CKB

Summary

CKB (creatine kinase B, HGNC:1991) is a protein-coding gene on chromosome 14q32.33, encoding Creatine kinase B-type (P12277). Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate).

The protein encoded by this gene is a cytoplasmic enzyme involved in energy homeostasis. The encoded protein reversibly catalyzes the transfer of phosphate between ATP and various phosphogens such as creatine phosphate. It acts as a homodimer in brain as well as in other tissues, and as a heterodimer with a similar muscle isozyme in heart. The encoded protein is a member of the ATP:guanido phosphotransferase protein family. A pseudogene of this gene has been characterized.

Source: NCBI Gene 1152 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 41 total
• Druggable target: yes
• MANE Select transcript: NM_001823

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1991
Approved symbol	CKB
Name	creatine kinase B
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166165
Ensembl biotype	protein_coding
OMIM	123280
Entrez	1152

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 11 protein_coding, 10 retained_intron, 2 nonsense_mediated_decay

ENST00000348956, ENST00000553528, ENST00000553610, ENST00000553652, ENST00000553878, ENST00000553994, ENST00000554282, ENST00000554426, ENST00000554705, ENST00000554989, ENST00000555039, ENST00000555366, ENST00000555659, ENST00000555770, ENST00000557287, ENST00000557530, ENST00000557569, ENST00000689346, ENST00000873263, ENST00000873264, ENST00000955391, ENST00000955392, ENST00000955393

RefSeq mRNA: 2 — MANE Select: NM_001823 NM_001362531, NM_001823

CCDS: CCDS91943, CCDS9981

Canonical transcript exons

ENST00000348956 — 8 exons

Exon	Start	End
ENSE00001100366	103519667	103520042
ENSE00002525462	103522766	103522830
ENSE00003498688	103522301	103522505
ENSE00003524543	103522023	103522177
ENSE00003554128	103520469	103520592
ENSE00003594505	103521818	103521950
ENSE00003648867	103520122	103520311
ENSE00003789149	103521263	103521434

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 434.2878 / max 6066.6402, expressed in 1743 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145101	413.8002	1670
145091	4.2967	808
145098	3.0790	702
145090	2.5540	670
145083	1.8954	565
145100	1.4897	512
145085	1.1711	594
145099	1.0986	433
145097	0.9565	421
145088	0.8824	361

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.94	gold quality
cerebellar hemisphere	UBERON:0002245	99.93	gold quality
cerebellar cortex	UBERON:0002129	99.92	gold quality
right frontal lobe	UBERON:0002810	99.92	gold quality
ventricular zone	UBERON:0003053	99.92	gold quality
prefrontal cortex	UBERON:0000451	99.87	gold quality
caudate nucleus	UBERON:0001873	99.86	gold quality
cerebellum	UBERON:0002037	99.86	gold quality
nucleus accumbens	UBERON:0001882	99.84	gold quality
amygdala	UBERON:0001876	99.78	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.78	gold quality
cingulate cortex	UBERON:0003027	99.77	gold quality
anterior cingulate cortex	UBERON:0009835	99.76	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.75	gold quality
frontal cortex	UBERON:0001870	99.73	gold quality
ganglionic eminence	UBERON:0004023	99.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.72	gold quality
right uterine tube	UBERON:0001302	99.71	gold quality
putamen	UBERON:0001874	99.71	gold quality
lower esophagus	UBERON:0013473	99.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.70	gold quality
neocortex	UBERON:0001950	99.68	gold quality
paraflocculus	UBERON:0005351	99.67	gold quality
cortical plate	UBERON:0005343	99.65	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.65	gold quality
transverse colon	UBERON:0001157	99.64	gold quality
body of stomach	UBERON:0001161	99.63	gold quality
middle frontal gyrus	UBERON:0002702	99.62	gold quality
mucosa of transverse colon	UBERON:0004991	99.59	gold quality

Single-cell (SCXA)

Detected in 38 experiment(s), a significant marker in 28.

Experiment	Marker?	Max mean expression
E-MTAB-6911	yes	5141.96
E-MTAB-7008	yes	3422.69
E-HCAD-5	yes	3161.78
E-MTAB-8410	yes	2915.44
E-GEOD-75140	yes	2890.89
E-MTAB-9388	yes	2868.21
E-MTAB-7407	yes	2305.35
E-MTAB-6701	yes	1832.78
E-CURD-11	yes	1275.99
E-CURD-6	yes	268.19
E-GEOD-125970	yes	47.40
E-MTAB-10287	yes	43.85
E-CURD-119	yes	43.17
E-HCAD-35	yes	42.83
E-CURD-112	yes	31.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, PARP1, TFAP2A, TP53

Literature-anchored findings (GeneRIF, showing 40)

• 2D fingerprinting & mass spectrometry reveal specific targets of protein oxidation in Alzheimer’s disease brain, including creatine kinase BB, suggesting involvement of oxidatively modified proteins in neurodegeneration. (PMID:12160938)
• Expression of CKB mRNA and CK-B sometimes occurred in blastic transformation of the hematopoietic system (PMID:15996648)
• CKB was expressed in 78% of colon tumors (PMID:16424007)
• GM130 and BB-CK co-localize specifically in a transient fashion during early prophase of mitosis, when GM130 plays an important role in Golgi fragmentation that starts also at early prophase. (PMID:17036164)
• The asymmetric unit contained two molecules of CKB, giving a crystal volume per protein mass (Vm) of 1.80 A3 Da-1 and a solvent content of 31.6%. (PMID:18309274)
• Autoantibodies to EsteD and BB-CK produced in experimental autoimmune uveoretinitis -induced mice were also detected in some endogenous uveitis patients, suggesting that these proteins might be autoantigens. (PMID:18552983)
• Using a yeast 2-hybrid it was discovered that the C-terminal domain of KCC3, that is lost in most hereditary motor and sensory neuropathy with agenesis of the corpus callosum-causing mutations, directly interacts with brain-specific creatine kinase. (PMID:18566107)
• The Tat-CK fusion protein markedly increased endogenous CK activity levels within PC12 cells. (PMID:18682038)
• Data show that dose-response inactivation by 4HNE (4-hydroxynonenal) of hBAT (human bile acid CoA:amino acid N-acyltransferase) and CKBB (cytosolic brain isoform of creatine kinase) is associated with site-specific modifications. (PMID:18793185)
• Three structural aspects of human-brain-type-creatine-kinase were identified by X-ray crystallography: the ligand-free-form at 2.2A; the ADP-Mg2+, nitrate, and creatine complex (transition-state-analogue complex; TSAC); and the ADP-Mg2+-complex at 2.0A. (PMID:18977227)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Report the effects of prior calcium channel blocker therapy on creatine kinase-MB (myocardial form) levels after percutaneous coronary interventions. (PMID:19337554)
• This protein has been found differentially expressed in the Wernicke’s Area from patients with schizophrenia. (PMID:19405953)
• The correlation of CK-BB as a disease biomarker in both CNS and peripheral tissues from Huntington’s disease mice and patients may provide a powerful means to assess disease progression and prognosis. (PMID:20460152)
• Phosphocreatine metabolism in the normal appearing white matter in multiple sclerosis is impaired due to decreased CK-B levels. (PMID:20520825)
• A single troponin I value at 3 days from symptom onset is a better predictor of infarct size compared to peak values and CK-MB. (PMID:20588136)
• CKB was up-regulated in women older than 38 years, and its expression in cumulus cells was associated with embryo quality (PMID:20721618)
• These observations suggested that the ability to generate the oxidized form could protect BBCK against the intracellular oxidative stress. (PMID:20923681)
• Data demonstrate that the downregulation of CKB may play an important role in colon cancer progression by promoting EMT. (PMID:21308735)
• The results suggested that the intra- and inter-subunit domain interactions modified the behavior of kinetic refolding. (PMID:21931810)
• Cigarette smoke induced carbonylation and subsequent degradation of creatine kinase B are involved in the regulation of senescence in bronchial epithelial cells. (PMID:21980054)
• de-methylated CKB gene is inherited that leads to high CKB expression levels in myeloic precursor cells in the bone marrow (PMID:22088263)
• His103 and Phe107 in hASB9-2 are essential for binding to CKB. (PMID:22418839)
• study found promoter SNPs of CKB and TPI1 were weakly associated with schizophrenia;in addition, IFNG polymorphisms were associated with schizophrenia; results suggest that IFNG and proteins affected by IFNG may play a role in the pathogenesis of schizophrenia (PMID:22623148)
• effects of osmolytes on human brain-type creatine kinase folding (PMID:22885020)
• analysis of SNPs and their effect on creatine kinase structure and function (PMID:23049898)
• Estimation of CK and its CK isoenzyme fractions can aid in quick and accurate diagnosis of tubal ectopic pregnancy. (PMID:23876027)
• We found that most patients with macular telangiectasia-2 possess retinal autoantibodies, the most prevalent of which were directed against AGL, RBP3, and CK-B. (PMID:23882694)
• increased serum Ckbb reflects failure of osteoclasts or suppression of osteoclasts in children with osteogenesis imperfecta during neridronate treatment (PMID:24518563)
• CK-MB levels were higher after ERCP in non-ischemic patients compared with a myocardial ischemia group. Creatine phosphokinase levels did not differ significantly between groups. (PMID:25141318)
• CK-B catalytic activity also helps in the formation of protrusive ruffle structures which are actin-dependent and abundant on the surface of both unstimulated and LPS-activated macrophages. (PMID:25538032)
• SRC, LYN and CKB expression or DNA methylation could be useful markers for predicting tumor progression. (PMID:26460485)
• membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations. (PMID:27318991)
• The data revealed a varying but significant increase of CK activity in CKBE individuals as compared to controls, reaching an almost 800-fold increase in two CKBE individuals which also had increased erythrocyte creatine. (PMID:28364583)
• These findings support increased CK activity as protection against ischaemia-reperfusion injury, in particular, protection via CKMT2 in a cardiac-relevant cell line, which merits further investigation in vivo. (PMID:28806770)
• Association and oligomerization of Prx II could take part in recovery and protection of the CK BB enzyme activity from inactivation during heat-induced stress. (PMID:29227081)
• Clinical impact of creatine phosphokinase and c-reactive protein as predictors of postgastrectomy complications in patients with gastric cancer. (PMID:33485312)
• Creatine kinase B controls futile creatine cycling in thermogenic fat. (PMID:33597756)
• CKB inhibits epithelial-mesenchymal transition and prostate cancer progression by sequestering and inhibiting AKT activation. (PMID:34706306)
• Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function. (PMID:37156912)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	ckbb	ENSDARG00000043257
danio_rerio	ckba	ENSDARG00000069752
mus_musculus	Ckb	ENSMUSG00000001270
rattus_norvegicus	Ckb	ENSRNOG00000010872
drosophila_melanogaster	Argk1	FBGN0000116
drosophila_melanogaster	Argk2	FBGN0035957
drosophila_melanogaster	CG4546	FBGN0038373
drosophila_melanogaster	CG30274	FBGN0050274
caenorhabditis_elegans		WBGENE00009706
caenorhabditis_elegans	ZC434.8	WBGENE00013894
caenorhabditis_elegans	F32B5.1	WBGENE00017975
caenorhabditis_elegans		WBGENE00018519
caenorhabditis_elegans	W10C8.5	WBGENE00021128

Paralogs (4): CKM (ENSG00000104879), CKMT2 (ENSG00000131730), CKMT1A (ENSG00000223572), CKMT1B (ENSG00000237289)

Protein

Protein identifiers

Creatine kinase B-type — P12277 (reviewed: P12277)

Alternative names: Brain creatine kinase, Creatine kinase B chain, Creatine phosphokinase B-type

All UniProt accessions (9): A0A0S2Z471, P12277, G3V2I1, G3V461, G3V4N7, H0YJG0, H0YJJ7, H0YJK0, V9HWH2

UniProt curated annotations — full annotation on UniProt →

Function. Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate). Creatine kinase isoenzymes play a central role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, brain and spermatozoa. Acts as a key regulator of adaptive thermogenesis as part of the futile creatine cycle: localizes to the mitochondria of thermogenic fat cells and acts by mediating phosphorylation of creatine to initiate a futile cycle of creatine phosphorylation and dephosphorylation. During the futile creatine cycle, creatine and N-phosphocreatine are in a futile cycle, which dissipates the high energy charge of N-phosphocreatine as heat without performing any mechanical or chemical work.

Subunit / interactions. Dimer of identical or non-identical chains, which can be either B (brain type) or M (muscle type). With MM being the major form in skeletal muscle and myocardium, MB existing in myocardium, and BB existing in many tissues, especially brain. Interacts with SLC12A6 (via C-terminus); the interaction may be required for SLC12A6 potassium-chloride cotransport activity.

Subcellular location. Cytoplasm. Cytosol. Mitochondrion. Cell membrane.

Post-translational modifications. Ubiquitinated by the ECS(ASB9) complex, leading to its degradation by the proteasome.

Domain organisation. The internal MTS-like signal (iMTS-L) mediates targeting to mitochondria thermogenic fat cells.

Similarity. Belongs to the ATP:guanido phosphotransferase family.

RefSeq proteins (2): NP_001349460, NP_001814* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000749	ATP-guanido_PTrfase	Family
IPR014746	Gln_synth/guanido_kin_cat_dom	Homologous_superfamily
IPR022413	ATP-guanido_PTrfase_N	Domain
IPR022414	ATP-guanido_PTrfase_cat	Domain
IPR022415	ATP-guanido_PTrfase_AS	Active_site
IPR036802	ATP-guanido_PTrfase_N_sf	Homologous_superfamily

Pfam: PF00217, PF02807

Enzyme classification (BRENDA):

• EC 2.7.3.2 — creatine kinase (BRENDA: 45 organisms, 67 substrates, 117 inhibitors, 317 Km, 122 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.042–20	133
CREATINE	0.35–167	102
PHOSPHOCREATINE	0.51–8.97	23
ADP	0.015–1.2	22
CREATINE PHOSPHATE	0.23–50	11
ALPHA-(RP)-BORANO SUBSTITUTED ADP	1	1
ALPHA-(SP)-BORANO SUBSTITUTED ADP	0.008	1
GLYCOCYAMINE	6.7	1
CYCLOCREATINE	—	0
N-ETHYLGLYCOCYAMINE	—	0

Catalyzed reactions (Rhea), 1 shown:

• creatine + ATP = N-phosphocreatine + ADP + H(+) (RHEA:17157)

UniProt features (81 total): helix 19, binding site 12, sequence conflict 11, strand 9, modified residue 7, turn 5, cross-link 4, mutagenesis site 4, sequence variant 3, domain 2, region of interest 2, initiator methionine 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7BF1	X-RAY DIFFRACTION	1.24
3B6R	X-RAY DIFFRACTION	2
3DRB	X-RAY DIFFRACTION	2
3DRE	X-RAY DIFFRACTION	2.2
7TUN	X-RAY DIFFRACTION	2.93
6V9H	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12277-F1	95.59	0.89

Functional residue map

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

Ligand- & substrate-binding residues (12): 132; 191; 232; 236; 285; 292; 320–325; 320; 335; 72; 128–132; 130

Post-translational modifications (11): 4, 35, 125, 199, 269, 309, 322, 45, 101, 107, 381

Mutagenesis-validated functional residues (4):

Position	Phenotype
283	complete loss of activity.
292	complete loss of activity.
292	42% of wild-type activity.
340	no change in activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-71288	Creatine metabolism
R-HSA-9696264	RND3 GTPase cycle
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 0 (showing top):

GO Biological Process (3): substantia nigra development (GO:0021762), phosphocreatine biosynthetic process (GO:0046314), futile creatine cycle (GO:0140651)

GO Molecular Function (9): creatine kinase activity (GO:0004111), ATP binding (GO:0005524), ubiquitin protein ligase binding (GO:0031625), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), transferase activity, transferring phosphorus-containing groups (GO:0016772)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
RHO GTPase cycle	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Metabolism	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
midbrain development	1
neural nucleus development	1
phosphocreatine metabolic process	1
phosphagen biosynthetic process	1
creatine kinase activity	1
metabolic process	1
phosphoamidase activity	1
adaptive thermogenesis	1
kinase activity	1
phosphotransferase activity, nitrogenous group as acceptor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ubiquitin-like protein ligase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
transferase activity	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1544 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CKB	SLC6A8	P48029	850
CKB	ASB9	Q96DX5	725
CKB	LDHAL6A	Q6ZMR3	713
CKB	LDHAL6B	Q9BYZ2	713
CKB	LDHC	P07864	679
CKB	ENO1	P06733	622
CKB	HSPA8	P11142	604
CKB	GOT1L1	Q8NHS2	598
CKB	PRDX2	P31945	593
CKB	SERPINA3	P01011	592
CKB	ACP5	P13686	544
CKB	LDHA	P00338	536
CKB	SNCB	Q16143	506
CKB	GOT1	P17174	503
CKB	DNM1	Q05193	497

IntAct

160 interactions, top by confidence:

A	B	Type	Score
CKB	ASB9	psi-mi:“MI:0915”(physical association)	0.940
ASB9	CKB	psi-mi:“MI:0915”(physical association)	0.940
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
ASB9	CKM	psi-mi:“MI:0914”(association)	0.870
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
CKB	CKM	psi-mi:“MI:0915”(physical association)	0.690
CKB	CKM	psi-mi:“MI:0914”(association)	0.690
CUL3	CKB	psi-mi:“MI:0915”(physical association)	0.620
ASB9	ARIH2	psi-mi:“MI:0914”(association)	0.530
SLC12A6	CKB	psi-mi:“MI:0915”(physical association)	0.530
SLC12A6	CKB	psi-mi:“MI:0403”(colocalization)	0.530
P/V/C	KPNA3	psi-mi:“MI:0914”(association)	0.530
TCF4	CKB	psi-mi:“MI:0915”(physical association)	0.500
CKB		psi-mi:“MI:0915”(physical association)	0.500
	CKB	psi-mi:“MI:0914”(association)	0.500
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
DNM1L	CKB	psi-mi:“MI:0403”(colocalization)	0.430
TNFAIP3	LRRIQ3	psi-mi:“MI:2364”(proximity)	0.420
	CKB	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (375): CKB (Two-hybrid), CKB (Affinity Capture-MS), CKB (Affinity Capture-MS), ASB9 (Two-hybrid), CKB (Affinity Capture-RNA), CKB (Affinity Capture-MS), CKB (Affinity Capture-MS), CKB (Affinity Capture-MS), CKB (Affinity Capture-MS), CKM (Affinity Capture-MS), ASB9 (Two-hybrid), SERP2 (Two-hybrid), ABCB7 (Co-fractionation), ACO2 (Co-fractionation), CKB (Co-fractionation)

ESM2 similar proteins: A0A286R7K5, A0A976YI25, B0FRF9, B1PVZ9, C7E3T4, C9EIP1, H6VGI2, H6VGI3, O61367, O77814, P00563, P00564, P00565, P00566, P00567, P04414, P05122, P05123, P05124, P06732, P07310, P07335, P09605, P11009, P12277, P14208, P17540, P24722, P25809, P30275, P48610, P51541, P51545, P70079, P91798, Q004B5, Q04447, Q29577, Q29594, Q3ZBP1

Diamond homologs: A0A286R7K5, A0A976YI25, A4J0X5, A5D5K7, A8F953, B0FRF9, B1PVZ9, C1KYG4, C7E3T4, C9EIP1, G1ESZ9, H6VGI2, H6VGI3, O15989, O15990, O15991, O15992, O61367, O77814, O96507, P00563, P00564, P00565, P00566, P00567, P04414, P05122, P05123, P05124, P06732, P07310, P07335, P09605, P11009, P12277, P12532, P14208, P16641, P17540, P18294

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
creatine	“up-regulates activity”	CKB	“chemical activation”
CKB	“up-regulates quantity”	N-phosphocreatine	“chemical modification”
CKB	“up-regulates quantity”	ACTB	relocalization
ASB9	“down-regulates quantity by destabilization”	CKB	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 174 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
Telomere Extension By Telomerase	5	18.0×	3e-03
Signaling by Interleukins	10	5.0×	4e-03
Cytokine Signaling in Immune system	13	4.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

960 predictions. Top by Δscore:

Variant	Effect	Δscore
14:103520039:CCGC:C	acceptor_gain	1.0000
14:103520040:C:CT	acceptor_gain	1.0000
14:103520040:CGC:C	acceptor_gain	1.0000
14:103520041:GCC:G	acceptor_loss	1.0000
14:103520043:C:CC	acceptor_gain	1.0000
14:103520043:CTGGG:C	acceptor_loss	1.0000
14:103520044:T:A	acceptor_loss	1.0000
14:103520118:TCA:T	donor_loss	1.0000
14:103520120:A:AC	donor_gain	1.0000
14:103520120:ACCT:A	donor_loss	1.0000
14:103520121:C:CC	donor_gain	1.0000
14:103520307:TCAAT:T	acceptor_gain	1.0000
14:103520308:CAAT:C	acceptor_gain	1.0000
14:103520308:CAATC:C	acceptor_gain	1.0000
14:103520309:AAT:A	acceptor_gain	1.0000
14:103520310:AT:A	acceptor_gain	1.0000
14:103520312:C:A	acceptor_loss	1.0000
14:103520312:C:CC	acceptor_gain	1.0000
14:103520320:G:T	acceptor_gain	1.0000
14:103520421:ACATC:A	donor_gain	1.0000
14:103520422:CATCC:C	donor_gain	1.0000
14:103520425:C:A	donor_gain	1.0000
14:103520460:C:A	donor_gain	1.0000
14:103520503:T:TA	donor_gain	1.0000
14:103521258:CGCA:C	donor_loss	1.0000
14:103521259:GCAC:G	donor_loss	1.0000
14:103521260:CA:C	donor_loss	1.0000
14:103521430:CAGGG:C	acceptor_gain	1.0000
14:103521819:TTCC:T	donor_gain	1.0000
14:103521946:CCGCC:C	acceptor_gain	1.0000

AlphaMissense

2520 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:103519996:G:C	N338K	1.000
14:103519996:G:T	N338K	1.000
14:103520220:C:T	G290E	1.000
14:103520221:C:A	G290W	1.000
14:103520226:C:A	G288V	1.000
14:103520226:C:T	G288D	1.000
14:103520227:C:G	G288R	1.000
14:103520231:G:C	N286K	1.000
14:103520231:G:T	N286K	1.000
14:103520235:G:A	S285F	1.000
14:103520240:G:C	C283W	1.000
14:103520242:A:G	C283R	1.000
14:103520256:C:A	G278V	1.000
14:103520256:C:T	G278D	1.000
14:103520548:T:A	D233V	1.000
14:103520548:T:G	D233A	1.000
14:103520549:C:G	D233H	1.000
14:103520551:T:A	E232V	1.000
14:103520553:C:A	E231D	1.000
14:103520553:C:G	E231D	1.000
14:103520554:T:A	E231V	1.000
14:103520564:A:G	W228R	1.000
14:103520564:A:T	W228R	1.000
14:103520569:A:G	L226P	1.000
14:103521283:C:A	W211C	1.000
14:103521283:C:G	W211C	1.000
14:103521285:A:G	W211R	1.000
14:103521285:A:T	W211R	1.000
14:103521334:G:C	F194L	1.000
14:103521334:G:T	F194L	1.000

dbSNP variants (sampled 300 via entrez): RS1000928715 (14:103524166 A>G), RS1001043594 (14:103524228 C>G), RS1001144563 (14:103523937 G>A), RS1001962775 (14:103523472 G>A), RS1002224019 (14:103521710 G>C,T), RS1002310721 (14:103523158 A>G), RS1003985388 (14:103522370 G>A,C), RS1004036130 (14:103523120 G>A), RS1004040466 (14:103521650 G>A,C), RS1004987960 (14:103524230 G>C), RS1005040402 (14:103524425 C>T), RS1005640118 (14:103521170 C>G,T), RS1005663749 (14:103524759 G>C,T), RS1006556536 (14:103523903 T>C), RS1007083207 (14:103523625 TA>T,TAA,TAAA)

Disease associations

OMIM: gene MIM:123280 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): premature menopause (MONDO:0001119)

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002539_23	Schizophrenia	1.000000e-13
GCST004521_15	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_262	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST005194_69	Coronary artery disease	2.000000e-06
GCST005951_9	Body mass index	4.000000e-09
GCST007044_22	Extremely high intelligence	4.000000e-08
GCST008163_202	Height	2.000000e-07
GCST008839_376	Height	9.000000e-17
GCST010703_23	Brain morphology (MOSTest)	2.000000e-09
GCST010988_549	Adult body size	1.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004337	intelligence
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6049 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases activity, decreases reaction, affects cotreatment, increases expression, decreases expression	6
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	5
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	5
Valproic Acid	affects expression, increases expression, increases methylation	5
Cyclosporine	decreases expression	4
trichostatin A	affects cotreatment, decreases expression	2
(+)-JQ1 compound	increases expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	increases expression	2
Doxorubicin	affects expression, decreases expression	2
Lipopolysaccharides	increases expression, affects expression, affects response to substance, decreases reaction	2
Mustard Gas	increases alkylation, increases expression	2
Progesterone	affects cotreatment, increases expression	2
Quercetin	decreases expression, increases activity	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression, affects cotreatment	2
Thapsigargin	decreases expression	2
Genistein	increases expression, decreases reaction, increases activity	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
TL8-506	affects cotreatment, increases expression	1
4-oxoretinoic acid	decreases expression	1
biochanin A	increases activity	1
bufotalin	increases expression	1
daidzein	increases activity, decreases reaction	1
triphenyl phosphate	increases expression	1
propionaldehyde	increases expression	1
lead acetate	affects cotreatment, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1054174	Binding	Activity of human creatine kinase isoform BB assessed as formation of RO2433 triphosphate at 200 uM	The mechanism of action of beta-D-2’-deoxy-2’-fluoro-2’-C-methylcytidine involves a second metabolic pathway leading to beta-D-2’-deoxy-2’-fluoro-2’-C-methyluridine 5’-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. — Antimicrob Agents Chemother

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SJ12	HAP1 CKB (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists