CDC45

Summary

CDC45 (cell division cycle 45, HGNC:1739) is a protein-coding gene on chromosome 22q11.21, encoding Cell division control protein 45 homolog (O75419). Required for initiation of chromosomal DNA replication. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

The protein encoded by this gene was identified by its strong similarity with Saccharomyces cerevisiae Cdc45, an essential protein required to the initiation of DNA replication. Cdc45 is a member of the highly conserved multiprotein complex including Cdc6/Cdc18, the minichromosome maintenance proteins (MCMs) and DNA polymerase, which is important for early steps of DNA replication in eukaryotes. This protein has been shown to interact with MCM7 and DNA polymerase alpha. Studies of the similar gene in Xenopus suggested that this protein play a pivotal role in the loading of DNA polymerase alpha onto chromatin. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 8318 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 7 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 392 total — 12 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 89
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_003504

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1739
Approved symbol	CDC45
Name	cell division cycle 45
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000093009
Ensembl biotype	protein_coding
OMIM	603465
Entrez	8318

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263201, ENST00000404724, ENST00000407835, ENST00000428937, ENST00000437685, ENST00000438587, ENST00000455750, ENST00000471470, ENST00000483431, ENST00000487669, ENST00000491520, ENST00000493724, ENST00000671972, ENST00000672837, ENST00000932444

RefSeq mRNA: 4 — MANE Select: NM_003504 NM_001178010, NM_001178011, NM_001369291, NM_003504

CCDS: CCDS13762, CCDS54499, CCDS54500

Canonical transcript exons

ENST00000263201 — 19 exons

Exon	Start	End
ENSE00000331191	19505362	19505481
ENSE00000650788	19514749	19514887
ENSE00000650789	19514965	19515048
ENSE00000650790	19516527	19516645
ENSE00003469360	19507386	19507517
ENSE00003479778	19494327	19494382
ENSE00003484026	19480158	19480217
ENSE00003505829	19480953	19481045
ENSE00003547547	19508530	19508691
ENSE00003560950	19499101	19499151
ENSE00003583698	19518844	19518909
ENSE00003600829	19497386	19497447
ENSE00003603046	19482690	19482827
ENSE00003614871	19507766	19507864
ENSE00003640334	19516817	19516893
ENSE00003688309	19495981	19496029
ENSE00003694637	19483862	19484005
ENSE00003890102	19479920	19480019
ENSE00003894286	19520481	19520608

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 96.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.2799 / max 568.7488, expressed in 1396 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191050	30.0264	1384
191049	0.2103	57
191048	0.0433	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	96.35	gold quality
secondary oocyte	CL:0000655	94.94	gold quality
right testis	UBERON:0004534	92.42	gold quality
left testis	UBERON:0004533	92.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.93	gold quality
testis	UBERON:0000473	90.11	gold quality
ventricular zone	UBERON:0003053	89.43	gold quality
ganglionic eminence	UBERON:0004023	88.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.32	gold quality
mucosa of transverse colon	UBERON:0004991	85.91	gold quality
embryo	UBERON:0000922	83.68	gold quality
rectum	UBERON:0001052	79.41	gold quality
stromal cell of endometrium	CL:0002255	79.17	gold quality
esophagus mucosa	UBERON:0002469	77.85	gold quality
bone marrow	UBERON:0002371	77.80	gold quality
vermiform appendix	UBERON:0001154	76.65	gold quality
bone marrow cell	CL:0002092	74.77	gold quality
lymph node	UBERON:0000029	73.94	gold quality
endometrium epithelium	UBERON:0004811	73.65	silver quality
lower esophagus mucosa	UBERON:0035834	72.87	gold quality
adult organism	UBERON:0007023	71.68	silver quality
caecum	UBERON:0001153	70.54	gold quality
trabecular bone tissue	UBERON:0002483	70.34	gold quality
spleen	UBERON:0002106	69.45	gold quality
granulocyte	CL:0000094	69.41	gold quality
transverse colon	UBERON:0001157	69.32	gold quality
small intestine Peyer’s patch	UBERON:0003454	68.55	gold quality
smooth muscle tissue	UBERON:0001135	68.38	gold quality
cortical plate	UBERON:0005343	67.89	gold quality
esophagus	UBERON:0001043	67.55	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ENAD-20	yes	385.53
E-ANND-3	yes	3.91
E-MTAB-6911	no	225.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, E2F1, E2F4, GLI2

miRNA regulators (miRDB)

12 targeting CDC45, 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-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-4676-5P	97.54	65.29	715
HSA-MIR-575	97.54	65.18	718
HSA-MIR-493-3P	97.50	66.44	731

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 39)

• the Chk1-mediated S-phase checkpoint targets initiation factor Cdc45 via a Cdc25A/Cdk2-independent mechanism (PMID:16912045)
• MCM4 phosphorylation by Cdc7 kinase facilitates its interaction with Cdc45 on chromatin (PMID:17046832)
• CDC45L is part of the GINS complex. (PMID:17557111)
• Cdc45 may play an important role in elongation of DNA replication by bridging the processive DNA polymerases delta and epsilon with the replicative helicase in the elongating machinery (PMID:17573775)
• Cdc45 expression is tightly associated with proliferating cell populations and Cdc45 seems to be a promising candidate for a novel proliferation marker in cancer cell biology (PMID:17608804)
• Thus, the evidences for ubiquitylation of Cdc45 refer the first posttranslational modification of this essential replication factor. (PMID:17767920)
• human TopBP1 is involved in the formation of the initiation complex of replication in human cells and is required for the recruitment of Cdc45 to origins of DNA replication (PMID:17887956)
• Results suggest that apoptosis induced by replication inhibitors in Chk1-depleted cells is dependent upon the helicase cofactor Cdc45. (PMID:18239674)
• CDT1 associates with CDC7 and recruits CDC45 to chromatin during S phase (PMID:19054765)
• interactions between Cdc45, Mcm2-7, and the GINS complex (collectively called the CMG complex), which seem to play a key role in the formation and progression of replication forks (PMID:19805216)
• The coordinated binding of DUE-B and Cdc45 to origins and the physical interactions of DUE-B, Cdc45, and TopBP1 suggest that complexes of these proteins are necessary for replication initiation. (PMID:20065034)
• Cdc45, which is known to be required for replication fork progression, shows similar patterns of origin association to those of Timeless (PMID:20124417)
• Structural and functional insights into the DNA replication factor Cdc45 reveal an evolutionary relationship to the DHH family of phosphoesterases (PMID:22147708)
• Data show that using a 200-nt primed circular DNA substrate, the combined action of DNA polymerase epsilon and the Cdc45/Mcm2-7/GINS (CMG complex) leads to the formation of products >10 kb in length. (PMID:22474384)
• After UV-damage, Cdc45 is still present in a large multi-protein complex and that its mobility within living cells is consistently similar following UVC-mediated DNA damage. (PMID:22536402)
• CDC45 directly interact with MCM2-7 proteins; with PSF2, PSF3 and SLD5 in GINS subunits; and with replication protein A2, AND-1. A considerable portion of CDC45 localizes in a region other than the DNA replication forks in nuclei. (PMID:23364835)
• Data suggest that CDC45 and MCM10 (minichromosome maintenance complex component 10) directly interact and establish a mutual co-operation in DNA binding; key domains appear to interact and then interact with DNA inside cells or in cell-free systems. (PMID:23750504)
• The findings suggest that hCdc45 not only binds to but also slides on DNA with a 3’-5’ polarity and, thereby acts as a molecular ‘wedge’ to initiate DNA strand displacement. (PMID:24293646)
• The depletion of HDHB from human cells diminishes Cdc45 association with chromatin, suggesting that HDHB may facilitate Cdc45 recruitment at G1/S in human cells. (PMID:25933514)
• ectopic expression of Cdc45 led to increased firing of replication origins, severe replication stress, an early S-phase arrest, replication fork stalling, and eventually cell death by apoptosis. (PMID:26919204)
• The size and relative position of the three helices (alpha2, alpha7 and alpha8) that contribute to the active site architecture are highly conserved between Cdc45 and RecJ, whereas the helical structure on the solvent-exposed DHH side (alpha3, alpha4 and alpha5) shows more conformational variability. (PMID:27189187)
• Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis (PMID:27374770)
• Date show that when Wee1 alone is inhibited, Chk1 suppresses CDC45 loading and thereby limits the extent of unscheduled replication initiation and subsequent S-phase DNA damage, despite very high CDK-activity. (PMID:28030798)
• strong evidence that Cdc45 directly loads RPA on the emerging nascent ssDNA (PMID:28100698)
• The oncogenic activity of cell division cycle 45 was also confirmed in vivo. In conclusion, cell division cycle 45 may serve as a novel biomarker and a potential therapeutic target for papillary thyroid cancer. (PMID:28474999)
• The conserved C-terminal domain of DUE-B is required for its binding to TopBP1, Treslin, Cdc45, and the MCM2-7 complex, as well as for the efficient loading of Treslin, Cdc45, and TopBP1 on chromatin (PMID:30037903)
• expression knockdown of CDC45 inhibited non-small cell lung cancer cell proliferation. (PMID:30887286)
• Pathogenic variants in CDC45 on the remaining allele in patients with a chromosome 22q11.2 deletion result in a novel autosomal recessive condition. (PMID:31474763)
• High level of DNAJA1 predicted poor prognosis for colorectal cancer (CRC) patients. Its expression was highly linked with E2F1 and CDC45 in CRC tissues. More importantly, KNK437 significantly suppressed the growth of DNAJA1 expressing tumor in vivo (PMID:31477839)
• Protein phosphatase 2A controls ongoing DNA replication by binding to and regulating cell division cycle 45 (PMID:31562245)
• RYBP suppresses esophageal squamous cell carcinoma proliferation by downregulating CDC6 and CDC45, thus inhibiting the G1-S transition (PMID:32209426)
• Expression of Cell Division Cycle Protein 45 in Tissue Microarrays and the CDC45 Gene by Bioinformatics Analysis in Human Hepatocellular Carcinoma and Patient Outcomes. (PMID:33622998)
• A synonymous variant in a non-canonical exon of CDC45 disrupts splicing in two affected sibs with Meier-Gorlin syndrome with craniosynostosis. (PMID:33639314)
• CircCDC45 promotes the malignant progression of glioblastoma by modulating the miR-485-5p/CSF-1 axis. (PMID:34627193)
• Knockdown of circular RNA hsa_circ_0062270 suppresses the progression of melanoma via downregulation of CDC45. (PMID:34931691)
• Systematic pancancer analysis identifies CDC45 as having an oncogenic role in human cancers. (PMID:36082823)
• IGF2BP2 promotes glycolysis and hepatocellular carcinoma stemness by stabilizing CDC45 mRNA via m6A modification. (PMID:37985379)
• A second hotspot for pathogenic exon-skipping variants in CDC45. (PMID:38467731)
• Validation of CDC45 as a novel biomarker for diagnosis and prognosis of gastric cancer. (PMID:38515458)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdc45	ENSDARG00000043720
mus_musculus	Cdc45	ENSMUSG00000000028
rattus_norvegicus	Cdc45	ENSRNOG00000070046
drosophila_melanogaster	Cdc45	FBGN0026143
caenorhabditis_elegans		WBGENE00009372

Protein

Protein identifiers

Cell division control protein 45 homolog — O75419 (reviewed: O75419)

Alternative names: PORC-PI-1

All UniProt accessions (7): O75419, A0A5F9ZH29, A0A5F9ZI22, A0A5K1VW85, C9J911, C9K087, H7BZ91

UniProt curated annotations — full annotation on UniProt →

Function. Required for initiation of chromosomal DNA replication. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built.

Subunit / interactions. Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex. Associated with ORC2. Interacts with HELB.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Widely expressed, highest levels are found in adult testis and thymus and in fetal liver.

Disease relevance. Meier-Gorlin syndrome 7 (MGORS7) [MIM:617063] A form of Meier-Gorlin syndrome, a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal. MGORS7 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CDC45 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75419-1	1	yes
O75419-2	2
O75419-3	3

RefSeq proteins (4): NP_001171481, NP_001171482, NP_001356220, NP_003495* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003874	CDC45	Family

Pfam: PF02724

UniProt features (74 total): helix 27, strand 16, sequence variant 15, sequence conflict 4, turn 4, modified residue 3, splice variant 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5DGO	X-RAY DIFFRACTION	2.1
9E2Z	ELECTRON MICROSCOPY	2.6
7PLO	ELECTRON MICROSCOPY	2.8
7PFO	ELECTRON MICROSCOPY	3.2
6XTX	ELECTRON MICROSCOPY	3.29
8B9D	ELECTRON MICROSCOPY	3.4
6XTY	ELECTRON MICROSCOPY	6.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75419-F1	92.59	0.85

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 (3): 130, 144, 148

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-176974	Unwinding of DNA
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-69205	G1/S-Specific Transcription
R-HSA-1640170	Cell Cycle
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69002	DNA Replication Pre-Initiation
R-HSA-69190	DNA strand elongation
R-HSA-69206	G1/S Transition
R-HSA-69239	Synthesis of DNA
R-HSA-69242	S Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69306	DNA Replication
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints

MSigDB gene sets: 578 (showing top): E2F_Q4, REACTOME_DNA_REPLICATION, MODULE_52, E2F_Q4_01, MODULE_451, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, CCAWYNNGAAR_UNKNOWN, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOLDRATH_ANTIGEN_RESPONSE, PATIL_LIVER_CANCER, PUJANA_CHEK2_PCC_NETWORK, MODULE_118

GO Biological Process (5): DNA replication checkpoint signaling (GO:0000076), double-strand break repair via break-induced replication (GO:0000727), DNA replication (GO:0006260), DNA replication initiation (GO:0006270), mitotic DNA replication preinitiation complex assembly (GO:1902977)

GO Molecular Function (4): chromatin binding (GO:0003682), DNA replication origin binding (GO:0003688), single-stranded DNA binding (GO:0003697), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), centrosome (GO:0005813), DNA replication preinitiation complex (GO:0031261), ciliary basal body (GO:0036064), CMG complex (GO:0071162), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
G1/S Transition	2
Cell Cycle, Mitotic	2
DNA Replication	2
Cell Cycle	2
G2/M Checkpoints	1
DNA strand elongation	1
DNA Replication Pre-Initiation	1
Synthesis of DNA	1
Mitotic G1 phase and G1/S transition	1
S Phase	1
Cell Cycle Checkpoints	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
binding	2
microtubule organizing center	2
DNA integrity checkpoint signaling	1
double-strand break repair via homologous recombination	1
DNA biosynthetic process	1
DNA-templated DNA replication	1
DNA replication preinitiation complex assembly	1
mitotic DNA replication	1
mitotic cell cycle process	1
sequence-specific double-stranded DNA binding	1
DNA binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
centriole	1
nucleoplasm	1
nuclear pre-replicative complex	1
protein-DNA complex	1
nuclear protein-containing complex	1
cilium	1
nuclear chromosome	1
GINS complex	1
DNA replication preinitiation complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3042 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDC45	MCM10	Q7L590	999
CDC45	GINS4	Q9BRT9	996
CDC45	TOPBP1	Q92547	995
CDC45	GINS3	Q9BRX5	993
CDC45	TICRR	Q7Z2Z1	977
CDC45	MCM5	P33992	976
CDC45	MCM3	P25205	974
CDC45	CDC6	Q99741	970
CDC45	WDHD1	O75717	970
CDC45	CDC7	O00311	970
CDC45	DBF4	Q9UBU7	969
CDC45	CDT1	Q9H211	964
CDC45	MCM7	P33993	962
CDC45	MRC1	P22897	958
CDC45	MCM6	Q14566	944

IntAct

133 interactions, top by confidence:

A	B	Type	Score
PDS5B	RAD21	psi-mi:“MI:0914”(association)	0.860
CEP55	CDC45	psi-mi:“MI:0915”(physical association)	0.780
CDC45	CEP55	psi-mi:“MI:0915”(physical association)	0.780
CLSPN	CDC45	psi-mi:“MI:0915”(physical association)	0.680
CDC45	CLSPN	psi-mi:“MI:0915”(physical association)	0.680
GINS1	CDC45	psi-mi:“MI:0914”(association)	0.620
GINS1	CDC45	psi-mi:“MI:0915”(physical association)	0.620
CDC45	RPA2	psi-mi:“MI:0915”(physical association)	0.580
RPA2	CDC45	psi-mi:“MI:0915”(physical association)	0.580
CDC45	RPA2	psi-mi:“MI:0914”(association)	0.580
MCM2	CDC45	psi-mi:“MI:0407”(direct interaction)	0.570
CDC45	GINS4	psi-mi:“MI:0407”(direct interaction)	0.570
MCM2	CDC45	psi-mi:“MI:0914”(association)	0.570
CDKN1A	CDC45	psi-mi:“MI:0407”(direct interaction)	0.570
CDC45	CDKN1A	psi-mi:“MI:2364”(proximity)	0.570
CDC45	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
CDC45	RAB4B	psi-mi:“MI:0915”(physical association)	0.560
CDC45	ZRANB1	psi-mi:“MI:0915”(physical association)	0.560
TOPBP1	CDC45	psi-mi:“MI:0915”(physical association)	0.540
CDC45	TOPBP1	psi-mi:“MI:0407”(direct interaction)	0.540
CDC45	TOPBP1	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (182): CEP55 (Two-hybrid), CDC45 (Affinity Capture-Western), CDC45 (Affinity Capture-Western), CDC45 (Affinity Capture-MS), ACTR1A (Co-fractionation), CDC45 (Co-fractionation), RFC1 (Co-fractionation), CDC45 (Affinity Capture-MS), CDKN1A (Co-localization), ORC2 (Two-hybrid), CDC45 (Reconstituted Complex), CDC45 (Affinity Capture-MS), CDC45 (Affinity Capture-MS), CDC45 (Affinity Capture-MS), CDC45 (Affinity Capture-MS)

ESM2 similar proteins: A3GFS1, A5DA88, A7TNS4, A8QHQ0, F4K2K3, G5EF68, O13943, O36023, O60072, O74113, O74458, O75419, O94590, O94679, P06777, P30666, P33339, P33755, P34466, P36070, P46682, P53914, P87145, P91133, P97393, Q06680, Q08032, Q09915, Q10110, Q10428, Q10429, Q13017, Q21407, Q2KJB1, Q3MNT0, Q55GA4, Q595W7, Q5R629, Q6BVE1, Q6CMD3

Diamond homologs: O75419, Q9YHZ6, Q9Z1X9, Q99107

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CDC45	“up-regulates activity”	MCM	binding
DTD1	“up-regulates activity”	CDC45	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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	8	33.4×	2e-08
Activation of the pre-replicative complex	6	27.2×	1e-05
DNA Replication	5	16.5×	1e-03
Mitotic G1 phase and G1/S transition	5	12.8×	3e-03
Assembly of the pre-replicative complex	5	9.7×	8e-03
Processing of DNA double-strand break ends	6	9.5×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
inner cell mass cell proliferation	5	51.1×	8e-06
DNA replication initiation	6	38.6×	3e-06
mitotic G2 DNA damage checkpoint signaling	5	22.9×	4e-04
DNA replication	11	18.7×	1e-08
protein import into nucleus	6	8.9×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	11
Uncertain significance	145
Likely benign	148
Benign	37

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1069021	NM_003504.5(CDC45):c.914_915del (p.Val305fs)	Pathogenic
1162262	NM_003504.5(CDC45):c.1445_1448del (p.Lys482fs)	Pathogenic
1373744	NM_003504.5(CDC45):c.790_791del (p.Ser264fs)	Pathogenic
1962655	NM_003504.5(CDC45):c.1489_1490del (p.Leu497fs)	Pathogenic
2021022	NM_003504.5(CDC45):c.121del (p.Gln41fs)	Pathogenic
2085627	NM_003504.5(CDC45):c.1180del (p.Thr394fs)	Pathogenic
253105	NM_003504.5(CDC45):c.(342+1_343-1)_(486+1_487-1)del	Pathogenic
2747512	NM_003504.5(CDC45):c.870del (p.Cys291fs)	Pathogenic
2780452	NM_003504.5(CDC45):c.1279C>T (p.Gln427Ter)	Pathogenic
3010292	NM_003504.5(CDC45):c.165G>A (p.Trp55Ter)	Pathogenic
4525735	NM_003504.5(CDC45):c.1642G>T (p.Glu548Ter)	Pathogenic
619950	NM_003504.5(CDC45):c.326_329dup (p.Asn111fs)	Pathogenic
1903361	NM_003504.5(CDC45):c.542+221_542+222del	Likely pathogenic
2113883	NM_003504.5(CDC45):c.52-2A>G	Likely pathogenic
253097	NM_003504.5(CDC45):c.677A>G (p.Asp226Gly)	Likely pathogenic
253099	NM_003504.5(CDC45):c.226A>C (p.Asn76His)	Likely pathogenic
253102	NM_003504.5(CDC45):c.203A>G (p.Gln68Arg)	Likely pathogenic
253104	NM_003504.5(CDC45):c.893C>T (p.Ala298Val)	Likely pathogenic
3068440	NM_003504.5(CDC45):c.204G>A (p.Gln68=)	Likely pathogenic
3627786	NM_003504.5(CDC45):c.591+1G>A	Likely pathogenic
3678842	NM_003504.5(CDC45):c.654-2A>G	Likely pathogenic
4849392	NM_003504.5(CDC45):c.1490del (p.Leu497fs)	Likely pathogenic
872336	NM_003504.5(CDC45):c.*1+5G>A	Likely pathogenic

SpliceAI

3163 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19483858:TTAGA:T	acceptor_loss	1.0000
22:19483859:TA:T	acceptor_loss	1.0000
22:19483860:A:AG	acceptor_gain	1.0000
22:19483860:A:G	acceptor_loss	1.0000
22:19483861:G:GT	acceptor_gain	1.0000
22:19483861:GAT:G	acceptor_gain	1.0000
22:19483861:GATC:G	acceptor_gain	1.0000
22:19483861:GATCA:G	acceptor_gain	1.0000
22:19484003:GAG:G	donor_gain	1.0000
22:19484005:GGTG:G	donor_loss	1.0000
22:19484007:T:A	donor_loss	1.0000
22:19505472:T:G	donor_gain	1.0000
22:19505472:T:TG	donor_gain	1.0000
22:19505474:GAGTA:G	donor_gain	1.0000
22:19505476:G:GG	donor_gain	1.0000
22:19505478:A:AG	donor_gain	1.0000
22:19505482:G:GG	donor_gain	1.0000
22:19507764:A:AG	acceptor_gain	1.0000
22:19507765:G:GA	acceptor_gain	1.0000
22:19507765:GTCTT:G	acceptor_gain	1.0000
22:19507863:GG:G	donor_gain	1.0000
22:19507864:GG:G	donor_gain	1.0000
22:19508525:GACA:G	acceptor_loss	1.0000
22:19508526:ACAG:A	acceptor_loss	1.0000
22:19508527:CA:C	acceptor_loss	1.0000
22:19508529:G:GA	acceptor_loss	1.0000
22:19514885:G:GT	donor_gain	1.0000
22:19516640:G:GT	donor_gain	1.0000
22:19516642:AGAAG:A	donor_loss	1.0000
22:19516643:G:GT	donor_gain	1.0000

AlphaMissense

3793 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19497446:T:A	W218R	0.998
22:19497446:T:C	W218R	0.998
22:19507426:A:C	S289R	0.998
22:19507428:C:A	S289R	0.998
22:19507428:C:G	S289R	0.998
22:19480213:T:C	L36P	0.997
22:19516842:G:C	A529P	0.997
22:19518877:T:C	F557S	0.996
22:19480197:T:C	C31R	0.995
22:19480199:T:G	C31W	0.995
22:19482809:T:A	N108K	0.995
22:19482809:T:G	N108K	0.995
22:19496028:C:G	S197W	0.995
22:19499114:G:A	G223R	0.995
22:19499114:G:C	G223R	0.995
22:19516609:G:A	G508D	0.995
22:19518889:T:C	L561P	0.995
22:19480191:G:C	A29P	0.994
22:19480996:T:A	V52D	0.994
22:19499115:G:A	G223E	0.994
22:19482718:G:A	G78E	0.993
22:19508592:C:A	A373D	0.993
22:19515026:T:C	L473P	0.993
22:19516558:T:C	L491P	0.993
22:19516608:G:C	G508R	0.993
22:19480198:G:A	C31Y	0.992
22:19482714:T:C	C77R	0.992
22:19482780:G:C	D99H	0.992
22:19482781:A:T	D99V	0.992
22:19497390:C:A	A199D	0.992

dbSNP variants (sampled 300 via entrez): RS1000111426 (22:19493249 T>G), RS1000140663 (22:19511400 G>A), RS1000163845 (22:19493611 T>G), RS1000191251 (22:19495696 C>G,T), RS1000264335 (22:19499516 G>A), RS1000318353 (22:19487088 G>GT), RS1000438260 (22:19487484 C>G), RS1000445474 (22:19499651 C>T), RS1000529765 (22:19521026 A>G), RS1000530205 (22:19510657 T>C), RS1000577814 (22:19506070 A>C), RS1000702491 (22:19505219 A>C,G), RS1000729743 (22:19500527 G>A), RS1000859321 (22:19483362 G>A), RS1000940285 (22:19494769 G>A)

Disease associations

OMIM: gene MIM:603465 | disease phenotypes: MIM:617063, MIM:300068

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 7	Definitive	Autosomal recessive
Meier-Gorlin syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Meier-Gorlin syndrome 7	Definitive	AR

Mondo (4): Meier-Gorlin syndrome 7 (MONDO:0014894), androgen insensitivity syndrome (MONDO:0019154), microcephaly (MONDO:0001149), Meier-Gorlin syndrome (MONDO:0016817)

Orphanet (3): Ear-patella-short stature syndrome (Orphanet:2554), Androgen insensitivity syndrome (Orphanet:754), Complete androgen insensitivity syndrome (Orphanet:99429)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000076	Vesicoureteral reflux
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000260	Wide anterior fontanel
HP:0000278	Retrognathia
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000453	Choanal atresia
HP:0000486	Strabismus
HP:0000520	Proptosis
HP:0000545	Myopia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003075_15	Cognitive decline rate in late mild cognitive impairment	1.000000e-06
GCST003075_68	Cognitive decline rate in late mild cognitive impairment	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D013734	Androgen-Insensitivity Syndrome	C12.050.351.875.253.096.500; C12.200.706.316.096.500; C12.800.316.096.500; C16.131.939.316.096.500; C16.320.322.061; C19.391.119.096.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C538012	Meier-Gorlin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3040 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	IC50	300	nM	MOLIBRESIB
5.07	IC50	8600	nM	CHEMBL168868

PubChem BioAssay actives

2 with measured affinity, of 11 total; 2 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178849: Inhibition of CDC45L (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.3000	uM
2-[(1R,3aS,4R,5R,7aR)-5-(6-cyanohexan-2-yl)-7a-methyl-1-(6-methylheptan-2-yl)-1,2,3,3a,4,5,6,7-octahydroinden-4-yl]acetic acid	52055: Inhibitory activity tested against human cell division cycle 45-like 2	ic50	8.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	5
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment, affects expression	4
bisphenol A	affects expression, decreases expression, increases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Arsenic Trioxide	decreases expression	2
Fluorouracil	affects expression, affects cotreatment, increases expression	2
Quercetin	decreases expression, increases expression	2
Tretinoin	decreases expression	2
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
lasiocarpine	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	decreases expression	1
geraniol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
cryptolepine	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
phenethyl isothiocyanate	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
azoxystrobin	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697579	Binding	Inhibition of CDC45L (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04422366	PHASE3	RECRUITING	Evaluate the Efficacy, Immunogenicity and Safety of 9-valent HPV Recombinant Vaccine in Chinese Healthy Females
NCT04425291	PHASE3	COMPLETED	Evaluate the Immunogenicity and Safety of 4-valent and 9-valent HPV Recombinant Vaccine in Chinese Healthy Females
NCT04895020	PHASE3	RECRUITING	Immunobridging Study of 9-valent Human Papillomavirus Recombinant Vaccine in Chinese Females Aged 9 to 19 Years
NCT05372016	PHASE3	COMPLETED	Evaluate the Immunogenicity and Safety of 9-valent HPV Recombinant Vaccine in Chinese Healthy Females
NCT05584332	PHASE3	TERMINATED	A Phase Ⅲ Study to Evaluate the Efficacy, Immunogenicity, Safety of Quadrivalent HPV Recombinant Vaccine in Chinese Healthy Females
NCT07520565	PHASE3	RECRUITING	A Multicentre, Randomised, Double-blind, Placebo-parallel Controlled Phase Ⅲ Clinical Trial Evaluating the Efficacy and Safety of BXOS110 Injection in the Treatment of Acute Ischaemic Stroke Within 3 Hours of Onset.
NCT02905565	PHASE2	COMPLETED	NBP in Adult Patients With Acute Ischemic Stroke (AIS)
NCT03676101	PHASE1	COMPLETED	Evaluate the Safety and Primary Immunogenicity of 9-valent HPV Recombinant Vaccine in Chinese Healthy Females
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry
NCT03105063	Not specified	UNKNOWN	Evaluation of the AIIS Using Hip Ultrasound(AIISUS)
NCT04252001	Not specified	NOT_YET_RECRUITING	Growing up With the Young Endocrine Support System (YESS!)
NCT04708431	Not specified	RECRUITING	Androgen Receptor, Implications for Health and Wellbeing: Natural History Study of Individuals With Androgen Insensitivity
NCT05152329	Not specified	UNKNOWN	Investigating the Potential Psychological Impact of Early Screening and Long-term Monitoring for Adolescent Idiopathic Scoliosis Among Patients and Caregivers
NCT05466383	Not specified	RECRUITING	Screening and Intervention for AIS in Haikou, Hainan Province, China
NCT05473975	Not specified	COMPLETED	Search for a Recanalization of the Sylvian Artery Electro-Physiological Biomarker
NCT05496361	Not specified	COMPLETED	A Prospective, Multi-center and Randomized Controlled Trial of Tianyi Revascularization Device in Acute Ischemic Stroke
NCT06251505	Not specified	COMPLETED	Cervical Alignment Changes After Correction of Thoracic Adolescent Idiopathic Scoliosis With Thoracic Hypokyphosis
NCT06702657	Not specified	NOT_YET_RECRUITING	A Randomized Clinical Trial on Urgent Angioplasty for IntraCranial Atherosclerotic Stenosis-related Large-Vessel Occlusion After Mechanical Thrombectomy
NCT07194564	Not specified	ACTIVE_NOT_RECRUITING	Acute Training Effect Assessment in Adolescent Idiopathic Scoliosis
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.