CACYBP

Summary

CACYBP (calcyclin binding protein, HGNC:30423) is a protein-coding gene on chromosome 1q25.1, encoding Calcyclin-binding protein (Q9HB71). May be involved in calcium-dependent ubiquitination and subsequent proteasomal degradation of target proteins.

The protein encoded by this gene is a calcyclin binding protein. It may be involved in calcium-dependent ubiquitination and subsequent proteosomal degradation of target proteins. It probably serves as a molecular bridge in ubiquitin E3 complexes and participates in the ubiquitin-mediated degradation of beta-catenin. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 27101 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 33 total
• Druggable target: yes
• MANE Select transcript: NM_014412

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30423
Approved symbol	CACYBP
Name	calcyclin binding protein
Location	1q25.1
Locus type	gene with protein product
Status	Approved
Aliases	SIP, S100A6BP
Ensembl gene	ENSG00000116161
Ensembl biotype	protein_coding
OMIM	606186
Entrez	27101

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 4 retained_intron

ENST00000367679, ENST00000405362, ENST00000406752, ENST00000426793, ENST00000461977, ENST00000469173, ENST00000473925, ENST00000483307, ENST00000613570, ENST00000901095, ENST00000924681, ENST00000924682, ENST00000924683, ENST00000924684

RefSeq mRNA: 2 — MANE Select: NM_014412 NM_001007214, NM_014412

CCDS: CCDS1315, CCDS30942

Canonical transcript exons

ENST00000367679 — 6 exons

Exon	Start	End
ENSE00001273868	174999947	175000195
ENSE00001848785	175009923	175012027
ENSE00002211810	175008609	175008706
ENSE00003608693	175007098	175007197
ENSE00003662941	175004614	175004833
ENSE00003679857	175006745	175006841

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 113.6287 / max 1883.5826, expressed in 1827 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6814	63.8114	1821
6813	43.3437	1820
6816	2.8743	1056
6812	1.5610	901
6811	0.6895	401
6815	0.6059	331
6810	0.2989	97
6809	0.2285	75
6817	0.2154	60

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.03	gold quality
pons	UBERON:0000988	98.25	gold quality
postcentral gyrus	UBERON:0002581	98.18	gold quality
entorhinal cortex	UBERON:0002728	98.12	gold quality
superior frontal gyrus	UBERON:0002661	98.02	gold quality
parietal lobe	UBERON:0001872	97.95	gold quality
middle temporal gyrus	UBERON:0002771	97.93	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.85	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.84	gold quality
orbitofrontal cortex	UBERON:0004167	97.65	gold quality
ventricular zone	UBERON:0003053	97.64	gold quality
superior vestibular nucleus	UBERON:0007227	97.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.36	gold quality
choroid plexus epithelium	UBERON:0003911	97.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.22	gold quality
calcaneal tendon	UBERON:0003701	97.22	gold quality
prefrontal cortex	UBERON:0000451	97.19	gold quality
cortical plate	UBERON:0005343	97.10	gold quality
hypothalamus	UBERON:0001898	97.07	gold quality
temporal lobe	UBERON:0001871	97.06	gold quality
ganglionic eminence	UBERON:0004023	97.06	gold quality
right frontal lobe	UBERON:0002810	97.04	gold quality
CA1 field of hippocampus	UBERON:0003881	97.02	gold quality
substantia nigra pars compacta	UBERON:0001965	96.99	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.95	gold quality
cingulate cortex	UBERON:0003027	96.94	gold quality
nucleus accumbens	UBERON:0001882	96.91	gold quality
occipital lobe	UBERON:0002021	96.90	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	2534.66
E-CURD-10	yes	1517.83
E-HCAD-13	yes	20.90
E-HCAD-1	yes	18.58
E-CURD-89	no	1968.67
E-GEOD-98556	no	1523.90
E-MTAB-10137	no	953.46
E-CURD-120	no	6.96
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

86 targeting CACYBP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4760-5P	99.80	69.88	1619

Literature-anchored findings (GeneRIF, showing 40)

• investigation of interaction with Siah1 (PMID:12421809)
• the translocation of CacyBP during the retinoic acid-induced differentiation of neuroblastoma SH-SY5Y cells suggested that this protein might play a role in neuronal differentiation (PMID:12895292)
• SIP engages Siah1 by means of two elements, both of which are required for mediating beta-catenin destruction in cells (PMID:16085652)
• Taken together, our work showed that CacyBP/SIP, as a novel down-regulated gene in renal cell carcinoma, suppressed proliferation and tumorigenesis of renal cancer cells. (PMID:17400182)
• CacyBP/SIP may be a potential inhibitor of cell growth and invasion in the gastric cancer cell, at least in part through the effect on beta-catenin protein expression and transcriptional activation of Tcf/LEF (PMID:18171983)
• The first study on the CacyBP/SIP expression pattern in a broad range of human normal and tumor tissues. (PMID:18443365)
• CacyBP/SIP protein might play an important role in the process of pancreatic carcinogenesis and high-level CacyBP/SIP expression might be related to the malignant potential of pancreatic cancer. (PMID:18765951)
• Poor cellular differentiation, lymph node invasion, and clinicopathological staging in breast cancer were associated with CacyBP/SIP expression. (PMID:20585948)
• CacyBP regulation of COX-2 expression may play an important role in human breast carcinogenesis (PMID:20878073)
• CacyBP/SIP exhibits a phosphatase activity toward ERK1/2 kinases while its E217K mutant does not. (PMID:21110948)
• Data show that CacyBP/SIP might develop into another possible therapeutic target. (PMID:21268134)
• CACYBP is associated with acute lung injury in mice (PMID:21297076)
• new insight into the interaction between S100 proteins and CacyBP/SIP (PMID:22295074)
• different activity of CacyBP/SIP in neuroblastoma NB2a and colon cancer HCT116 cells might affect the ERK1/2 pathway in the differentiation or proliferation processes (PMID:22480271)
• These findings reveal a novel function for SNRK in the regulation of colon cancer cell proliferation and beta-catenin signaling. (PMID:22874833)
• CacyBP enhances multidrug resistance of pancreatic cancer cells by regulation of P-gp and Bcl-2. (PMID:23463283)
• This study presents CacyBP as a promising candidate biomarker for colorectal cancer (CRC) metastasis and also sheds light on the underlying molecular mechanism by which CacyBP promotes CRC metastasis. (PMID:23543800)
• Overexpression of CacyBP is associated with glioma. (PMID:24740456)
• CacyBP/SIP nuclear translocation promotes the proliferation and cell cycle progression of gastric cancer cells. (PMID:25110433)
• CacyBP/SIP is a useful indicator of dis processes in Chronic Lymphocytic Leukemia (CLL) and plays an important role in sustaining the balance of cell proliferation and apoptosis. (PMID:26603518)
• CacyBP/SIP plays an important role in inhibiting apoptosis of glioma cells which might be mediated by ERK1/2 signaling pathway. (PMID:26825673)
• The biological characteristics and target proteins of CacyBP/SIP and its exact role in various cancers are discussed. Review. (PMID:26873490)
• CacyBP/SIP nuclear translocation contributes to the proliferation of gastric cancer cells, and CacyBP/SIP exerts this effect, at least in part, by stimulating ubiquitin-mediated degradation of p27Kip1. (PMID:27099442)
• These results suggest that CacyBP/SIP may be promoting growth of colon cancer cells by enhancing ubiquitin-mediated degradation of p27kip1. (PMID:28196083)
• Our data have shown for the first time the regulation of CacyBP/SIP gene expression by NFAT1. Since NFAT transcription factors are involved in processes related to immune response, these results indicate potential involvement of CacyBP/SIP in the immune system. (PMID:28526484)
• Results suggest that CacyBP/SIP plays an important role in inhibiting glioma cell migration and invasion through promoting the degradation of cytoplasmic p27. (PMID:29024247)
• CacyBP/SIP nuclear localization, dependent on S100 protein, suppresses gastric cancer tumorigenesis through beta-catenin degradation and the dephosphorylation of ERK1/2 during the G2 phase. (PMID:29099417)
• CacyBP expression is regulated by E2F1, EGR1, and CREB transcription factors in colorectal cancer HCT116 cells. (PMID:29197151)
• Data show that S100 calcium binding protein A6 (S100A6) is required for the Ca2+-dependent nuclear translocation of calcyclin binding protein (CacyBP/SIP) in colon cancer SW480 cells. (PMID:29534068)
• ur results show for the first time that CacyBP/SIP binds to and affects the properties of a nuclear protein, NPM1, and that it is indispensable for preserving the structure of nucleoli under oxidative stress. (PMID:29806702)
• Together, the data presented here indicate a close interaction between ageing and sex on the distribution and levels of cannabinoid receptors (CB1, CB2), S100A6 and CacyBP/SIP in the human heart. (PMID:30482253)
• REVIEW: cellular function of S100A6 and its ligands, CacyBP/SIP and Sgt1 (PMID:30656909)
• promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation (PMID:31213539)
• CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells. (PMID:32880469)
• HSP90 Co-Chaperone, CacyBP/SIP, Protects alpha-Synuclein from Aggregation. (PMID:33049998)
• [CacyBP promotes the proliferation and invasion of non-small cell lung cancer]. (PMID:34530574)
• Knockout of Calcyclin Binding Protein Impedes the Growth of Breast Cancer Cells by Regulating Cell Apoptosis and beta-Catenin Signaling. (PMID:34591648)
• Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct. (PMID:35087201)
• CACYBP knockdown inhibits progression of prostate cancer via p53. (PMID:36576589)
• Involvement of CacyBP/SIP in differentiation and the immune response of HaCaT keratinocytes. (PMID:37156124)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacybp	ENSDARG00000014731
mus_musculus	Cacybp	ENSMUSG00000014226
rattus_norvegicus	Cacybp	ENSRNOG00000002572
drosophila_melanogaster	CG3226	FBGN0029882

