CASP9

Summary

CASP9 (caspase 9, HGNC:1511) is a protein-coding gene on chromosome 1p36.21, encoding Caspase-9 (P55211). Involved in the activation cascade of caspases responsible for apoptosis execution.

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein can undergo autoproteolytic processing and activation by the apoptosome, a protein complex of cytochrome c and the apoptotic peptidase activating factor 1; this step is thought to be one of the earliest in the caspase activation cascade. This protein is thought to play a central role in apoptosis and to be a tumor suppressor. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 842 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 111 total — 1 pathogenic
• GTEx eGene: eQTL in 45 tissues, sQTL in 40 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.99 (unconstrained)
• MANE Select transcript: NM_001229
• Interaction hub: 3,226 STRING partners (top 2% of genes corpus-wide)
• Notable: 111 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1511
Approved symbol	CASP9
Name	caspase 9
Location	1p36.21
Locus type	gene with protein product
Status	Approved
Aliases	MCH6, ICE-LAP6, APAF-3, PPP1R56
Ensembl gene	ENSG00000132906
Ensembl biotype	protein_coding
OMIM	602234
Entrez	842

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 6 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000333868

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 3, TSL 4: 1, TSL 5: 1

ENST00000333868, ENST00000348549, ENST00000375890, ENST00000400777, ENST00000424908, ENST00000440484, ENST00000447522, ENST00000469637, ENST00000474305, ENST00000546424, ENST00000546969, ENST00000922642, ENST00001004944, ENST00001004945, ENST00001012926, ENST00001012927, ENST00001012929, ENST00001130476, ENST00001145738

RefSeq mRNA: 3 — MANE Select: NM_001229 NM_001229, NM_001278054, NM_032996

CCDS: CCDS158, CCDS159, CCDS59995

Canonical transcript exons

ENST00000333868 — 9 exons

Exon	Start	End
ENSE00002686918	15524069	15524215
ENSE00003469239	15505990	15506079
ENSE00003485753	15504611	15504758
ENSE00003488698	15518110	15518395
ENSE00003501673	15506899	15507075
ENSE00003506519	15507873	15507907
ENSE00003572221	15493892	15494001
ENSE00003784959	15495273	15495452
ENSE00003843812	15491401	15493035

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 95.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9275 / max 169.9771, expressed in 1752 samples.

Highest expression (Bgee): adrenal tissue, uterine tube, ovary, secondary oocyte, pituitary gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CASP9 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 45 tissues and its splicing (sQTL) in 40 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 85 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	4.0e-78	+0.53	1:15581413:C:G
Thyroid	eqtl	2.4e-48	+0.39	1:15525539:C:T
Testis	sqtl	1.3e-44	-0.93	1:15553556:T:C
Thyroid	sqtl	4.3e-43	+0.88	1:15498916:A:T
Heart Atrial Appendage	eqtl	1.0e-41	+0.55	1:15524058:C:CGGGGGCG
Esophagus Muscularis	eqtl	1.1e-40	+0.41	1:15524058:C:CGGGGGCG
Colon Transverse	eqtl	1.6e-38	+0.52	1:15522556:T:A
Esophagus Mucosa	eqtl	1.6e-37	+0.39	1:15525539:C:T
Nerve Tibial	eqtl	8.2e-36	+0.41	1:15524058:C:CGGGGGCG
Lung	sqtl	9.6e-33	+0.82	1:15503318:G:A
Colon Sigmoid	eqtl	3.3e-31	+0.43	1:15505288:T:C
Stomach	eqtl	3.8e-31	+0.55	1:15539921:A:G
Adipose Subcutaneous	eqtl	6.1e-31	+0.40	1:15528844:A:C
Breast Mammary Tissue	eqtl	7.6e-31	+0.52	1:15525539:C:T
Nerve Tibial	sqtl	2.7e-30	+0.80	1:15523247:G:T
Prostate	eqtl	9.5e-29	+0.48	1:15552042:T:A
Heart Left Ventricle	eqtl	1.0e-28	+0.41	1:15505288:T:C
Adipose Visceral Omentum	eqtl	2.6e-28	+0.38	1:15521251:A:C
Lung	eqtl	3.0e-28	+0.41	1:15502731:T:C
Muscle Skeletal	sqtl	1.8e-27	+0.68	1:15523247:G:T

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
10456	10.1829	1717
10458	0.5401	298
10457	0.1343	39
10459	0.0527	17
10455	0.0175	4

