CDC14A

Summary

CDC14A (cell division cycle 14A, HGNC:1718) is a protein-coding gene on chromosome 1p21.2, encoding Dual specificity protein phosphatase CDC14A (Q9UNH5). Dual-specificity phosphatase.

The protein encoded by this gene is a member of the dual specificity protein tyrosine phosphatase family. It is highly similar to Saccharomyces cerevisiae Cdc14, a protein tyrosine phosphatase involved in the exit of cell mitosis and initiation of DNA replication, suggesting a role in cell cycle control. This protein has been shown to interact with, and dephosphorylate tumor suppressor protein p53, and is thought to regulate the function of p53. Alternative splicing of this gene results in several transcript variants encoding distinct isoforms.

Source: NCBI Gene 8556 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 313 total — 8 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• MANE Select transcript: NM_003672

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1718
Approved symbol	CDC14A
Name	cell division cycle 14A
Location	1p21.2
Locus type	gene with protein product
Status	Approved
Aliases	Cdc14A1, Cdc14A2, cdc14, DFNB105
Ensembl gene	ENSG00000079335
Ensembl biotype	protein_coding
OMIM	603504
Entrez	8556

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 4 nonsense_mediated_decay, 2 retained_intron

ENST00000336454, ENST00000361544, ENST00000370124, ENST00000455467, ENST00000469387, ENST00000635056, ENST00000644676, ENST00000644813, ENST00000644844, ENST00000646563, ENST00000646583, ENST00000646665, ENST00000647005, ENST00000647203, ENST00000717967, ENST00000873832, ENST00000873833, ENST00000955911

RefSeq mRNA: 6 — MANE Select: NM_003672 NM_001319210, NM_001319211, NM_001319212, NM_003672, NM_033312, NM_033313

CCDS: CCDS769, CCDS770, CCDS771, CCDS81353, CCDS86000

Canonical transcript exons

ENST00000336454 — 16 exons

Exon	Start	End
ENSE00001067745	100424222	100424301
ENSE00001067746	100455405	100455492
ENSE00001350573	100442934	100442996
ENSE00001350583	100390732	100390824
ENSE00001732967	100518251	100520277
ENSE00001950989	100352506	100353003
ENSE00003541609	100353762	100353852
ENSE00003552267	100377546	100377621
ENSE00003560902	100494818	100494930
ENSE00003579292	100496002	100496049
ENSE00003588004	100467956	100468094
ENSE00003603924	100439932	100439998
ENSE00003604246	100498929	100499262
ENSE00003639265	100462651	100462881
ENSE00003654840	100498085	100498207
ENSE00003687136	100484292	100484451

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 94.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.9556 / max 668.0536, expressed in 1631 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4227	14.8797	1575
4228	0.9579	401
4230	0.8305	319
4225	0.6211	103
4231	0.2748	158
4232	0.1994	77
4224	0.0942	42
4229	0.0584	14
4226	0.0324	4
4222	0.0051	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	94.14	gold quality
male germ cell	CL:0000015	92.89	gold quality
buccal mucosa cell	CL:0002336	92.45	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.32	gold quality
right uterine tube	UBERON:0001302	89.87	gold quality
right testis	UBERON:0004534	88.31	gold quality
left testis	UBERON:0004533	87.80	gold quality
testis	UBERON:0000473	86.62	gold quality
renal glomerulus	UBERON:0000074	85.67	gold quality
metanephric glomerulus	UBERON:0004736	84.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.27	gold quality
calcaneal tendon	UBERON:0003701	82.91	gold quality
tendon	UBERON:0000043	82.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.92	gold quality
granulocyte	CL:0000094	81.60	gold quality
leukocyte	CL:0000738	81.03	gold quality
monocyte	CL:0000576	80.86	gold quality
tendon of biceps brachii	UBERON:0008188	80.79	silver quality
mononuclear cell	CL:0000842	80.68	gold quality
germinal epithelium of ovary	UBERON:0001304	80.41	gold quality
colonic epithelium	UBERON:0000397	80.25	gold quality
jejunal mucosa	UBERON:0000399	80.17	gold quality
bone marrow cell	CL:0002092	80.02	gold quality
ventricular zone	UBERON:0003053	79.67	gold quality
sural nerve	UBERON:0015488	78.98	gold quality
fallopian tube	UBERON:0003889	78.27	gold quality
right lung	UBERON:0002167	78.06	gold quality
rectum	UBERON:0001052	77.52	gold quality
oviduct epithelium	UBERON:0004804	77.35	gold quality
cortex of kidney	UBERON:0001225	77.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	32.41
E-ANND-3	yes	6.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, KDM5B