Protein

Protein identifiers

Calcyclin-binding protein — Q9HB71 (reviewed: Q9HB71)

Alternative names: S100A6-binding protein, Siah-interacting protein

All UniProt accessions (2): Q9HB71, B2ZWH1

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in calcium-dependent ubiquitination and subsequent proteasomal degradation of target proteins. Probably serves as a molecular bridge in ubiquitin E3 complexes. Participates in the ubiquitin-mediated degradation of beta-catenin (CTNNB1).

Subunit / interactions. Homodimer. Interacts with proteins of the S100 family S100A1, S100A6, S100B, S100P and S100A12 in a calcium-dependent manner. Component of some large E3 complex at least composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts directly with SIAH1, SIAH2 and SKP1.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Phosphorylated on serine residues. Phosphorylated upon induction by RA or at high calcium concentrations.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HB71-1	1	yes
Q9HB71-2	2, SIP-S, S
Q9HB71-3	3

RefSeq proteins (2): NP_001007215, NP_055227* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007052	CS_dom	Domain
IPR007699	SGS_dom	Domain
IPR008978	HSP20-like_chaperone	Homologous_superfamily
IPR015120	Siah-Interact_N	Domain
IPR037201	CacyBP_N	Homologous_superfamily
IPR037893	CS_CacyBP	Domain
IPR052289	Calcyclin-binding_UBL-bridge	Family

Pfam: PF04969, PF05002, PF09032

UniProt features (42 total): strand 12, modified residue 8, sequence conflict 4, splice variant 3, mutagenesis site 3, helix 3, region of interest 3, domain 2, turn 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2A26	X-RAY DIFFRACTION	1.2
2A25	X-RAY DIFFRACTION	2.2
1X5M	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HB71-F1	82.05	0.55

Functional residue map

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

Post-translational modifications (8): 19, 34, 85, 118, 1, 2, 3, 8

Mutagenesis-validated functional residues (3):

Position	Phenotype
23–26	abolishes interaction with siah1.
64	abolishes interaction with siah1; when associated with n-66.
66	abolishes interaction with siah1; when associated with n-64.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 275 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GOBP_MUSCLE_TISSUE_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_RESPONSE_TO_PEPTIDE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP

GO Biological Process (6): heart development (GO:0007507), positive regulation of DNA replication (GO:0045740), cardiac muscle cell differentiation (GO:0055007), response to growth hormone (GO:0060416), cellular response to calcium ion (GO:0071277), cellular response to leukemia inhibitory factor (GO:1990830)

GO Molecular Function (6): tubulin binding (GO:0015631), protein domain specific binding (GO:0019904), ubiquitin protein ligase binding (GO:0031625), protein homodimerization activity (GO:0042803), S100 protein binding (GO:0044548), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), nuclear envelope lumen (GO:0005641), nucleoplasm (GO:0005654), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), beta-catenin destruction complex (GO:0030877), cell body (GO:0044297), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	2
animal organ development	1
circulatory system development	1
DNA replication	1
regulation of DNA replication	1
positive regulation of DNA metabolic process	1
cardiocyte differentiation	1
cardiac muscle tissue development	1
striated muscle cell differentiation	1
response to peptide hormone	1
response to calcium ion	1
cellular response to metal ion	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
cytoskeletal protein binding	1
ubiquitin-like protein ligase binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear envelope	1
organelle envelope lumen	1
nuclear lumen	1
cytoplasm	1
cullin-RING ubiquitin ligase complex	1
intracellular protein-containing complex	1
catalytic complex	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1616 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACYBP	SIAH1	Q8IUQ4	997
CACYBP	SKP1	P34991	991
CACYBP	S100A6	P06703	991
CACYBP	MAPK3	P27361	775
CACYBP	CUL1	Q13616	692
CACYBP	HSP90AA1	P07900	674
CACYBP	S100A12	P80511	623
CACYBP	S100A1	P23297	602
CACYBP	S100B	P04271	593
CACYBP	SIAH2	O43255	543
CACYBP	DNAJB1	P25685	542
CACYBP	CTNNB1	P35222	536
CACYBP	ANAPC10	Q9UM13	509
CACYBP	HSP90AB1	P08238	508
CACYBP	ZMYND12	Q9H0C1	497