Top tissues by expression

showing 100 of 294 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	95.93	gold quality
right uterine tube	UBERON:0001302	95.02	gold quality
left ovary	UBERON:0002119	94.66	gold quality
secondary oocyte	CL:0000655	93.03	gold quality
right ovary	UBERON:0002118	92.58	gold quality
pituitary gland	UBERON:0000007	92.33	gold quality
adenohypophysis	UBERON:0002196	92.11	gold quality
ovary	UBERON:0000992	91.91	gold quality
lower esophagus mucosa	UBERON:0035834	91.67	gold quality
right testis	UBERON:0004534	90.86	gold quality
apex of heart	UBERON:0002098	90.70	gold quality
left testis	UBERON:0004533	90.29	gold quality
left lobe of thyroid gland	UBERON:0001120	90.19	gold quality
right lobe of thyroid gland	UBERON:0001119	89.91	gold quality
thyroid gland	UBERON:0002046	89.81	gold quality
adrenal cortex	UBERON:0001235	89.57	gold quality
right adrenal gland cortex	UBERON:0035827	89.56	gold quality
mucosa of urinary bladder	UBERON:0001259	89.43	gold quality
oocyte	CL:0000023	89.33	gold quality
left adrenal gland cortex	UBERON:0035825	89.24	gold quality
right adrenal gland	UBERON:0001233	89.10	gold quality
adrenal gland	UBERON:0002369	89.04	gold quality
parotid gland	UBERON:0001831	88.92	gold quality
body of pancreas	UBERON:0001150	88.68	gold quality
left adrenal gland	UBERON:0001234	88.67	gold quality
left uterine tube	UBERON:0001303	88.64	gold quality
buccal mucosa cell	CL:0002336	88.59	gold quality
testis	UBERON:0000473	88.56	gold quality
male germ cell	CL:0000015	88.06	gold quality
sperm	CL:0000019	88.00	gold quality
olfactory bulb	UBERON:0002264	87.91	silver quality
body of uterus	UBERON:0009853	87.81	gold quality
endocervix	UBERON:0000458	87.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.37	gold quality
metanephros cortex	UBERON:0010533	87.19	gold quality
tongue squamous epithelium	UBERON:0006919	87.15	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.87	gold quality
spinal cord	UBERON:0002240	86.59	gold quality
putamen	UBERON:0001874	86.48	gold quality
caudate nucleus	UBERON:0001873	86.46	gold quality
type B pancreatic cell	CL:0000169	86.38	gold quality
metanephric glomerulus	UBERON:0004736	86.22	gold quality
cortex of kidney	UBERON:0001225	86.13	gold quality
ectocervix	UBERON:0012249	86.13	gold quality
pancreas	UBERON:0001264	86.12	gold quality
nucleus accumbens	UBERON:0001882	86.08	gold quality
epithelium of esophagus	UBERON:0001976	85.91	gold quality
renal glomerulus	UBERON:0000074	85.87	gold quality
nephron tubule	UBERON:0001231	85.74	gold quality
heart left ventricle	UBERON:0002084	85.50	gold quality
epithelium of bronchus	UBERON:0002031	85.48	gold quality
esophagus squamous epithelium	UBERON:0006920	85.44	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.42	gold quality
cardiac ventricle	UBERON:0002082	85.36	gold quality
seminal vesicle	UBERON:0000998	85.32	gold quality
mucosa of transverse colon	UBERON:0004991	85.32	gold quality
bronchus	UBERON:0002185	85.26	gold quality
cervix squamous epithelium	UBERON:0006922	85.25	silver quality
popliteal artery	UBERON:0002250	85.24	gold quality
tibial artery	UBERON:0007610	85.24	gold quality
gall bladder	UBERON:0002110	85.23	gold quality
middle temporal gyrus	UBERON:0002771	85.22	gold quality
bronchial epithelial cell	CL:0002328	85.19	gold quality
tibial nerve	UBERON:0001323	85.19	gold quality
prostate gland	UBERON:0002367	85.13	gold quality
metanephros	UBERON:0000081	85.09	gold quality
monocyte	CL:0000576	85.02	gold quality
right coronary artery	UBERON:0001625	84.99	gold quality
amygdala	UBERON:0001876	84.97	gold quality
amniotic fluid	UBERON:0000173	84.92	gold quality
blood	UBERON:0000178	84.88	gold quality
fallopian tube	UBERON:0003889	84.88	gold quality
squamous epithelium	UBERON:0006914	84.84	gold quality
leukocyte	CL:0000738	84.77	gold quality
mononuclear cell	CL:0000842	84.76	gold quality
female reproductive system	UBERON:0000474	84.75	gold quality
right frontal lobe	UBERON:0002810	84.71	gold quality
renal medulla	UBERON:0000362	84.66	gold quality
esophagus mucosa	UBERON:0002469	84.60	gold quality
adult mammalian kidney	UBERON:0000082	84.56	gold quality
right atrium auricular region	UBERON:0006631	84.42	gold quality
right lobe of liver	UBERON:0001114	84.40	gold quality
uterine cervix	UBERON:0000002	84.36	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.35	gold quality
sural nerve	UBERON:0015488	84.29	gold quality
prefrontal cortex	UBERON:0000451	84.18	gold quality
middle frontal gyrus	UBERON:0002702	84.18	gold quality
body of stomach	UBERON:0001161	84.14	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.07	gold quality
aorta	UBERON:0000947	84.02	gold quality
myometrium	UBERON:0001296	84.02	gold quality
esophagus	UBERON:0001043	83.96	gold quality
pharyngeal mucosa	UBERON:0000355	83.88	gold quality
heart	UBERON:0000948	83.86	gold quality
forebrain	UBERON:0001890	83.81	gold quality
cingulate cortex	UBERON:0003027	83.74	gold quality
gluteal muscle	UBERON:0002000	83.71	gold quality
gastrocnemius	UBERON:0001388	83.70	gold quality
lower esophagus	UBERON:0013473	83.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.63	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.39

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pancreas	tissue	35.7	medium
Pituitary gland	tissue	32.6
Adrenal gland	tissue	22.2	medium
Choroid plexus	tissue	17.1
Locus coeruleus	tissue	16.9
Nucleus accumbens	tissue	16.1
Hippocampus	tissue	15.6	medium
Postcentral gyrus	tissue	14.9
Frontal cortex	tissue	14.1
Ovary	tissue	13.6	low
Vagina	tissue	12.8	low
Testis	tissue	12.5	medium
Endometrium 1	tissue	12.2	medium
Skeletal muscle	tissue	11.9	low
Caudate putamen	tissue	11.9
Epididymis	tissue	11.8	medium
Fallopian tube	tissue	11.8	medium
Retina	tissue	11.4
Parathyroid gland	tissue	11.3	medium
Spinal cord	tissue	11.3
Bone marrow	tissue	10.8	medium
Corpus callosum	tissue	10.6
Substantia nigra	tissue	10.4
Prefrontal cortex	tissue	10.1
Cerebral cortex	tissue	10.1	medium
Motor cortex	tissue	10.1
Somatosensory cortex	tissue	10.1
Hippocampal formation	tissue	10.0
Medulla oblongata	tissue	9.9
Pons	tissue	9.8
Midbrain	tissue	9.6
Occipital cortex	tissue	9.4
Seminal vesicle	tissue	9.3	medium
Entorhinal cortex	tissue	9.2
Retrosplenial and cingulate cortex	tissue	9.2
Hypothalamus	tissue	9.1
Thalamus	tissue	9.0
Superior colliculi	tissue	9.0
Cerebellum	tissue	8.9	medium
Gallbladder	tissue	8.9	medium
Tongue	tissue	8.8
Insular cortex	tissue	8.8
Retrosplenial cortex	tissue	8.7
Thyroid gland	tissue	8.6	medium
Kidney	tissue	8.6	medium
Temporal cortex	tissue	8.6
Periaqueductal gray	tissue	8.2
Heart muscle	tissue	8.0	medium
Amygdala	tissue	8.0
Prostate	tissue	8.0	low
Thymus	tissue	8.0
Septum	tissue	8.0
Adipose tissue	tissue	7.9	low
Ventral forebrain	tissue	7.7
Liver	tissue	7.5	low
Small intestine	tissue	7.4	medium
Tonsil	tissue	7.4	medium
Putamen	tissue	7.3
Stomach 1	tissue	7.2	medium
Lung	tissue	7.2	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Parieto-temporal junction (white matter) (23.9), Corpus callosum, genu (white matter) (21.7), Flocculonodular lobe (21.2), Corpus callosum, splenium (white matter) (21.0), Nucleus tractus solitarii (20.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DDIT3, FOS, FOXO1, FOXO3, FOXP3, IRF1, MYC, MYCN, NFKB1, NKX3-1, PARP1, RARA, RELA, TP53

miRNA regulators (miRDB)

Targeting CASP9 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 56 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-130A-5P	99.33	70.26	2623

Functional genomics

gnomAD constraint: pLI 7e-08, LOEUF 0.994, missense Z -0.758 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000333868 — one region, missense o/e 1.07.

Literature-anchored findings (GeneRIF, showing 40)

• regulation of alternative splicing in lung adenocarcinoma cells by de novo ceramide (PMID:11801602)
• Caspase-9 at chromosome 1 reveal rare allelic variants in neuroblastoma tumors (PMID:11870543)
• inhibition of caspase-9 activity represents another mechanism of acquired cisplatin resistance (PMID:11905052)
• Activation of caspase-9 is required for UV-induced apoptosis of human keratinocytes (PMID:11919192)
• activation by an alternative mechanism virally infected cells beside the well characterized pathways via death receptors or mitochondrial cytochrome c release (PMID:12021264)
• Down-regulation of caspase-9 is involved during serum-factor dependent phagocytosis of platelets by monocytes. (PMID:12055227)
• Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. (PMID:12096338)
• Pro-CASP9 moved from the nucleus to the mitochondria of U937 cells during TPA-induced differentiation. (PMID:12145703)
• processing and activation upon dsRNA-dependent protein kinase expression (PMID:12372609)
• Data suggest that the expression levels of caspase 9 or caspase 9S do not play a major role in determining vulnerability to apoptosis in human astrocytoma cells. (PMID:12393263)
• blocks apocytochrome c activation and Bax-induced apoptosis (PMID:12393884)
• Presentation of nitric oxide regulates monocyte survival through effects on this enzyme and caspase-3 activation. (PMID:12566444)
• single amino acid substitutions at the dimer interface abrogate the activity of caspases-8 and -9 (PMID:12620239)
• aggregation of multiple procaspase-9 molecules can induce their activation independent of the apoptosome (PMID:12637514)
• Smac-induced apoptosis proceeds via a pathway mediated by caspase-9 that can be inhibited by zLEHD-fmk and overexpression of XIAP protein. (PMID:12749848)
• caspase-9 redistribution is a regulated process and requires the activity of a caspase other than the caspase-9- this is required to control the activity of caspase-9 (PMID:12782307)
• CASP 9 by itself can activate caspase 7 in the absence of the caspase 3-dependent pathway in TNF-alpha-induced apoptosis (PMID:12804035)
• caspase-9 is activated by reactive oxygen species (ROS) without involvement of cytochrome c release in hypoxic injury (PMID:12914932)
• caspase 9 is not critical for ultraviolet ray-induced apoptosis in tumor cells (PMID:12954616)
• AMF regulates expression of Apaf-1 and caspase-9 genes via a complex signaling pathway and indirectly regulates formation of the apoptosome. (PMID:14566819)
• Caspase-9 is activated in oxidized low-density lipoprotein (ox-LDL) induces apoptosis in endothelial cells. (PMID:14684629)
• S-nitrosation regulates activation of endogenous procaspase-9 in HT-29 cells (PMID:14701803)
• procaspase-9 is dimerized and processed by redox stress in mitochondria (PMID:14747474)
• RGDS directly binds and activates caspases 8 and 9, inhibits chemotaxis, and induces apoptosis of HUVECs with a mechanism independent from its antiadhesive effect. (PMID:14982875)
• caspase-9 activation in human disease can play a prominent role in localized cellular degenerative processes without causing nuclear or cell death. (PMID:14991812)
• the functional apoptosome complex in apoptotic cells consists primarily of Apaf-1 and processed caspase-9 (PMID:14993223)
• BCR-signal causes Bax translocation, followed by mitochondrial depolarization, and cytC release; subsequent caspase-9 activation can account for events further downstream (PMID:15214043)
• required for Parvovirus B19 virus-induced apoptosis in primary hepatocytes and hepatocellular carcinoma cell line HepG2 (PMID:15220451)
• Low-dose 5-aza-2’-deoxycytidine (DAC) induced enhancement of apoptosis mediated by Adenovirus-p53 infection, and ectopic overexpression of procaspase-9. (PMID:15273730)
• caspase-9 binds to NAIP in an ATP-dependent manner (PMID:15280366)
• Apollon binds to, ubiquitinates and facilitates proteasomal degradation of SMAC and caspase-9, results suggesting that Apollon has an essential function in preventing SMAC-induced apoptosis (PMID:15300255)
• These data suggest that increased proneness to caspase activation in lymphocytes could reflect an ongoing systemic response in neurodegenerative disease with pathogenetic implications. (PMID:15473998)
• ILP2 is an unstable protein, and cannot inhibit caspase 9 in a physiological way on its own; possibly ILP2 requires assistance from unidentified cellular factors to be an effective inhibitor of apoptosis in vivo (PMID:15485395)
• results suggest that ML-IAP might regulate apoptosis by sequestering Smac and preventing it from antagonizing XIAP-mediated inhibition of caspases, rather than by direct inhibition of caspases (PMID:15485396)
• Dopamine[DA] neurons were labeled and transduced with dominant negative Casp9. Progressive DA neuron lesion was induced by striatal 6-OHDA injection.Inhibiting apoptosis at caspase-9 is protective in vitro, but not in vivo. (PMID:15629764)
• caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress. (PMID:15657060)
• Gossypol induced complete cytochrome c release from mitochondria amd increased caspases-3 and -9 activity in large cell lymphoma cells. (PMID:15657349)
• Role for caspase-9 mediated cleavage of Raf-1 in the negative feedback regulation of hematopoietic cell apoptosis induced by growth factor withdrawal. (PMID:15674327)
• Protein kinase A regulates caspase-9 activation by Apaf-1 downstream of cytochrome c (PMID:15703181)
• OGG1 targeted to mitochondria reduces the activation of caspase-9 (PMID:15811855)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp9	ENSDARG00000004325
mus_musculus	Casp9	ENSMUSG00000028914
rattus_norvegicus	Casp9	ENSRNOG00000012944
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP6 (ENSG00000138794), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1277950) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 38 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal apoptosis	3
decreased neuron apoptosis	3
abnormal cerebral cortex morphology	2
abnormal lateral ventricle morphology	2
abnormal forebrain development	2
abnormal thymocyte apoptosis	2
abnormal embryonic neuroepithelial layer differentiation	1
abnormal telencephalon morphology	1
abnormal brain ventricle morphology	1
abnormal third ventricle morphology	1
abnormal brain development	1
exencephaly	1
abnormal telencephalon development	1
decreased body size	1
hydrocephaly	1
intracerebral hemorrhage	1
perinatal lethality	1
abnormal brain morphology	1
absent corpus callosum	1
abnormal brain commissure morphology	1
decreased cellular sensitivity to gamma-irradiation	1
abnormal neural tube closure	1
abnormal cell physiology	1
decreased apoptosis	1
decreased T cell apoptosis	1

+13 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	Q5IS54	99.6%	Diamond
Pongo abelii	Q5RD56	98.3%	Diamond
Macaca fascicularis	Q2PFV2	96.0%	Diamond
Saimiri boliviensis boliviensis	Q5IS99	96.0%	Diamond
Mesocricetus auratus	Q60431	92.1%	Diamond
Oryctolagus cuniculus	Q8MJC3	90.6%	Diamond
Felis catus	Q8MJU1	89.9%	Diamond
Canis lupus familiaris	Q8MKI5	89.9%	Diamond
Sus scrofa	Q95ND5	88.8%	Diamond
Bos taurus	Q3T0P5	88.3%	Diamond
Caenorhabditis remanei	P45436	84.5%	Diamond
Gallus gallus	F1NV61	73.9%	Diamond
Xenopus laevis	P55866	59.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
EFHD2-AS1	ncRNA	101927441
CTRC	protein-coding	11330
CELA2B	protein-coding	51032
CELA2A	protein-coding	63036
EFHD2	protein-coding	79180
DNAJC16	protein-coding	23341
AGMAT	protein-coding	79814
SCARNA21B	ncRNA	107397391

Protein

Protein identifiers

Caspase-9 — P55211 (reviewed: P55211)

Alternative names: Apoptotic protease Mch-6, Apoptotic protease-activating factor 3, ICE-like apoptotic protease 6

All UniProt accessions (8): A0A087WX72, F8VVS7, F8VWA5, H0Y3S8, H0Y6Y2, P55211, Q5JRU2, Q5JRU8

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates effector caspases caspase-3 (CASP3) or caspase-7 (CASP7). Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP). Cleaves BIRC6 following inhibition of BIRC6-caspase binding by DIABLO/SMAC. Lacks activity is an dominant-negative inhibitor of caspase-9.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts (inactive form) with EFHD2. Interacts with HAX1. Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Interacts with BCL2L10. Interacts with NleF from pathogenic E.coli.

Tissue specificity. Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. Within the heart, specifically expressed in myocytes.

Post-translational modifications. Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events. Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the response of cells to DNA damage. (Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP9 processing, preventing CASP9 activation and ability to mediate intrinsic apoptosis. Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC.

Activity regulation. Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis. Inhibited by BIRC6; following inhibition of BIRC6-caspase binding by DIABLO/SMAC, BIRC6 is subjected to caspase cleavage, leading to an increase in active caspases.

Miscellaneous. May function as an endogenous apoptotic inhibitor, inhibits the BAX-mediated cleavage of procaspase-3.

Similarity. Belongs to the peptidase C14A family.

Isoforms (4)

UniProt ID	Names	Canonical?
P55211-1	1, 9L, Alpha	yes
P55211-2	2, 9S, Beta
P55211-3	3, Gamma
P55211-4	4

RefSeq proteins (3): NP_001220, NP_001264983, NP_127463 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001309	Pept_C14_p20	Domain
IPR001315	CARD	Domain
IPR002138	Pept_C14_p10	Domain
IPR002398	Pept_C14	Family
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR011600	Pept_C14_caspase	Domain
IPR015917	Pept_C14A	Domain
IPR016129	Caspase_his_AS	Active_site
IPR029030	Caspase-like_dom_sf	Homologous_superfamily
IPR033139	Caspase_cys_AS	Active_site
IPR042147	CARD_CASP9	Domain

Pfam: PF00619, PF00656

Enzyme classification (BRENDA)

• EC 3.4.22.62 — caspase-9 (BRENDA: 11 organisms, 139 substrates, 67 inhibitors, 7 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-LEHD-7-AMIDO-4-TRIFLUOROMETHYL COUMARIN	0.466–0.686	2
ACETYL-LEHD-7-AMIDO-4-TRIFLUOROMETHYLCOUMARIN	0.466–0.686	2
ACETYL-VEHD-7-AMIDO-4-METHYLCOUMARIN	0.408–0.78	2
PROCASPASE-3	0.139	1

UniProt features (71 total): helix 18, strand 14, sequence variant 11, modified residue 6, turn 5, splice variant 4, sequence conflict 3, propeptide 2, chain 2, mutagenesis site 2, active site 2, domain 1, region of interest 1

Structure

Experimental structures (PDB)

13 structures by resolution:

PDB	Title	Method	Resolution (Å)
3D9T	CIAP1-BIR3 in complex with N-terminal peptide from Caspase-9 (ATPFQE)	X-RAY DIFFRACTION	1.5
4RHW	Crystal structure of Apaf-1 CARD and caspase-9 CARD complex	X-RAY DIFFRACTION	2.1
1NW9	STRUCTURE OF CASPASE-9 IN AN INHIBITORY COMPLEX WITH XIAP-BIR3	X-RAY DIFFRACTION	2.4
9R44	Crystal structure of human caspase-9 CARD	X-RAY DIFFRACTION	2.46
3YGS	APAF-1 CARD IN COMPLEX WITH PRODOMAIN OF PROCASPASE-9	X-RAY DIFFRACTION	2.5
1JXQ	Structure of cleaved, CARD domain deleted Caspase-9	X-RAY DIFFRACTION	2.8
2AR9	Crystal structure of a dimeric caspase-9	X-RAY DIFFRACTION	2.8
5WVC	Structure of the CARD-CARD disk	X-RAY DIFFRACTION	2.99
9S6F	Cryo-EM structure of human caspase-9 CARD (WT) filament	ELECTRON MICROSCOPY	3.3
3V3K	Human caspase 9 in complex with bacterial effector protein	X-RAY DIFFRACTION	3.49
9S6E	Cryo-EM structure of human caspase-9 CARD (H38R) mutant filament	ELECTRON MICROSCOPY	3.5
5JUY	Active human apoptosome with procaspase-9	ELECTRON MICROSCOPY	4.1
5WVE	Apaf-1-Caspase-9 holoenzyme	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55211-F1	80.86	0.55

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2)

Position	Role
237
287

Post-translational modifications (6)

Type	Positions
Phosphoserine	302, 307, 310
(microbial infection) adp-riboxanated arginine	355
Phosphothreonine	125
Phosphotyrosine	153

Mutagenesis-validated functional residues (2)

Position	Phenotype
153	inhibits tyrosine phosphorylation. reduces caspase-9 subunit p35 formation in response to genotoxic stress. attenuates abl1/c-abl-mediated …
355	abolished adp-riboxanation by c.violaceum copc.

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 25; 4 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

25 pathways:

ID	Pathway	Evidence
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer ⚕	curated
R-HSA-198323	AKT phosphorylates targets in the cytosol	curated
R-HSA-111459	Activation of caspases through apoptosome-mediated cleavage	curated
R-HSA-418889	Caspase activation via Dependence Receptors in the absence of ligand	curated
R-HSA-111458	Formation of apoptosome	curated
R-HSA-168638	NOD1/2 Signaling Pathway	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-2219528	PI3K/AKT Signaling in Cancer ⚕	—
R-HSA-109581	Apoptosis	—
R-HSA-111471	Apoptotic factor-mediated response	—
R-HSA-5357769	Caspase activation via extrinsic apoptotic signalling pathway	—
R-HSA-111461	Cytochrome c-mediated apoptotic response	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-9006925	Intracellular signaling by second messengers	—
R-HSA-109606	Intrinsic Pathway for Apoptosis	—
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	—
R-HSA-1257604	PIP3 activates AKT signaling	—
R-HSA-5357801	Programmed Cell Death	—
R-HSA-9627069	Regulation of the apoptosome activity	electronic
R-HSA-111463	SMAC (DIABLO) binds to IAPs	electronic
R-HSA-111464	SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	electronic
R-HSA-111469	SMAC, XIAP-regulated apoptotic response	—
R-HSA-162582	Signal Transduction	—

MSigDB gene sets: 366 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, REACTOME_INNATE_IMMUNE_SYSTEM, CHIBA_RESPONSE_TO_TSA_UP, GOBP_RESPONSE_TO_ESTRADIOL, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_METAL_ION

GO Biological Process (27): response to hypoxia (GO:0001666), kidney development (GO:0001822), response to ischemia (GO:0002931), apoptotic process (GO:0006915), DNA damage response (GO:0006974), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), protein processing (GO:0016485), platelet formation (GO:0030220), response to cobalt ion (GO:0032025), response to estradiol (GO:0032355), response to lipopolysaccharide (GO:0032496), glial cell apoptotic process (GO:0034349), cellular response to UV (GO:0034644), signal transduction in response to DNA damage (GO:0042770), positive regulation of apoptotic process (GO:0043065), positive regulation of neuron apoptotic process (GO:0043525), response to ethanol (GO:0045471), protein maturation (GO:0051604), cellular response to dexamethasone stimulus (GO:0071549), response to indole-3-methanol (GO:0071680), leukocyte apoptotic process (GO:0071887), response to anesthetic (GO:0072347), intrinsic apoptotic signaling pathway (GO:0097193), positive regulation of execution phase of apoptosis (GO:1900119), proteolysis (GO:0006508), response to UV (GO:0009411), regulation of apoptotic process (GO:0042981)

GO Molecular Function (10): cysteine-type endopeptidase activity (GO:0004197), enzyme activator activity (GO:0008047), peptidase activity (GO:0008233), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protease binding (GO:0002020), protein binding (GO:0005515), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), death domain binding (GO:0070513)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), protein-containing complex (GO:0032991), apoptosome (GO:0043293)

Reactome top-level categories

14 top-level categories:

Category	Pathways
Cytochrome c-mediated apoptotic response	2
SMAC, XIAP-regulated apoptotic response	2
Apoptotic factor-mediated response	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
PIP3 activates AKT signaling	1
Caspase activation via extrinsic apoptotic signalling pathway	1
PI3K/AKT Signaling in Cancer	1
Formation of apoptosome	1
Programmed Cell Death	1
Apoptosis	1
Intrinsic Pathway for Apoptosis	1
Intracellular signaling by second messengers	1
Immune System	1
Innate Immune System	1

GO top-level categories

55 GO namespaces:

Category	Terms
response to stress	2
DNA damage response	2
response to lipid	2
response to oxygen-containing compound	2
apoptotic process	2
response to alcohol	2
catalytic activity	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
response to decreased oxygen levels	1
animal organ development	1
renal system development	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
intrinsic apoptotic signaling pathway	1
proteolysis	1
protein maturation	1
myeloid cell differentiation	1
platelet morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to metal ion	1
response to molecule of bacterial origin	1
response to UV	1
cellular response to light stimulus	1
intracellular signal transduction	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
gene expression	1
protein metabolic process	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
response to nitrogen compound	1
endopeptidase activity	1
cysteine-type peptidase activity	1
enzyme regulator activity	1
molecular function activator activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
kinase binding	1
protein binding	1
enzyme binding	1
binding	1
peptidase activity	1
protein domain specific binding	1
intracellular anatomical structure	1
cellular_component	1
cytosol	1
protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 17 of 43 annotations. The rest are phylogenetic / computational / electronic (IEA).

17 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	direct assay
apoptotic process	BP	mutant phenotype
cellular response to UV	BP	direct assay
intrinsic apoptotic signaling pathway	BP	direct assay
intrinsic apoptotic signaling pathway in response to DNA damage	BP	mutant phenotype
positive regulation of apoptotic process	BP	mutant phenotype
positive regulation of execution phase of apoptosis	BP	direct assay
protein maturation	BP	direct assay
signal transduction in response to DNA damage	BP	direct assay
apoptosome	CC	direct assay
cytosol	CC	direct assay
mitochondrion	CC	direct assay
protein-containing complex	CC	direct assay
cysteine-type endopeptidase activity	MF	direct assay
identical protein binding	MF	physical interaction
peptidase activity	MF	direct assay
protein kinase binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,226 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP9	CYCS	P00001	978
CASP9	APAF1	O14727	977
CASP9	BCL2L1	Q07817	945
CASP9	BAX	P55269	938
CASP9	BCL2	P10415	934
CASP9	PARP1	P09874	904
CASP9	CASP3	P42574	893
CASP9	XIAP	P98170	893
CASP9	ANXA5	P08758	887
CASP9	TP53	P04637	882
CASP9	DIABLO	Q9NR28	881
CASP9	FADD	Q13158	847
CASP9	BCL2L11	O43521	837
CASP9	FASLG	P48023	832
CASP9	CASP7	P55210	825

IntAct

Human interaction partners of CASP9 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

20 partners by confidence:

Partner	Interaction type	MIscore	Records
XIAP	physical association	0.970	25
APAF1	direct interaction	0.960	19
BIRC7	physical association	0.920	13
BIRC2	physical association	0.920	12
CASP3	cleavage reaction	0.640	3
DCC	physical association	0.590	2
BIRC8	physical association	0.560	3
HTRA4	colocalization	0.550	2
BIRC5	physical association	0.540	2
BIRC3	physical association	0.520	2
CASP7	cleavage reaction	0.440	1
ILK	physical association	0.400	2
CARD8	physical association	0.400	1
NOD1	physical association	0.400	1
HSD17B4	physical association	0.370	1
MSTO1	physical association	0.370	1
HMGB1P1	association	0.350	1
HPRT1	association	0.350	1
BCL2L1	proximity	0.270	1
CYCS	proximity	0.270	1

BioGRID (154 interactions; top human partners by supporting records): XIAP (Two-hybrid; 30 records), APAF1 (Reconstituted Complex; 16 records), BIRC2 (Two-hybrid; 13 records), BIRC6 (Biochemical Activity; 8 records), BIRC3 (Affinity Capture-Western; 7 records), BIRC7 (Two-hybrid; 5 records), BIRC8 (Two-hybrid; 5 records), CASP3 (Co-localization; 5 records), ABL1 (Affinity Capture-Western; 3 records), CASP8 (Biochemical Activity; 3 records), HECTD3 (Affinity Capture-Western; 3 records), ARNT (Biochemical Activity; 2 records), ATG7 (Affinity Capture-Western; 2 records), BCL2L1 (Co-localization; 2 records), BIRC5 (Co-localization; 2 records)

SIGNOR signaling

showing 46 of 60 signaling interactions:

A	Effect	B	Mechanism
MAPK1	“down-regulates activity”	CASP9	phosphorylation
MAPK3	“down-regulates activity”	CASP9	phosphorylation
XIAP	“down-regulates quantity by destabilization”	CASP9	binding
AKT2	down-regulates	CASP9	phosphorylation
NAIP	down-regulates	CASP9	binding
ABL1	up-regulates	CASP9	phosphorylation
CASP3	“up-regulates activity”	CASP9	cleavage
CASP9	“up-regulates activity”	CASP3	cleavage
PRKACA	down-regulates	CASP9	phosphorylation
APAF1	“up-regulates activity”	CASP9	binding
CDK1	down-regulates	CASP9	phosphorylation
PRKCZ	down-regulates	CASP9	phosphorylation
CARD8	down-regulates	CASP9	binding
PPP1CA	up-regulates	CASP9	dephosphorylation
CyclinB/CDK1	down-regulates	CASP9	phosphorylation
PPP1CA	“up-regulates activity”	CASP9	dephosphorylation
AKT1	down-regulates	CASP9	phosphorylation
AKT1	“down-regulates activity”	CASP9	phosphorylation
“Caspase 3 complex”	“up-regulates activity”	CASP9	cleavage
PTMA	down-regulates	CASP9	binding
ANP32A	“up-regulates activity”	CASP9	binding
M	“up-regulates activity”	CASP9
3a	“up-regulates activity”	CASP9
ABL1	“up-regulates activity”	CASP9	phosphorylation
MYCT1	“up-regulates activity”	CASP9
Gbeta	“down-regulates activity”	CASP9	phosphorylation
ERK1/2	“down-regulates activity”	CASP9	phosphorylation
HECTD3	“down-regulates activity”	CASP9	polyubiquitination
DYRK1A	“down-regulates activity”	CASP9	phosphorylation
APAF1	up-regulates	CASP9	binding
CYCS	“up-regulates activity”	CASP9	binding
BCL2L1	“down-regulates activity”	CASP9	binding
BIRC3	down-regulates	CASP9	binding
AKT3	down-regulates	CASP9	phosphorylation
AKT	“down-regulates activity”	CASP9	phosphorylation
DIABLO	up-regulates	CASP9
BIRC5	down-regulates	CASP9	binding
CASP12	up-regulates	CASP9	cleavage
MAP2K1	“down-regulates activity”	CASP9	phosphorylation
MAP2K2	“down-regulates activity”	CASP9	phosphorylation
CASP9	“form complex”	“Caspase 9 complex”	binding
CASP9	“form complex”	Apoptosome	binding
“Caspase 8 complex”	“up-regulates activity”	CASP9
MEK1/2	“down-regulates activity”	CASP9	phosphorylation
SRC	“up-regulates activity”	CASP9	phosphorylation
CASP8	“up-regulates activity”	CASP9

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
Aposome complex	4	APAF1, CASP3, CASP7, CASP9
Apoptosome, 700 kDa	3	APAF1, CASP9, CYCS
NAIP-CASP9 complex	2	CASP9, NAIP

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Intrinsic Pathway for Apoptosis	5	91.5×	3e-08
Programmed Cell Death	7	64.0×	2e-10
Apoptosis	6	63.0×	7e-09
Cytokine Signaling in Immune system	5	12.8×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein ubiquitination	5	56.1×	2e-06
neuron apoptotic process	5	48.7×	3e-06
regulation of apoptotic process	6	26.3×	4e-06
regulation of cell cycle	5	19.6×	1e-04
positive regulation of canonical NF-kappaB signal transduction	5	19.1×	1e-04
negative regulation of apoptotic process	7	12.8×	2e-05

Disease & clinical

Genetic variants

Variant evidence for CASP9: 111 ClinVar records (1 pathogenic / likely pathogenic); 20 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

111 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	71
Likely benign	15
Benign	13

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2446820	NC_000001.10:g.4481271_20530242del	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CASP9’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 937):

Position(s)	Effect	Δscore	Sites
1:15495271–15495272	donor_loss	1.0000	4
1:15495453–15495454	acceptor_loss	1.0000	6
1:15504609–15504610	donor_loss	1.0000	4
1:15504648	donor_gain	1.0000
1:15504760	acceptor_loss	1.0000
1:15506897–15506898	donor_loss	1.0000	3
1:15518108–15518109	donor_loss	1.0000	5
1:15524068	donor_loss	1.0000	2
1:15494002–15494003	acceptor_loss	0.9900	5
1:15495271	donor_loss	0.9900

AlphaMissense

712 missense substitutions predicted likely pathogenic (of 2,720 scored), across 192 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D340	8	0.955	0.988
D186	8	0.915	0.952
H237	8	0.900	0.965
F35	8	0.882	0.965
F413	8	0.868	0.972
F282	8	0.861	0.979
D293	8	0.848	0.940
F194	8	0.847	0.958
F73	8	0.804	0.974
F267	8	0.790	0.971
F171	7	0.937	0.988
C287	7	0.914	0.957
F199	7	0.912	0.967
F406	7	0.882	0.969
W362	7	0.881	0.944
C163	7	0.875	0.984
W354	7	0.874	0.934
F246	7	0.872	0.959
R355	7	0.869	0.974
F351	7	0.864	0.985

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	0.000128

Disease associations

OMIM: gene MIM:602234 | disease phenotypes: MIM:607872

GenCC curated gene-disease

Mondo (1): chromosome 1p36 deletion syndrome (MONDO:0011929)

Orphanet (1): 1p36 deletion syndrome (Orphanet:1606)

GWAS associations

20 associations:

Study	Trait	p-value
GCST012020_469	Serum metabolite levels	7e-50
GCST009733_51	Urinary metabolite levels in chronic kidney disease	1e-44
GCST009733_16	Urinary metabolite levels in chronic kidney disease	6e-31
GCST004860_93	Alcoholic chronic pancreatitis	3e-22
GCST004860_131	Alcoholic chronic pancreatitis	1e-16
GCST004860_144	Alcoholic chronic pancreatitis	1e-11
GCST007344_35	Estimated glomerular filtration rate	2e-10
GCST007344_103	Estimated glomerular filtration rate	3e-10
GCST004292_1	Glomerular filtration rate (creatinine)	1e-9
GCST003372_32	Glomerular filtration rate (creatinine)	2e-9
GCST003401_5	Glomerular filtration rate in non diabetics (creatinine)	5e-9
GCST004860_85	Alcoholic chronic pancreatitis	6e-9
GCST008971_79	Urate levels	8e-9
GCST007344_112	Estimated glomerular filtration rate	2e-7
GCST012362_1	Orofacial cleft x maternal periconceptional multivitamin use interaction (2df)	3e-7
GCST004860_119	Alcoholic chronic pancreatitis	6e-7
GCST012365_1	Orofacial cleft x maternal periconceptional multivitamin use interaction (1df)	9e-7
GCST004860_142	Alcoholic chronic pancreatitis	3e-6
GCST004860_97	Alcoholic chronic pancreatitis	3e-6
GCST007344_86	Estimated glomerular filtration rate	3e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0005116	urinary metabolite measurement
EFO:0009116	vitamin supplement exposure measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C535362	Chromosome 1p36 Deletion Syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2273 (SINGLE PROTEIN), CHEMBL3831289 (PROTEIN FAMILY), CHEMBL3885517 (PROTEIN COMPLEX)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CASP9 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
NIVOCASAN	Small molecule	2

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs4661636		Efficacy	Allele C is associated with increased severity of Leukocytosis in children with Acute lymphoblastic leukemia as compared to allele T.	PMID:39733427
rs1052576		Efficacy	Allele T is associated with increased severity of Leukocytosis in children with Acute lymphoblastic leukemia as compared to allele C.	PMID:39733427

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C14: Caspase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
isatin sulfonamide 34 [PMID: 11384246]	Inhibition	6.92	pKi

Binding affinities (BindingDB)

412 measured of 498 human assays (523 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3S)-3-[[2-[4-(benzenesulfonyl)piperazin-1-yl]acetyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid	IC50	2 nM	US-11447497: (S)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases
(3S)-3-[[2-(4-benzyl-2-oxopiperazin-1-yl)acetyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid	IC50	4 nM	US-11447497: (S)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases
(3S)-3-[[2-(4-benzyl-3-oxopiperazin-1-yl)acetyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid	IC50	9 nM	US-11447497: (S)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases
2-(2-((S)-2-(benzyloxycarbonyl)-3-methylbutanamido)benzamido)-4-fluoro-3-oxobutanoic acid	IC50	12 nM
CHEMBL1091826	EC50	16 nM
CHEMBL2323966	IC50	20 nM
3-[(S)-2-(2,4-Dichloro-benzyloxycarbonylamino)-3-methyl-butyrylamino]-5-fluoro-4-oxo-pentanoic acid	IC50	25 nM
CHEMBL2324340	IC50	26 nM
SMR000278513	IC50	57.2 nM
(3S)-3-[[2-(4-benzyl-3-oxopiperazin-1-yl)acetyl]amino]-4-oxo-5-[2-(trifluoromethyl)pyrimidin-4-yl]oxypentanoic acid	IC50	65 nM	US-11447497: (S)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases
Methylene Blue anhydrous	KI	110 nM
cid_1002248	EC50	210 nM
CHEMBL4460352	EC50	240 nM
(2S)-1-[(2S)-3,3-dimethyl-2-[(2S)-2-(methylamino)propanamido]butanoyl]-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide	EC50	290 nM
Z-Asp-(D,L Ala(2’-quinolyl))-Val- Aspphenyl vinylsulfone	IC50	300 nM	US-10167313: Selective caspase inhibitors and uses thereof
CHEMBL4459769	EC50	310 nM
SMR000151472	IC50	335 nM
cid_9549688	IC50	411 nM
8-fluoranylindolo[2,1-b]quinazoline-6,12-dione	IC50	433 nM
(NE)-N-[3-[(4-hydroxyphenyl)amino]-4-oxidanylidene-naphthalen-1-ylidene]-4-methoxy-benzenesulfonamide	IC50	441 nM
MLS002153809	IC50	443 nM
MLS000585839	IC50	453 nM
(4S)-5-[[(2S)-1-[[(E,2S)-1-carboxy-4-methylsulfonylbut-3-en-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-[[(2S)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-5-oxopentanoic acid	IC50	500 nM	US-9045524: Selective caspase inhibitors and uses thereof
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	700 nM	US-9045524: Selective caspase inhibitors and uses thereof
SMR000186252	IC50	707 nM
cid_4422714	IC50	798 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)acetyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	900 nM	US-9045524: Selective caspase inhibitors and uses thereof
1-Decyloxycarbonylmethyl-3-methyl-2-o-tolyloxymethyl-3H-benzoimidazol-1-ium	EC50	1020 nM
(6E)-6-[[[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]hydrazo]methylidene]-1-cyclohexa-2,4-dienone	IC50	1030 nM
CHEMBL2324341	IC50	1050 nM
2-[[2-[2-(dimethylamino)ethylamino]-1-oxoethyl]amino]-4-(4-phenylphenyl)-3-thiophenecarboxylic acid ethyl ester;hydrochloride	EC50	1090 nM
N2,N2,N4,N4-tetramethyl-N6-[(phenylmethylidene)amino]pyrimidine-2,4,6-triamine	IC50	1100 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-quinolin-2-ylpropanoyl]amino]-3-methylbutanoyl]amino]-5-phenoxysulfonylpent-4-enoic acid	IC50	1200 nM	US-9045524: Selective caspase inhibitors and uses thereof
MLS002471441	IC50	1220 nM
SMR000516584	IC50	1270 nM
(E,3S)-5-(benzenesulfonyl)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]pent-4-enoic acid	IC50	1300 nM	US-9045524: Selective caspase inhibitors and uses thereof
MLS000071738	IC50	1310 nM
cid_738951	IC50	1380 nM
(4S)-5-[[(2S)-1-[[(E,2S)-1-carboxy-4-methylsulfonylbut-3-en-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-5-oxopentanoic acid	IC50	1400 nM	US-9045524: Selective caspase inhibitors and uses thereof
3-(4-fluorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid	EC50	1450 nM
SMR000313158	IC50	1480 nM
6-bromo-3-(2-methoxyanilino)-2H-isoquinolin-1-one	IC50	1510 nM
1,3,6-Trimethyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1610 nM
N-[[1,3-bis(oxidanylidene)inden-2-ylidene]amino]benzamide	IC50	1660 nM
1-Decyloxycarbonylmethyl-3-methyl-2-p-tolyloxymethyl-3H-benzoimidazol-1-ium	EC50	1800 nM
MLS000590906	IC50	1800 nM
methyl 2-[[(4E)-1-oxidanylidene-4-thiophen-2-ylsulfonylimino-naphthalen-2-yl]amino]benzoate	IC50	1820 nM
cid_2851959	IC50	1840 nM
SMR000151319	IC50	1850 nM
1,2-Dione-Based Compound, 14	IC50	1920 nM

ChEMBL bioactivities

53 potent at pChembl≥5 of 82 total, top 47 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5715932
8.68	IC50	2.1	nM	CHEMBL5715925
8.30	IC50	5	nM	CHEMBL23226
8.22	IC50	6	nM	CHEMBL237310
8.05	IC50	9	nM	CHEMBL185356
7.80	EC50	16	nM	CHEMBL1091826
7.52	IC50	30	nM	CHEMBL180263
7.46	IC50	35	nM	CHEMBL5715934
7.42	IC50	38	nM	CHEMBL5792878
7.32	Ki	48	nM	CHEMBL5723323
7.31	IC50	49.2	nM	CHEMBL5715921
7.14	IC50	72.8	nM	CHEMBL5723349
6.97	IC50	107	nM	CHEMBL5822466
6.92	Ki	120	nM	CHEMBL439753
6.91	IC50	122	nM	CHEMBL6026985
6.80	IC50	160	nM	CHEMBL90224
6.67	AC50	214	nM	CHEMBL1325945
6.64	IC50	230	nM	CHEMBL90307
6.62	EC50	240	nM	CHEMBL4460352
6.62	IC50	240	nM	CHEMBL5715929
6.54	EC50	290	nM	CHEMBL2096803
6.52	IC50	300	nM	CHEMBL3673267
6.51	EC50	310	nM	CHEMBL4459769
6.50	AC50	317	nM	CHEMBL1463659
6.30	IC50	500	nM	CHEMBL3673265
6.30	IC50	500	nM	CHEMBL3673259
6.10	IC50	800	nM	CHEMBL2324339
6.07	Ki	850	nM	CHEMBL1907830
6.00	IC50	1000	nM	CHEMBL2324341
6.00	IC50	1000	nM	CHEMBL5752244
5.96	IC50	1100	nM	CHEMBL2323967
5.96	Ki	1100	nM	CHEMBL60190
5.92	IC50	1200	nM	CHEMBL3673259
5.92	Ki	1200	nM	CHEMBL62993
5.87	AC50	1340	nM	CHEMBL1210769
5.80	IC50	1600	nM	CHEMBL3678067
5.76	IC50	1740	nM	CHEMBL2324340
5.64	IC50	2300	nM	CHEMBL2323966
5.57	IC50	2720	nM	CHEMBL330535
5.55	IC50	2800	nM	CHEMBL3678074
5.52	AC50	3040	nM	CHEMBL1522941
5.52	IC50	3000	nM	CHEMBL4438921
5.30	IC50	5000	nM	CHEMBL3287898
5.30	IC50	5000	nM	GRASSYSTATIN A
5.30	Ki	5000	nM	CHEMBL60306
5.14	Ki	7200	nM	CHEMBL293622
5.00	AC50	1.009e+04	nM	CHEMBL1707033

PubChem BioAssay actives

37 with measured affinity, of 116 total; 31 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-fluoro-3-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-4-oxopentanoic acid	49729: Compound was evaluated for its inhibitory activity against the Caspase-9 enzyme	ic50	0.0050	uM
4-fluoro-2-[[2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]benzoyl]amino]-3-oxobutanoic acid	302018: Inhibition of human caspase 9	ic50	0.0060	uM
3-[[(2S)-2-[(2,4-dichlorophenyl)methoxycarbonylamino]-3-methylbutanoyl]amino]-5-fluoro-4-oxopentanoic acid	240705: Inhibition concentration required against caspase-9	ic50	0.0090	uM
N-(4-methoxyphenyl)-N-methyl-1,2,3-benzotriazin-4-amine	1393168: Activation of caspase cascade in human T47D cells using N-(Ac-DEVD)-N’-ethoxycarbonyl-R110 fluorogenic substrate incubated for 48 hrs by fluorescent plate reader based assay	ec50	0.0160	uM
5-fluoro-3-[[(2S)-3-methyl-2-(phenylcarbamoyloxy)butanoyl]amino]-4-oxopentanoic acid	240593: Inhibitory concentration against Caspase-9	ic50	0.0300	uM
1-benzyl-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	0.1200	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49728: Binding affinity towards human Caspase-9	ic50	0.1600	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)-2-oxoacetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49728: Binding affinity towards human Caspase-9	ic50	0.2300	uM
(2S,3R)-1-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-phenoxy-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide	1553567: Inhibition of N-terminal CARD domain of caspase 9 (unknown origin)	ec50	0.2400	uM
(2S)-1-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide	1553567: Inhibition of N-terminal CARD domain of caspase 9 (unknown origin)	ec50	0.2900	uM
2-[4-(3-oxo-1H-isoindol-2-yl)phenyl]propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.3000	uM
(2S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide	1553567: Inhibition of N-terminal CARD domain of caspase 9 (unknown origin)	ec50	0.3100	uM
4-oxo-4-(4-phenylphenyl)butanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.7600	uM
(E,3S)-3-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	0.8000	uM
Ketorolac	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.8500	uM
5-[(2S)-2-(anilinomethyl)pyrrolidin-1-yl]sulfonyl-1H-indole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	0.8500	uM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-phenylacetyl]amino]-3-methylbutanoyl]amino]-6-ethoxy-6-oxohex-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	1.0000	uM
(E,3S)-3-[[(2S)-1-[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3,3-dimethylbutanoyl]azetidine-2-carbonyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	1.1000	uM
5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl-1H-indole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	1.1000	uM
5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl-1H-indole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	1.2000	uM
(E,3S)-3-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-3-(1H-indol-3-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	1.7400	uM
2-(4-phenylphenyl)acetic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	1.8000	uM
2-(5-benzoylthiophen-2-yl)propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	2.2000	uM
(E,3S)-3-[[(2S)-1-[(2R)-2-[(4-amino-3-chlorobenzoyl)amino]-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	2.3000	uM
(3S)-3-[[(2S)-4-methyl-2-[(2-naphthalen-1-yloxyacetyl)amino]pentanoyl]amino]-4-oxobutanoic acid	49728: Binding affinity towards human Caspase-9	ic50	2.7200	uM
N-[(E)-1,3-benzodioxol-5-ylmethylideneamino]-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxamide	1653209: Activation of caspase 9 in human SMMC7721 cells	ic50	3.0000	uM
2-[4-(2-methylpropyl)phenyl]propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	4.9000	uM
1-benzyl-5-nitroindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	5.0000	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S,3R)-2-[[(3S,4S)-4-[[(2S)-4-amino-2-[[(2S)-2-[[(2R)-2-[(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanoyl]oxy-3-methylbutanoyl]oxy-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxy-6-methylheptanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	448867: Inhibition of caspase 9 after 10 to 15 mins by fluorescence assay	ic50	5.0000	uM
2-[4-[4-[(2R)-4-[(2-ethylphenyl)carbamoyl]-2-methyl-2,3-dihydro-1,4-benzoxazin-7-yl]phenyl]cyclohexyl]acetic acid	1155020: Inhibition of CASP9 (unknown origin)	ic50	5.0000	uM
1-methyl-5-nitroindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	7.2000	uM

CTD chemical–gene interactions

1043 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases cleavage, decreases reaction, increases activity, decreases expression, increases expression (+3 more)	53
Doxorubicin	increases activity, decreases response to substance, affects binding, decreases activity, increases expression (+9 more)	46
Cisplatin	decreases reaction, increases activity, increases response to substance, increases reaction, affects cotreatment (+4 more)	44
Quercetin	affects activity, increases cleavage, increases reaction, decreases expression, decreases reaction (+6 more)	41
Acetylcysteine	increases cleavage, increases reaction, decreases expression, affects activity, increases activity (+5 more)	40
Bortezomib	affects cotreatment, increases activity, increases expression, increases response to substance, affects reaction (+4 more)	33
Resveratrol	increases expression, increases reaction, decreases activity, affects cotreatment, increases cleavage (+2 more)	31
Hydrogen Peroxide	increases cleavage, increases reaction, decreases reaction, increases expression, increases activity (+3 more)	18
Plant Extracts	increases cleavage, decreases reaction, increases activity, decreases expression, increases expression (+1 more)	18
benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone	increases activity, increases cleavage, affects cotreatment, increases expression, affects reaction (+3 more)	17
Fluorouracil	increases activity, affects cotreatment, decreases reaction, decreases expression, increases reaction (+4 more)	17
Paclitaxel	decreases expression, increases cleavage, affects cotreatment, increases activity, affects reaction (+6 more)	16
Curcumin	increases expression, increases reaction, increases activity, decreases reaction, decreases expression (+2 more)	13
bisphenol A	increases expression, decreases reaction, affects cotreatment, decreases expression, increases cleavage (+1 more)	12
sodium arsenite	affects response to substance, increases response to substance, decreases reaction, decreases response to substance, increases cleavage (+8 more)	11
hydroquinone	decreases expression, increases activity, increases cleavage, increases expression, decreases reaction	11
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, affects cotreatment, increases cleavage, increases expression, decreases activity (+3 more)	11
pyrazolanthrone	decreases reaction, increases cleavage, increases expression, increases activity, increases reaction	11
Paraquat	affects cotreatment, decreases reaction, increases reaction, decreases cleavage, increases expression (+4 more)	11
3-methyladenine	affects cotreatment, increases expression, increases activity, decreases reaction, increases cleavage (+2 more)	10
Etoposide	affects expression, increases reaction, affects cotreatment, affects reaction, increases activity (+2 more)	10
Cadmium Chloride	decreases expression, increases abundance, affects phosphorylation, increases reaction, increases cleavage (+3 more)	10
Celecoxib	increases cleavage, increases reaction, affects cotreatment, increases activity, decreases reaction	9
Sorafenib	affects cotreatment, decreases reaction, increases cleavage, increases activity, increases reaction	9
Tretinoin	increases activity, increases cleavage, increases reaction, increases expression, affects cotreatment	9
Staurosporine	affects response to substance, increases activity, increases cleavage	9
Particulate Matter	increases activity, decreases expression, increases secretion, decreases reaction, increases abundance (+5 more)	9
SB 203580	increases activity, decreases reaction, increases cleavage, affects cotreatment	8
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases cleavage, increases activity, increases expression, increases reaction (+2 more)	8
pifithrin	affects cotreatment, increases reaction, decreases reaction, increases cleavage, increases activity	8

ChEMBL screening assays

65 unique, capped per target: 63 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1020511	Binding	Inhibition of caspase 9 assessed as ratio of rate constant k3 to Ki for enzyme	Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease. — *Bioorg Med Chem Lett*
CHEMBL5723108	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002190aAD CASP9	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 2 telomerase immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1A9	Abcam THP-1 CASP9 KO	Cancer cell line	Male
CVCL_C6VW	MSOD	Telomerase immortalized cell line	Female
CVCL_C6VX	MSOD-B	Telomerase immortalized cell line	Female
CVCL_D7LT	Ubigene A-549 CASP9 KO	Cancer cell line	Male
CVCL_D8II	Ubigene HCT 116 CASP9 KO	Cancer cell line	Male
CVCL_D9B3	Ubigene HEK293 CASP9 KO	Transformed cell line	Female
CVCL_D9ZI	Ubigene HeLa CASP9 KO	Cancer cell line	Female
CVCL_KT46	HeLa SilenciX Caspase 9	Cancer cell line	Female
CVCL_SH00	HAP1 CASP9 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

2 trials:

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CASP9 across ~30M SureChEMBL compounds — explore on Sugi Predict.