CLSPN

Summary

CLSPN (claspin, HGNC:19715) is a protein-coding gene on chromosome 1p34.3, encoding Claspin (Q9HAW4). Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication or to DNA damage induced by both ionizing and UV irradiation. It is a selective cancer dependency (DepMap: 80.4% of cell lines).

The product of this gene is an essential upstream regulator of checkpoint kinase 1 and triggers a checkpoint arrest of the cell cycle in response to replicative stress or DNA damage. The protein is also required for efficient DNA replication during a normal S phase. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 63967 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 198 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 80.4% of screened cell lines
• MANE Select transcript: NM_022111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19715
Approved symbol	CLSPN
Name	claspin
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000092853
Ensembl biotype	protein_coding
OMIM	605434
Entrez	63967

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000251195, ENST00000318121, ENST00000373220, ENST00000466308, ENST00000517467, ENST00000520551, ENST00000939005, ENST00000939006

RefSeq mRNA: 3 — MANE Select: NM_022111 NM_001190481, NM_001330490, NM_022111

CCDS: CCDS396, CCDS53297, CCDS81299

Canonical transcript exons

ENST00000318121 — 25 exons

Exon	Start	End
ENSE00000594892	35745451	35745562
ENSE00000765315	35737992	35738097
ENSE00000765316	35738455	35738582
ENSE00000765317	35739136	35739257
ENSE00000765318	35739365	35739529
ENSE00000765320	35743141	35743241
ENSE00000765376	35743455	35743530
ENSE00000765378	35746766	35746992
ENSE00000765382	35748405	35748604
ENSE00000765410	35749467	35749531
ENSE00000765426	35760342	35760916
ENSE00000765461	35761096	35761204
ENSE00000765500	35761998	35762070
ENSE00000765532	35764266	35764714
ENSE00000765534	35765218	35765326
ENSE00000861197	35749633	35749811
ENSE00000861199	35753745	35753936
ENSE00000861200	35762404	35762481
ENSE00000861201	35763160	35763321
ENSE00001036904	35751250	35751506
ENSE00003536964	35747907	35748061
ENSE00003573755	35737339	35737421
ENSE00003624322	35736914	35737075
ENSE00003842984	35769847	35769978
ENSE00003846840	35732112	35736606

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 84.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4998 / max 354.5567, expressed in 1344 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11700	9.3630	1295
11699	0.5866	328
11698	0.4279	245
11697	0.1155	37
11695	0.0067	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.64	gold quality
ganglionic eminence	UBERON:0004023	81.72	gold quality
ventricular zone	UBERON:0003053	80.96	gold quality
bone marrow cell	CL:0002092	79.65	gold quality
stromal cell of endometrium	CL:0002255	76.69	gold quality
pancreatic ductal cell	CL:0002079	72.87	gold quality
vermiform appendix	UBERON:0001154	72.25	gold quality
buccal mucosa cell	CL:0002336	71.86	silver quality
right testis	UBERON:0004534	71.20	gold quality
testis	UBERON:0000473	69.90	gold quality
left testis	UBERON:0004533	68.71	gold quality
rectum	UBERON:0001052	67.76	gold quality
lymph node	UBERON:0000029	67.29	gold quality
mucosa of transverse colon	UBERON:0004991	66.83	gold quality
caecum	UBERON:0001153	66.19	gold quality
tibialis anterior	UBERON:0001385	65.16	silver quality
secondary oocyte	CL:0000655	64.30	silver quality
oocyte	CL:0000023	63.87	silver quality
smooth muscle tissue	UBERON:0001135	63.58	gold quality
leukocyte	CL:0000738	63.35	gold quality
monocyte	CL:0000576	63.04	gold quality
islet of Langerhans	UBERON:0000006	62.59	gold quality
colonic epithelium	UBERON:0000397	62.02	silver quality
adrenal tissue	UBERON:0018303	61.85	gold quality
bone marrow	UBERON:0002371	61.41	gold quality
spleen	UBERON:0002106	61.33	gold quality
prefrontal cortex	UBERON:0000451	60.50	gold quality
esophagus mucosa	UBERON:0002469	60.39	gold quality
tonsil	UBERON:0002372	58.98	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	1669.30
E-MTAB-6379	yes	722.13
E-MTAB-6075	yes	578.13
E-MTAB-8271	yes	522.74
E-MTAB-7051	yes	468.87
E-ENAD-27	yes	385.73
E-GEOD-75140	yes	331.91
E-MTAB-10290	yes	294.93
E-MTAB-10287	yes	275.09
E-MTAB-10485	yes	266.05
E-MTAB-10662	yes	219.96
E-MTAB-8530	yes	176.17
E-HCAD-13	yes	162.96
E-CURD-114	yes	132.35
E-GEOD-99795	yes	120.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): REL

miRNA regulators (miRDB)

151 targeting CLSPN, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 80.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Claspin has a potentially critical role in replication checkpoint control in mammalian cells (PMID:12766152)
• determination of properties of both a tumor suppressor and an oncogene (PMID:15096610)
• has a ring-like structure and binds with high affinity to branched DNA molecules. (PMID:15226314)
• Claspin has roles in the Chk1 pathway and functions in checkpoint control [review] (PMID:15279790)
• cleavage of Claspin by caspase-7 inactivates the Chk1 signaling pathway (PMID:16123041)
• Claspin and Chk1 proteins regulate each other and thus ensure the proper cell cycle progression and replication checkpoint control. (PMID:16501606)
• the Chk1 pathway is regulated through both phosphorylation of Claspin and its controlled degradation. (PMID:16828751)
• These results suggest that while TopBP1 is a general regulator of ATR, Claspin operates downstream of TopBP1 to selectively regulate the Chk1-controlled branch of the genotoxic stress response. (PMID:16880517)
• Data suggest that degradation of Claspin by SCFbetaTrCP restrains Chk1 activation. (PMID:16885021)
• The SCFbetaTrCP-dependent degradation of claspin is necessary for the efficient and timely termination of the DNA replication checkpoint. (PMID:16885022)
• The degradation of Claspin at the onset of mitosis is an essential step for the recovery of a cell from a DNA-damage-induced cell-cycle arrest. (PMID:16934469)
• Chk1 can be activated in a claspin-dependent manner leading to cyclin B1 down-regulation and providing the cells of an additional mechanism to inhibit mitosis entry in Hela cells. (PMID:16951182)
• phosphorylation of Claspin repeats in human Claspin is important for Claspin function and the regulation of Claspin-Checkpoint kinase 1 interaction in human cells (PMID:16963448)
• Tipin is a checkpoint mediator that cooperates with Tim and may regulate the nuclear relocation of Claspin in response to replication checkpoint (PMID:17102137)
• human Claspin is found in complex with PCNA, an essential component of the DNA replication machinery, and is released upon DNA replication arrest. dissociation of Claspin-PCNA could be part of the signal leading to Chk1 activation. (PMID:17274954)
• downregulation of Claspin protein levels by short interfering RNA resulted in an increase in apoptotic induction both in the presence and absence of DNA damage (PMID:17431426)
• Altogether seven different sequence changes were observed, but none of them appeared to associate with breast cancer susceptibility. (PMID:18077083)
• These results demonstrate that phosphorylation of Claspin within the Chk1-binding domain is catalysed by an ATR-dependent kinase distinct from Chk1. (PMID:18331829)
• Depletion of Chk1 and Claspin together doubled the percentage of very slow forks, compared with depletion of either protein alone. (PMID:18353973)
• Data show that Chk1 and the Claspin-Timeless module of replication forks not only participate in ATR signaling, but also protect stressed forks independently of ATR. (PMID:18451105)
• Claspin plays a role regulating replication fork stability that is independent of its function in mediating Chk1 phosphorylation. (PMID:19270516)
• Cdh1 reciprocally regulates the Rb pathway through competing with E2F1 to bind the hypophosphorylated form of Rb. (PMID:19477924)
• Resequenced CLSPN from the germline of selected cancer families; eight nonsynonymous variants, including a recurrent mutation, were id’d from the germline of two cancer-prone individuals and 5 cancer cell lines of breast, ovarian, & hematopoietic origin. (PMID:19737971)
• Data show that the ATR-dependent phosphorylation of Chk1, but not p53, is strongly stimulated by Claspin. (PMID:19828454)
• Rad9A-mediated Claspin localization is a vital step during checkpoint activation. (PMID:20081369)
• RPA-covered ssDNA not only supports recruitment and activation of ATR but also, through Tipin and Claspin, it plays an important role in the action of ATR on its critical downstream target Chk1 (PMID:20233725)
• Here, the authors demonstrate that both the NF-kappaB family of transcription factors and their upstream kinase IKK can regulate Claspin levels by controlling its mRNA expression. (PMID:20657549)
• The multiple protein-DNA and protein-protein interactions is important for Claspin function during DNA replication and DNA replication checkpoint signaling. (PMID:21478680)
• Tethering DNA damage checkpoint mediator proteins topoisomerase IIbeta-binding protein 1 (TopBP1) and Claspin to DNA activates ataxia-telangiectasia mutated and RAD3-related (ATR) phosphorylation of checkpoint kinase 1 (Chk1). (PMID:21502314)
• In the presence of BRCA1, endogenous HERC2 interacts with Claspin, a protein essential for G(2)-M checkpoint activation and replication fork stability. (PMID:21775519)
• the functions of Claspin and the functional relationship between Claspin and Rad17 were studied. (PMID:21945441)
• analysis of claspin expression could be clinically relevant in the diagnosis of HPV-related cervical lesions, in particular when applied to cervico-vaginal cytology (PMID:22731782)
• The conserved C terminus of Claspin interacts with Rad9 and ensures timely activation of the ATR-Chk1 pathway. (PMID:22732499)
• findings identify claspin as an in vivo substrate for the BRCA1 E3 ligase and suggest that its modification selectively triggers CHK1 activation for the homology-directed repair of a subset of genotoxic lesions (PMID:22863316)
• Rad9, Rad17, TopBP1 and claspin play essential roles in heat-induced activation of ATR kinase and heat tolerance. (PMID:23383325)
• USP29 interacts with Claspin and is able to deubiquitinate it both in vivo and in vitro. (PMID:24632611)
• Functional analyses indicat that the expression TopBP1 and Claspin positively affects the survival of brain cancer cells after exposure to radiation. (PMID:25216549)
• And-1 coordinates with Claspin for efficient Chk1 activation in response to replication stress. (PMID:26082189)
• found that USP9X regulated the expression and stability of CLASPIN in an S-phase-specific manner. USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive endogenous DNA damage (PMID:26921344)
• Results unveil a new aspect of PERK function and previously unknown roles for Claspin and Chk1 as negative regulators of DNA replication in the absence of genotoxic stress. (PMID:27375025)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Clspn	ENSMUSG00000042489
rattus_norvegicus	Clspn	ENSRNOG00000011332
drosophila_melanogaster	Claspin	FBGN0052251
caenorhabditis_elegans	clsp-1	WBGENE00009127