IntAct

364 interactions, top by confidence:

A	B	Type	Score
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
SNX4	SNX30	psi-mi:“MI:0914”(association)	0.830
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSP90AA1	CHUK	psi-mi:“MI:0914”(association)	0.670
S100A6	CACYBP	psi-mi:“MI:0407”(direct interaction)	0.660
CACYBP	S100A6	psi-mi:“MI:0915”(physical association)	0.660
HRAS	RGL2	psi-mi:“MI:0914”(association)	0.660
SIAH1	CACYBP	psi-mi:“MI:2364”(proximity)	0.640
S100A5	CACYBP	psi-mi:“MI:0407”(direct interaction)	0.610
CACYBP	S100A5	psi-mi:“MI:0915”(physical association)	0.610
ERBB2	CACYBP	psi-mi:“MI:0915”(physical association)	0.570
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
S100A4	CACYBP	psi-mi:“MI:0407”(direct interaction)	0.540
CACYBP	S100A4	psi-mi:“MI:0915”(physical association)	0.540
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
STK3	PLK1	psi-mi:“MI:0914”(association)	0.530
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
S100A2	CACYBP	psi-mi:“MI:0407”(direct interaction)	0.440
S100P	CACYBP	psi-mi:“MI:0407”(direct interaction)	0.440
CACYBP	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
CACYBP	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
CACYBP	AHNAK	psi-mi:“MI:0407”(direct interaction)	0.440
CACYBP	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (386): CACYBP (Affinity Capture-MS), ANXA2 (Co-fractionation), CACYBP (Co-fractionation), CACYBP (Co-fractionation), CACYBP (Co-fractionation), NAA20 (Co-fractionation), NAA25 (Co-fractionation), TAGLN2 (Co-fractionation), USP19 (Co-fractionation), CACYBP (Affinity Capture-MS), CACYBP (Biochemical Activity), CACYBP (Proximity Label-MS), CACYBP (Proximity Label-MS), CACYBP (Proximity Label-MS), CACYBP (Proximity Label-MS)

ESM2 similar proteins: A0A3L6DPG1, A4QVI3, A6IPG1, B0BN85, B4JXU2, B5XEX1, C0HBG1, C1BH56, C3YFB4, F4HQD4, O22785, O42766, O70251, P15705, P17624, P23231, P24534, P26446, P29412, P34826, P35189, Q08446, Q0JL44, Q11118, Q23280, Q2KIK0, Q3T168, Q43468, Q4R4P3, Q4SK88, Q4WTC0, Q5E983, Q5R6Z8, Q5RHR0, Q5ZIN1, Q6AYK6, Q6AZB3, Q6AZN0, Q7Q9C0, Q94BR4

Diamond homologs: Q3T168, Q4R4P3, Q5R6Z8, Q6AYK6, Q9CXW3, Q9HB71, Q2KIK0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 222 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
Ras activation upon Ca2+ influx through NMDA receptor	5	18.2×	2e-03
Assembly and cell surface presentation of NMDA receptors	7	11.3×	1e-03
Ovarian tumor domain proteases	6	10.6×	4e-03
Neurexins and neuroligins	8	10.0×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	6	16.9×	6e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	6	14.4×	9e-04
mitotic spindle organization	8	10.6×	6e-04
protein autophosphorylation	11	7.8×	3e-04
positive regulation of JNK cascade	9	7.2×	1e-03
Wnt signaling pathway	11	5.3×	2e-03
protein phosphorylation	13	4.3×	2e-03
intracellular signal transduction	19	3.5×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

656 predictions. Top by Δscore:

Variant	Effect	Δscore
1:175004610:A:AG	acceptor_gain	1.0000
1:175004610:ACAGC:A	acceptor_loss	1.0000
1:175004611:C:G	acceptor_gain	1.0000
1:175004612:A:AG	acceptor_gain	1.0000
1:175004613:G:GG	acceptor_gain	1.0000
1:175004613:GC:G	acceptor_gain	1.0000
1:175004613:GCT:G	acceptor_gain	1.0000
1:175004613:GCTA:G	acceptor_gain	1.0000
1:175004613:GCTAC:G	acceptor_gain	1.0000
1:175004806:GGCTA:G	donor_gain	1.0000
1:175004807:GCTA:G	donor_gain	1.0000
1:175004825:G:GG	donor_gain	1.0000
1:175006736:C:A	acceptor_gain	1.0000
1:175006741:CCAG:C	acceptor_loss	1.0000
1:175006742:CAG:C	acceptor_loss	1.0000
1:175006743:AGGA:A	acceptor_loss	1.0000
1:175006744:G:GT	acceptor_loss	1.0000
1:175006839:GAG:G	donor_gain	1.0000
1:175007091:GTTGC:G	acceptor_loss	1.0000
1:175007092:TTGCA:T	acceptor_loss	1.0000
1:175007093:TGCA:T	acceptor_loss	1.0000
1:175007094:GCA:G	acceptor_loss	1.0000
1:175007095:CA:C	acceptor_loss	1.0000
1:175007097:G:C	acceptor_loss	1.0000
1:175007194:AAAA:A	donor_gain	1.0000
1:175007194:AAAAG:A	donor_loss	1.0000
1:175007195:AAA:A	donor_gain	1.0000
1:175007196:AA:A	donor_gain	1.0000
1:175007196:AAG:A	donor_loss	1.0000
1:175007197:AGTG:A	donor_loss	1.0000

AlphaMissense

1505 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:175006747:T:A	W80R	1.000
1:175006747:T:C	W80R	1.000
1:175008663:T:A	W163R	1.000
1:175008663:T:C	W163R	1.000
1:175008665:G:C	W163C	1.000
1:175008665:G:T	W163C	1.000
1:175009997:G:A	G202E	1.000
1:175009997:G:T	G202V	1.000
1:175010013:G:C	K207N	1.000
1:175010013:G:T	K207N	1.000
1:175010021:T:A	I210N	1.000
1:175010021:T:C	I210T	1.000
1:175010021:T:G	I210S	1.000
1:175010032:T:A	W214R	1.000
1:175010032:T:C	W214R	1.000
1:175006745:G:A	G79E	0.999
1:175006748:G:C	W80S	0.999
1:175006748:G:T	W80L	0.999
1:175006749:G:C	W80C	0.999
1:175006749:G:T	W80C	0.999
1:175007109:T:C	L115P	0.999
1:175008612:A:G	K146E	0.999
1:175008625:T:A	V150D	0.999
1:175008631:T:A	I152K	0.999
1:175008636:T:C	C154R	0.999
1:175008664:G:C	W163S	0.999
1:175009964:T:C	L191S	0.999
1:175009973:T:A	V194D	0.999
1:175009976:T:A	L195Q	0.999
1:175009976:T:C	L195P	0.999

dbSNP variants (sampled 300 via entrez): RS1000477940 (1:175003222 G>A), RS1000633641 (1:175007862 CAGAT>C), RS1000839845 (1:175000318 T>C), RS1001814361 (1:175008384 T>A), RS1002278217 (1:175012159 C>T), RS1002330436 (1:175012026 C>A), RS1002355854 (1:174999982 C>G,T), RS1002455487 (1:175006394 G>A), RS1002476896 (1:175011066 T>C), RS1002608580 (1:175010866 C>G), RS1002691255 (1:174999101 G>A), RS1002758364 (1:175010780 AAAGTT>A,AAAGTTAAGTT), RS1003063852 (1:174999640 C>G,T), RS1003202392 (1:175005036 T>C), RS1003340291 (1:175009384 G>A)

Disease associations

OMIM: gene MIM:606186 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295948 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.30	Kd	505.7	nM	CHEMBL5653589
6.30	ED50	505.7	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147978: Binding affinity to human CACYBP incubated for 45 mins by Kinobead based pull down assay	kd	0.5057	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
cadmium sulfate	increases expression	3
Benzo(a)pyrene	increases expression, increases methylation, affects reaction	3
Valproic Acid	affects expression, increases expression	3
bisphenol A	decreases expression	2
trichostatin A	affects expression, increases expression	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
Copper	affects binding, decreases expression	2
Disulfiram	increases expression, affects binding, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Okadaic Acid	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
daidzein	affects cotreatment, affects expression	1
sodium arsenate	increases abundance, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
daidzin	affects expression, affects cotreatment	1
arsenite	increases reaction, affects binding	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
genistin	affects cotreatment, affects expression	1
M-VAC protocol	increases response to substance	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118599	Binding	Binding affinity to CACYBP in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.