Literature-anchored findings (GeneRIF, showing 29)

• human Cdc14A phosphatase disrupts centrosome separation (PMID:11901424)
• Data suggest that hCdc14A phosphatase plays a role in the regulation of the centrosome cycle, mitosis, and cytokinesis, thereby influencing chromosome partitioning and genomic stability in human cells. (PMID:12134069)
• hCdc14A and hCdc14B have functional homology to S. pombe Cdc25 and flp1 (PMID:15911625)
• analysis of iron-responsive elements in the 3’UTR of CDC14a protein (PMID:16760464)
• hCdc14A is differentially expressed in human cancer cells and can interact with both p53 and the Cdk1/cyclin B complex; it may play a role in carcinogenesis (PMID:16784539)
• Cdc14A may be involved in the cell cycle regulation of Cdc25A stability. (PMID:17172867)
• RN-tre phosphorylation is critical for efficient hCdc14A association (PMID:17371873)
• PLK1-HsCdc14A interaction provides a temporal regulation of HsCdc14A in chromosome segregation during mitosis. (PMID:17623655)
• Cdc14A forms a stable complex with atypical mitogen-activated protein kinase Erk3 in human cells independent of its intrinsic phosphatase activity but mediated by its regulatory C-terminal domain. (PMID:18235225)
• The authors found that Brap2, which has intrinsic RING domain dependent E3 ligase activity, facilitates HsCdc14A Lys-63 linked ubiquitin modification, indicating that Brap2 may be the ubiquitin E3 Ligase of HsCdc14A. (PMID:19152073)
• human HCT116, and human telomerase reverse transcription-immortalized retinal pigment epithelial cells deleted for Cdc14A are DNA damage checkpoint proficient and arrest efficiently in G2 in response to irradiation. (PMID:20479464)
• Cdc14A phosphatase prevents premature activation of Cdk1 regulating Cdc25A and Cdc25B at the entry into mitosis. (PMID:20956543)
• Cdc14 phosphatase plays a role in cell cycle control in higher eukaryotes. (PMID:21233601)
• CDC (cell division cycle) 14A/B phosphatases associate with KIBRA, and CDK1-non-phosphorylatable KIBRA has greatly reduced interaction with CDC14B. (PMID:22784093)
• These data support the hypothesis that Cdc14A counteracts Cdk1-cyclin B1 activity through Wee1 dephosphorylation. (PMID:23051732)
• hCdc14A might be involved in cell cycle regulation in cultured human brain vascular endothelial cells during high glucose-, free fatty acids-, and hypoxia-induced injury. (PMID:25463242)
• These findings indicated that ZIPK may also be involved in the regulation of the cell cycle in human cells, by interacting with HsCdc14A. (PMID:25503649)
• hCDC14A is down-regulated in many tumor tissues and reduced hCDC14A expression is correlated with poorer survival of patients with cancer (PMID:26747605)
• Mutations in CDC14A gene are associated with Autosomal-Recessive Severe to Profound Deafness. (PMID:27259055)
• Overexpressed miR-301a may increase CDC14A expression and promote cell proliferation and migration in osteosarcomacells. Therefore, miR- 301a may be useful for osteosarcoma diagnosis and therapy. (PMID:27323075)
• Reduction in the levels of hCDC14A and eplin mRNA is frequently associated with colorectal carcinoma and is correlated with poor prognosis. Authors therefore propose that eplin dephosphorylation by hCDC14A reduces actin dynamics to restrict tumor malignancy. (PMID:28465438)
• CDC14A activity is necessary for hearing and male fertility. (PMID:29293958)
• Point to differences in Cdk1-mediated mechanisms of regulation between human and yeast Cdc14 orthologues. (PMID:30089874)
• we show that drebrin and hCDC14A regulate the recruitment of the actin organizer Arp2 to centrosomes. In addition, during ciliogenesis hCDC14A also regulates endocytosis and targeting of myosin Va vesicles to the basal body in a drebrin-independent manner, indicating that it impacts primary cilia formation in a multilayered manner. (PMID:30467237)
• The study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss. (PMID:31906439)
• When transcripts matter: delineating between non-syndromic hearing loss DFNB32 and hearing impairment infertile male syndrome (HIIMS). (PMID:32231217)
• UNC5B mediates G2/M phase arrest of bladder cancer cells by binding to CDC14A and P53. (PMID:32372016)
• The phosphorylation of hCDC14A modulated by ZIPK regulates autophagy of murine pancreatic islet beta-TC3 cells upon glucose stimulation. (PMID:33090408)
• Human cells lacking CDC14A and CDC14B show differences in ciliogenesis but not in mitotic progression. (PMID:33328327)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdc14ab	ENSDARG00000057016
mus_musculus	Cdc14a	ENSMUSG00000033502
rattus_norvegicus	Cdc14a	ENSRNOG00000014515

Paralogs (8): CDC14B (ENSG00000081377), CDKN3 (ENSG00000100526), PALD1 (ENSG00000107719), PTP4A1 (ENSG00000112245), PTPDC1 (ENSG00000158079), PTP4A2 (ENSG00000184007), PTP4A3 (ENSG00000184489), CDC14C (ENSG00000218305)

Protein

Protein identifiers

Dual specificity protein phosphatase CDC14A — Q9UNH5 (reviewed: Q9UNH5)

Alternative names: CDC14 cell division cycle 14 homolog A

All UniProt accessions (9): Q9UNH5, A0A0U1RQX7, A0A2R8Y3W8, A0A2R8Y5L8, A0A2R8Y6L0, A0A2R8YDJ8, A0A2R8YEK7, A0A2R8YGM0, C9JSP6

UniProt curated annotations — full annotation on UniProt →

Function. Dual-specificity phosphatase. Required for centrosome separation and productive cytokinesis during cell division. Dephosphorylates SIRT2 around early anaphase. May dephosphorylate the APC subunit FZR1/CDH1, thereby promoting APC-FZR1 dependent degradation of mitotic cyclins and subsequent exit from mitosis. Required for normal hearing.

Subunit / interactions. Interacts with KIF20A, which is required to localize CDC14 to the midzone of the mitotic spindle.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle pole. Spindle. Cell projection. Kinocilium. Stereocilium.

Disease relevance. Deafness, autosomal recessive, 32, with or without immotile sperm (DFNB32) [MIM:608653] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNB32 is characterized by prelingual, progressive, moderate to profound sensorineural deafness. Some affected men are infertile. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Composed of two structurally equivalent A and B domains that adopt a dual specificity protein phosphatase (DSP) fold.

Similarity. Belongs to the protein-tyrosine phosphatase family. Non-receptor class CDC14 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9UNH5-1	1, CDC14A1	yes
Q9UNH5-2	2, CDC14A2
Q9UNH5-3	3, CDC14A3
Q9UNH5-4	4, CDC14A4
Q9UNH5-5	5

RefSeq proteins (6): NP_001306139, NP_001306140, NP_001306141, NP_003663, NP_201569, NP_201570 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000387	Tyr_Pase_dom	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR016130	Tyr_Pase_AS	Active_site
IPR020422	TYR_PHOSPHATASE_DUAL_dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029260	DSPn	Domain
IPR044506	CDC14_C	Domain
IPR050561	PTP	Family

Pfam: PF14671, PF22785

Catalyzed reactions (Rhea), 3 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)
• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (36 total): sequence variant 10, splice variant 6, region of interest 5, mutagenesis site 5, compositionally biased region 3, modified residue 2, sequence conflict 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNH5-F1	73.77	0.56

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): 278 (phosphocysteine intermediate)

Post-translational modifications (2): 484, 583

Mutagenesis-validated functional residues (5):

Position	Phenotype
251	loss of phosphatase activity.
278	loss of phosphatase activity.
284	loss of phosphatase activity.
362	inappropriate nucleolar localization; when associated with a-364.
364	inappropriate nucleolar localization; when associated with a-362.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-176407	Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-174143	APC/C-mediated degradation of cell cycle proteins
R-HSA-453276	Regulation of mitotic cell cycle
R-HSA-5683057	MAPK family signaling cascades
R-HSA-69278	Cell Cycle, Mitotic

MSigDB gene sets: 355 (showing top): CREL_01, REACTOME_CONVERSION_FROM_APC_C_CDC20_TO_APC_C_CDH1_IN_LATE_ANAPHASE, GAANYNYGACNY_UNKNOWN, SCHWAB_TARGETS_OF_BMYB_POLYMORPHIC_VARIANTS_DN, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GEORGES_CELL_CYCLE_MIR192_TARGETS, GOBP_REGULATION_OF_EXIT_FROM_MITOSIS, USF_C, GOCC_MICROTUBULE_ORGANIZING_CENTER, NFKB_Q6, NFKB_C, SRF_C, NEBEN_AML_WITH_FLT3_OR_NRAS_DN, GOBP_ORGANELLE_FISSION

GO Biological Process (8): microtubule cytoskeleton organization (GO:0000226), regulation of exit from mitosis (GO:0007096), sensory perception of sound (GO:0007605), positive regulation of cytokinesis (GO:0032467), cell division (GO:0051301), cilium assembly (GO:0060271), protein dephosphorylation (GO:0006470), dephosphorylation (GO:0016311)

GO Molecular Function (5): protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (17): spindle pole (GO:0000922), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), centrosome (GO:0005813), cytosol (GO:0005829), stereocilium tip (GO:0032426), kinocilium (GO:0060091), mitotic spindle (GO:0072686), kinociliary basal body (GO:1902636), nucleus (GO:0005634), microtubule organizing center (GO:0005815), spindle (GO:0005819), cytoskeleton (GO:0005856), stereocilium (GO:0032420), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
APC/C-mediated degradation of cell cycle proteins	1
MAPK family signaling cascades	1
Regulation of mitotic cell cycle	1
Cell Cycle, Mitotic	1
Signal Transduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
intracellular membraneless organelle	3
phosphoprotein phosphatase activity	2
spindle	2
nuclear lumen	2
cytoplasm	2
intracellular membrane-bounded organelle	2
stereocilium bundle	2
neuron projection	2
microtubule cytoskeleton	2
cytoskeleton organization	1
microtubule-based process	1
exit from mitosis	1
regulation of mitotic cell cycle phase transition	1
sensory perception of mechanical stimulus	1
cytokinesis	1
regulation of cytokinesis	1
positive regulation of cell division	1
positive regulation of cell cycle process	1
cellular process	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
dephosphorylation	1
protein modification process	1
phosphate-containing compound metabolic process	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
endomembrane system	1
centriole	1
microtubule organizing center	1
stereocilium	1

Protein interactions and networks

STRING

2004 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDC14A	SIRT2	Q8IXJ6	990
CDC14A	SIRT1	Q96EB6	989
CDC14A	ESPL1	Q14674	941
CDC14A	CDK1	P06493	879
CDC14A	INCENP	Q9NQS7	836
CDC14A	CDC7	O00311	824
CDC14A	AURKB	Q96GD4	760
CDC14A	PTTG1	O95997	754
CDC14A	PTTG2	Q9NZH5	740
CDC14A	CDC20	Q12834	735
CDC14A	CCNL2	Q96S94	721
CDC14A	LYPLA1	O75608	717
CDC14A	WEE1	P30291	694
CDC14A	SIDT1	Q9NXL6	674
CDC14A	CCNB1	P14635	656

IntAct

21 interactions, top by confidence:

A	B	Type	Score
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
ATPAF2	CDC14A	psi-mi:“MI:0915”(physical association)	0.560
CDC14A	ATPAF2	psi-mi:“MI:0915”(physical association)	0.560
CDC14A	C14orf119	psi-mi:“MI:0915”(physical association)	0.560
CDC14A	LMTK2	psi-mi:“MI:0915”(physical association)	0.370
CDC14A	AATK	psi-mi:“MI:0915”(physical association)	0.370
CDC14A	ROR2	psi-mi:“MI:0915”(physical association)	0.370
CDC14A	PTK7	psi-mi:“MI:0915”(physical association)	0.370
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAQ	MCRIP1	psi-mi:“MI:0914”(association)	0.350
SLC7A6	DDX46	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
PTBP3		psi-mi:“MI:0914”(association)	0.350
C14orf119	CDC14A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (123): PLK1 (Affinity Capture-Western), CDC14A (Biochemical Activity), CDC14A (Two-hybrid), CUL7 (Affinity Capture-MS), DAPK3 (Proximity Label-MS), TRIM36 (Proximity Label-MS), CEP135 (Proximity Label-MS), C2CD3 (Proximity Label-MS), CKAP2 (Proximity Label-MS), IFT57 (Proximity Label-MS), KIAA1462 (Proximity Label-MS), POC5 (Proximity Label-MS), EFTUD1 (Proximity Label-MS), MTUS1 (Proximity Label-MS), CEP290 (Proximity Label-MS)

ESM2 similar proteins: A0A0R4IVA4, A1Z7A6, A4D256, A6N3Q4, A8XQD5, B3M301, B3P8A3, B4G437, B4HGG6, B4JII0, B4K799, B4M0H8, B4NBP4, B4PL32, B4QSF0, B7WN72, G5EFD2, O02626, O43078, O43166, O60729, P24583, P34400, P34680, P43125, P50527, P81299, Q00684, Q07292, Q19469, Q19857, Q298L4, Q59NH8, Q5B323, Q61UC4, Q6GQT0, Q6NRL1, Q6PFY9, Q8BXK8, Q8I0P1

Diamond homologs: A0A0R4IVA4, A1L1R5, A2VDT1, A4D256, A6N3Q4, O60729, O61722, O70274, O75365, P81299, Q00684, Q12974, Q1LWL2, Q59NH8, Q5B323, Q5R7J8, Q63739, Q6GQT0, Q6NZK8, Q6P9X4, Q6PFY9, Q78EG7, Q86BN8, Q93096, Q9D658, Q9JLY7, Q9P7H1, Q9TSM6, Q9UNH5, Q9ZQP1, A2A3K4, A7E379, P35821, Q196Z3, Q4CUJ8, Q6NT99, Q86IL4, Q9BVJ7, Q6NKR2, Q4QEZ7

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
CDC14A	down-regulates	MAPK6	dephosphorylation
CDC14A	“down-regulates activity”	TP53	dephosphorylation
CDC14A	“up-regulates activity”	IREB2	dephosphorylation
CDC14A	“down-regulates quantity by destabilization”	MAPK6	dephosphorylation
CDC14A	unknown	SIRT2	dephosphorylation
CDC14A	“down-regulates quantity by destabilization”	KMT5A	dephosphorylation
CDC14A	“up-regulates quantity by stabilization”	WEE1	dephosphorylation
BRAP	“up-regulates activity”	CDC14A	polyubiquitination
CDC14A	“down-regulates activity”	CDC25B	dephosphorylation
CDC14A	“down-regulates activity”	CDC25A	dephosphorylation
CDC14A	“down-regulates activity”	SPAG5	dephosphorylation
CDK1	“up-regulates activity”	CDC14A	phosphorylation

Enriched among interaction partners

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

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	351.4×	2e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	310.1×	3e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	310.1×	3e-13
Activation of BH3-only proteins	6	229.2×	2e-12
RHO GTPases activate PKNs	6	146.4×	2e-11
Intrinsic Pathway for Apoptosis	6	135.2×	4e-11
SARS-CoV-1-host interactions	6	81.1×	8e-10
Apoptosis	6	77.5×	9e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	101.8×	2e-07
intracellular protein localization	6	34.9×	9e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	8
Uncertain significance	124
Likely benign	86
Benign	54

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
2065531	NM_003672.4(CDC14A):c.907G>T (p.Glu303Ter)	Pathogenic
2197194	NM_003672.4(CDC14A):c.375del (p.Tyr126fs)	Pathogenic
235146	NM_003672.4(CDC14A):c.1015C>T (p.Arg339Ter)	Pathogenic
2507228	NM_003672.4(CDC14A):c.781C>T (p.Arg261Ter)	Pathogenic
2811591	NM_003672.4(CDC14A):c.612T>A (p.Tyr204Ter)	Pathogenic
559437	NM_003672.4(CDC14A):c.376del (p.Tyr126fs)	Pathogenic
638290	NM_003672.4(CDC14A):c.417C>G (p.Tyr139Ter)	Pathogenic
691620	NM_003672.4(CDC14A):c.1351_1352del (p.Ala451fs)	Pathogenic
1299312	NM_003672.4(CDC14A):c.50-1G>T	Likely pathogenic
1707252	NM_003672.4(CDC14A):c.581C>G (p.Pro194Arg)	Likely pathogenic
4526676	NM_003672.4(CDC14A):c.6dup (p.Ala3fs)	Likely pathogenic
4691173	NM_003672.4(CDC14A):c.456+2T>G	Likely pathogenic
4749640	NM_003672.4(CDC14A):c.1137+1G>A	Likely pathogenic
559438	NM_003672.4(CDC14A):c.839-3C>G	Likely pathogenic
638289	NM_003672.4(CDC14A):c.959A>C (p.Gln320Pro)	Likely pathogenic
667367	NM_003672.4(CDC14A):c.520C>T (p.Arg174Ter)	Likely pathogenic