Protein

Protein identifiers

Claspin — Q9HAW4 (reviewed: Q9HAW4)

All UniProt accessions (2): Q9HAW4, E7ESG2

UniProt curated annotations — full annotation on UniProt →

Function. Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication or to DNA damage induced by both ionizing and UV irradiation. Adapter protein which binds to BRCA1 and the checkpoint kinase CHEK1 and facilitates the ATR-dependent phosphorylation of both proteins. Also required to maintain normal rates of replication fork progression during unperturbed DNA replication. Binds directly to DNA, with particular affinity for branched or forked molecules and interacts with multiple protein components of the replisome such as the MCM2-7 complex and TIMELESS. Important for initiation of DNA replication, recruits kinase CDC7 to phosphorylate MCM2-7 components.

Subunit / interactions. Interacts (phosphorylation-dependent) with CHEK1; regulates CLSPN function in checkpoint for DNA damage and replication. Interacts with ATR and RAD9A and these interactions are slightly reduced during checkpoint activation. Interacts with BRCA1 and this interaction increases during checkpoint activation. Interacts with TIMELESS; the interaction is required for leading-strand replication. Associates with the MCM2-7 complex and other replisome factors. Interacts (via the acidic patch) with CDC7; the interaction is required for phosphorylation of MCM proteins and CLASPIN by CDC7. Interacts with PCNA. Interacts with FZR1.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated. Undergoes ATR-dependent phosphorylation by CHEK1 during activation of DNA replication or damage checkpoints. Phosphorylation by CSNK1G1/CK1 promotes CHEK1 binding. Phosphorylated by CDC7 during DNA replication, phosphorylation inhibits interaction between the acidic patch and N-terminal segments leading to increased binding to DNA and PCNA. Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) during G1 phase, leading to its degradation by the proteasome. Ubiquitination is mediated via its interaction with FZR1/CDH1. Following DNA damage, it is deubiquitinated by USP28 in G2 phase, preventing its degradation. Proteolytically cleaved by caspase-7 (CASP7) in response to apoptosis, leading to its inactivation.

Domain organisation. The C-terminus of the protein contains 3 potential CHEK1-binding motifs (CKB motifs). Potential phosphorylation sites within CKB motif 1 and CKB motif 2 are required for interaction with CHEK1. The acidic patch region is required for normal DNA replication. Interacts with the N-terminal segments and inhibits binding to DNA and PCNA. Mediates the interaction with the kinase CDC7 as well as some replisome factors and DNA polymerases.

Induction. Expression peaks at S/G2 phases of the cell cycle.

Similarity. Belongs to the claspin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HAW4-1	1	yes
Q9HAW4-2	2
Q9HAW4-3	3

RefSeq proteins (3): NP_001177410, NP_001317419, NP_071394* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024146	Claspin	Family

UniProt features (87 total): modified residue 33, compositionally biased region 13, region of interest 10, mutagenesis site 9, sequence conflict 6, sequence variant 4, repeat 3, coiled-coil region 2, splice variant 2, helix 2, chain 1, short sequence motif 1, site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9TDZ	X-RAY DIFFRACTION	1.35
7AKO	X-RAY DIFFRACTION	1.8
7PLO	ELECTRON MICROSCOPY	2.8
7PFO	ELECTRON MICROSCOPY	3.2
8B9D	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAW4-F1	51.32	0.07

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 (1): 1072–1073 (cleavage; by caspase-7)

Post-translational modifications (33): 26, 42, 46, 53, 65, 67, 83, 110, 113, 225, 260, 516, 718, 720, 723, 731, 744, 762, 808, 810 …

Mutagenesis-validated functional residues (9):

Position	Phenotype
311–318	strongly decreases interaction with pcna.
841	does not affect cleavage by caspase-7 (casp7).
916	impairs interaction with chek1.
945	impairs interaction with chek1.
982	no effect on interaction with chek1.
1031	does not affect cleavage by caspase-7 (casp7).
1072	abolished cleavage by caspase-7 (casp7).
1085	does not affect cleavage by caspase-7 (casp7).
1158	does not affect cleavage by caspase-7 (casp7).

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-5689880	Ub-specific processing proteases
R-HSA-5693607	Processing of DNA double-strand break ends

MSigDB gene sets: 226 (showing top): E2F_Q4, E2F4DP1_01, FISCHER_G1_S_CELL_CYCLE, GOBP_CELL_CYCLE_PHASE_TRANSITION, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, GGAMTNNNNNTCCY_UNKNOWN, IWANAGA_E2F1_TARGETS_INDUCED_BY_SERUM, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, E2F1DP1_01, E2F1DP2_01, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, PID_PLK1_PATHWAY, GOBP_REGULATION_OF_CELL_CYCLE

GO Biological Process (8): DNA replication checkpoint signaling (GO:0000076), DNA damage checkpoint signaling (GO:0000077), DNA repair (GO:0006281), mitotic G2 DNA damage checkpoint signaling (GO:0007095), mitotic DNA replication checkpoint signaling (GO:0033314), DNA damage response (GO:0006974), peptidyl-serine phosphorylation (GO:0018105), activation of protein kinase activity (GO:0032147)

GO Molecular Function (4): DNA secondary structure binding (GO:0000217), anaphase-promoting complex binding (GO:0010997), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Apoptotic execution phase	1
G2/M Checkpoints	1
Deubiquitination	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA integrity checkpoint signaling	2
mitotic G2/M transition checkpoint	2
intracellular membrane-bounded organelle	2
signal transduction in response to DNA damage	1
DNA metabolic process	1
DNA damage response	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
DNA replication checkpoint signaling	1
mitotic cell cycle	1
mitotic DNA integrity checkpoint signaling	1
cellular response to stress	1
protein phosphorylation	1
peptidyl-serine modification	1
positive regulation of protein kinase activity	1
DNA binding	1
protein-containing complex binding	1
nucleic acid binding	1
binding	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

1746 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLSPN	CHEK1	O14757	998
CLSPN	TIMELESS	Q9UNS1	998
CLSPN	TIPIN	Q9BVW5	997
CLSPN	WDHD1	O75717	991
CLSPN	TOPBP1	Q92547	977
CLSPN	RAD9A	Q99638	957
CLSPN	HUS1	O60921	956
CLSPN	ATRIP	Q8WXE1	951
CLSPN	RAD17	O75943	929
CLSPN	MCM10	Q7L590	909
CLSPN	ATM	Q13315	889
CLSPN	CDC45	O75419	878
CLSPN	BTRC	Q9Y297	847
CLSPN	PLK1	P53350	809
CLSPN	CDC25A	P30304	760

IntAct

52 interactions, top by confidence:

A	B	Type	Score
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
CLSPN	CDC45	psi-mi:“MI:0915”(physical association)	0.680
CDC45	CLSPN	psi-mi:“MI:0915”(physical association)	0.680
FZR1	CLSPN	psi-mi:“MI:0915”(physical association)	0.640
CLSPN	CHEK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
CLSPN	CHEK1	psi-mi:“MI:0915”(physical association)	0.600
CHEK1	CLSPN	psi-mi:“MI:0915”(physical association)	0.600
CDC45	RPA2	psi-mi:“MI:0914”(association)	0.580
CDK9	ATR	psi-mi:“MI:0914”(association)	0.560
CDK9	CLSPN	psi-mi:“MI:0915”(physical association)	0.560
PRIMPOL	RPA2	psi-mi:“MI:0914”(association)	0.510
CLSPN	RAD9A	psi-mi:“MI:0915”(physical association)	0.400
Tipin	NEMF	psi-mi:“MI:0914”(association)	0.350
Timeless	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
GJB2	SNX3	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
CSNK2B	OSBPL8	psi-mi:“MI:0914”(association)	0.350
MIF	BLTP3B	psi-mi:“MI:0914”(association)	0.350
SRP14	EIF3F	psi-mi:“MI:0914”(association)	0.350

BioGRID (195): CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), CLSPN (Affinity Capture-Western)

ESM2 similar proteins: A0A3Q2UEI8, A0JNH9, A2BIL8, A8PUI7, B1H1S4, B2GUZ2, E7FAP1, E9Q309, F1R983, O60284, P49452, P51960, P86345, Q0P5H2, Q3T0A6, Q3T8J9, Q4KLP8, Q4QY64, Q4R731, Q535K8, Q563C3, Q58EL7, Q5FBB7, Q5QJE6, Q5VT06, Q5XG21, Q65Z40, Q6KAQ7, Q6NWJ0, Q6P0N0, Q6P6I6, Q76FK4, Q7YQM1, Q7YQM2, Q80WQ8, Q8C263, Q8C551, Q8IYH5, Q8NA57, Q8R2M2

Diamond homologs: Q80YR7, Q9DF50, Q9HAW4, Q8IRB5

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
FBXW11	down-regulates	CLSPN	ubiquitination
PLK1	down-regulates	CLSPN	phosphorylation
CHEK1	up-regulates	CLSPN	phosphorylation
PI4K2A	down-regulates	CLSPN	phosphorylation
WDHD1	“up-regulates activity”	CLSPN	binding
USP20	“up-regulates quantity by stabilization”	CLSPN	deubiquitination
CDC7	“up-regulates activity”	CLSPN	phosphorylation
CLSPN	up-regulates	CHEK1	binding
APC-c	“down-regulates quantity by destabilization”	CLSPN	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 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
Activation of ATR in response to replication stress	9	57.5×	7e-12
Activation of the pre-replicative complex	6	41.6×	5e-07
Presynaptic phase of homologous DNA pairing and strand exchange	6	34.7×	1e-06
Impaired BRCA2 binding to RAD51	5	32.8×	2e-05
HDR through Single Strand Annealing (SSA)	5	31.1×	2e-05
Regulation of TP53 Activity through Phosphorylation	8	20.0×	5e-07
G2/M DNA damage checkpoint	6	15.3×	9e-05
Processing of DNA double-strand break ends	6	14.6×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
DNA replication	10	31.8×	2e-10
DNA repair	9	11.1×	2e-05
DNA damage response	7	7.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	170
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2814 predictions. Top by Δscore:

Variant	Effect	Δscore
1:35736908:CCATA:C	donor_loss	1.0000
1:35736909:CATA:C	donor_loss	1.0000
1:35736910:ATAC:A	donor_loss	1.0000
1:35736911:TACC:T	donor_loss	1.0000
1:35736912:A:T	donor_loss	1.0000
1:35737071:TTCAC:T	acceptor_gain	1.0000
1:35737073:CAC:C	acceptor_gain	1.0000
1:35737074:AC:A	acceptor_gain	1.0000
1:35737074:ACC:A	acceptor_loss	1.0000
1:35737075:CC:C	acceptor_gain	1.0000
1:35737075:CCTG:C	acceptor_loss	1.0000
1:35737076:C:CC	acceptor_gain	1.0000
1:35737076:CTGAG:C	acceptor_loss	1.0000
1:35737986:GCTCA:G	donor_loss	1.0000
1:35737987:CTCAC:C	donor_loss	1.0000
1:35737988:TCA:T	donor_loss	1.0000
1:35737989:CA:C	donor_loss	1.0000
1:35737990:A:AC	donor_gain	1.0000
1:35737990:AC:A	donor_gain	1.0000
1:35737991:C:CC	donor_gain	1.0000
1:35737991:CC:C	donor_gain	1.0000
1:35737991:CCATT:C	donor_gain	1.0000
1:35738093:TGTGC:T	acceptor_gain	1.0000
1:35738094:GTGC:G	acceptor_gain	1.0000
1:35738095:TGC:T	acceptor_gain	1.0000
1:35738096:GC:G	acceptor_gain	1.0000
1:35738097:CC:C	acceptor_gain	1.0000
1:35738098:C:CC	acceptor_gain	1.0000
1:35738098:C:T	acceptor_gain	1.0000
1:35738098:CTGA:C	acceptor_loss	1.0000

AlphaMissense

8941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:35738477:C:G	R1179P	0.999
1:35739148:A:G	W1140R	0.999
1:35739148:A:T	W1140R	0.999
1:35738486:C:G	R1176P	0.998
1:35739146:C:A	W1140C	0.998
1:35739146:C:G	W1140C	0.998
1:35739152:A:C	F1138L	0.998
1:35739152:A:T	F1138L	0.998
1:35739153:A:G	F1138S	0.998
1:35739154:A:G	F1138L	0.998
1:35739201:A:G	L1122P	0.998
1:35739225:A:G	L1114P	0.998
1:35739158:C:A	R1136S	0.997
1:35739158:C:G	R1136S	0.997
1:35739222:C:G	R1115P	0.997
1:35739231:C:G	R1112P	0.997
1:35762000:C:G	R298P	0.997
1:35762009:C:G	R295P	0.997
1:35739147:C:G	W1140S	0.996
1:35751440:C:G	R613P	0.996
1:35751476:A:G	L601P	0.996
1:35739213:T:G	Q1118P	0.995
1:35739392:A:G	L1094P	0.995
1:35751468:C:G	A604P	0.995
1:35762006:A:G	L296P	0.995
1:35739159:C:G	R1136T	0.994
1:35739186:A:G	L1127P	0.994
1:35738494:C:A	R1173S	0.993
1:35738494:C:G	R1173S	0.993
1:35739153:A:C	F1138C	0.993

dbSNP variants (sampled 300 via entrez): RS1000009644 (1:35736718 G>A), RS1000027309 (1:35755440 T>A), RS1000258982 (1:35750293 C>T), RS1000292083 (1:35733001 G>A), RS1000369246 (1:35742129 A>C), RS1000390976 (1:35740562 G>A,C), RS1000425210 (1:35757015 C>G), RS1000683595 (1:35733316 TTTTC>T), RS1000784827 (1:35769340 C>A,G), RS1000855194 (1:35762209 A>G), RS1000864787 (1:35769382 C>T), RS1000950843 (1:35762680 T>C), RS1001015676 (1:35721003 C>T), RS1001026925 (1:35734780 C>T), RS1001074219 (1:35762887 A>G)

Disease associations

OMIM: gene MIM:605434 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): myoepithelial tumor (MONDO:0002380)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007483_11	Waist-to-hip ratio adjusted for BMI (additive genetic model)	4.000000e-07
GCST007487_18	Waist-to-hip ratio adjusted for BMI (additive genetic model)	7.000000e-06
GCST90002390_593	Mean corpuscular hemoglobin	3.000000e-10
GCST90002392_158	Mean corpuscular volume	7.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067307 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.29	Kd	50.82	nM	CHEMBL5653589
7.03	ED50	93.85	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2148089: Binding affinity to human CLSPN incubated for 45 mins by Kinobead based pull down assay	kd	0.0508	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Benzo(a)pyrene	increases phosphorylation, affects response to substance, increases expression, increases mutagenesis, affects reaction (+1 more)	3
lasiocarpine	increases expression, decreases expression, increases metabolic processing	2
Silicon Dioxide	decreases expression	2
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
picrasidine I	increases cleavage, decreases expression, decreases reaction	1
JNK-IN-8	decreases reaction, increases cleavage	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
lead acetate	increases expression	1
riddelliine	increases metabolic processing, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
zinc chromate	increases abundance, decreases expression	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
phenethyl isothiocyanate	decreases expression	1
polyhexamethyleneguanidine	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
nickel acetate	decreases reaction, increases expression, decreases expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
incobotulinumtoxinA	decreases expression	1
Dasatinib	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651131	Binding	Binding affinity to human CLSPN incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis