymphoid tissues |
| Epithelial barriers | GI mucosa (intestinal, colonic), nasopharynx, esophagus, conjunctiva |
| Developmental | Ventricular zone, ganglionic eminence, cortical plate (neurogenesis), germ cells |
| Endocrine | Adrenal tissue |
| Connective tissue | Calcaneal tendon |
Expression Breadth Summary
- Ubiquitous (present in most tissues)
- High quality: 229 of 277 conditions with gold-standard evidence
- Tissue enrichment: Strongest in rapidly turning over epithelial tissues and immune-active sites where apoptosis is constitutive
- Gene function correlation: Expression pattern aligns with CASP3’s role as the executioner caspase in apoptosis—highly present where programmed cell death is active (GI epithelium renewal, immune surveillance, developmental neural pruning)
Disease associations
Mendelian / Monogenic Disease
No well-documented monogenic diseases are currently listed in curated gene-disease databases (GenCC, OMIM) for CASP3 mutations. While 27 CASP3 variants are recorded in ClinVar, most are classified as “Uncertain significance” with unspecified phenotypes, indicating insufficient evidence for a defined Mendelian disease phenotype.
Phenotype Associations
No direct Human Phenotype Ontology (HPO) terms are associated with CASP3 in current biobtree data.
Complex-Disease / GWAS Associations
| Trait/Disease | SNP | Mapped Gene | Effect Size (OR/Beta) | P-value | Study | First Author | Year |
|---|---|---|---|---|---|---|---|
| Kawasaki disease | rs2720378 | CASP3 | 0.83 [0.78-0.89] | 2 × 10⁻⁸ | GCST010979 | Johnson TA | 2020 |
| Kawasaki disease | rs2720378 | CASP3 | 0.741 [0.676-0.812] | 1 × 10⁻¹⁰ | GCST90013537 | Hoggart C | 2021 |
| Hippocampal volume in Alzheimer’s disease dementia | rs17488073 | IRF2* | 0.83 [0.54-1.12] | 2 × 10⁻⁷ | GCST006993 | Chung J | 2017 |
*CASP3 is listed as a reported gene for this variant, though mapped to IRF2. The variants are intronic mutations in the chromosome 4q35.1 region.
Key findings:
- Kawasaki disease shows the strongest association with CASP3 (two independent GWAS studies with p-values <1 × 10⁻⁸), suggesting a protective effect of the G allele
- The Alzheimer’s disease association appears secondary, with CASP3 as a reported gene in a region-level analysis