SpliceAI

3548 predictions. Top by Δscore:

Variant	Effect	Δscore
1:100353536:G:T	donor_gain	1.0000
1:100353848:GAAAA:G	donor_gain	1.0000
1:100353850:AAA:A	donor_gain	1.0000
1:100353851:AA:A	donor_gain	1.0000
1:100353852:AGTA:A	donor_loss	1.0000
1:100353853:G:GG	donor_gain	1.0000
1:100353854:TAAG:T	donor_loss	1.0000
1:100377536:T:A	acceptor_gain	1.0000
1:100377540:T:G	acceptor_gain	1.0000
1:100377544:A:AG	acceptor_gain	1.0000
1:100377545:G:GA	acceptor_gain	1.0000
1:100377545:GT:G	acceptor_gain	1.0000
1:100377545:GTT:G	acceptor_gain	1.0000
1:100377545:GTTT:G	acceptor_gain	1.0000
1:100377545:GTTTC:G	acceptor_gain	1.0000
1:100377617:TAAAA:T	donor_gain	1.0000
1:100377619:AAA:A	donor_gain	1.0000
1:100377619:AAAGT:A	donor_loss	1.0000
1:100377620:AA:A	donor_gain	1.0000
1:100377620:AAGTG:A	donor_loss	1.0000
1:100377621:AG:A	donor_loss	1.0000
1:100377622:G:GG	donor_gain	1.0000
1:100377622:GT:G	donor_loss	1.0000
1:100377623:T:A	donor_loss	1.0000
1:100377624:GAGTA:G	donor_loss	1.0000
1:100377625:AG:A	donor_loss	1.0000
1:100390730:A:AG	acceptor_gain	1.0000
1:100390731:G:GT	acceptor_gain	1.0000
1:100390731:GT:G	acceptor_gain	1.0000
1:100390731:GTC:G	acceptor_gain	1.0000

AlphaMissense

3900 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:100353822:T:C	F37S	1.000
1:100353845:T:C	Y45H	1.000
1:100377547:T:C	F48L	1.000
1:100377548:T:C	F48S	1.000
1:100377549:C:A	F48L	1.000
1:100377549:C:G	F48L	1.000
1:100377556:G:C	D51H	1.000
1:100377557:A:T	D51V	1.000
1:100377559:T:C	F52L	1.000
1:100377561:T:A	F52L	1.000
1:100377561:T:G	F52L	1.000
1:100377562:G:A	G53R	1.000
1:100377562:G:C	G53R	1.000
1:100377563:G:A	G53E	1.000
1:100377563:G:T	G53V	1.000
1:100377566:C:A	P54Q	1.000
1:100377605:T:C	L67P	1.000
1:100377617:T:C	L71P	1.000
1:100390760:T:A	V82E	1.000
1:100390798:G:C	A95P	1.000
1:100439933:G:C	D131H	1.000
1:100439934:A:T	D131V	1.000
1:100439937:C:A	A132D	1.000
1:100439987:G:A	G149R	1.000
1:100439987:G:C	G149R	1.000
1:100455417:G:C	G178R	1.000
1:100455418:G:A	G178D	1.000
1:100455418:G:T	G178V	1.000
1:100455420:G:C	D179H	1.000
1:100455421:A:T	D179V	1.000

dbSNP variants (sampled 300 via entrez): RS1000006643 (1:100473361 A>C,G), RS1000052674 (1:100348323 G>A,C,T), RS1000096285 (1:100392499 C>T), RS1000140594 (1:100413437 G>A), RS1000145272 (1:100375074 T>A), RS1000189062 (1:100501772 T>C), RS1000197866 (1:100353349 C>A,T), RS1000205920 (1:100444321 C>T), RS1000214717 (1:100454162 A>G), RS1000228165 (1:100356571 G>T), RS1000244319 (1:100454526 G>A), RS1000265341 (1:100471300 C>T), RS1000271494 (1:100433100 A>C), RS1000279882 (1:100363852 C>T), RS1000288050 (1:100365608 A>T)

Disease associations

OMIM: gene MIM:603504 | disease phenotypes: MIM:608653, MIM:128600

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
autosomal recessive nonsyndromic deafness 105	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 32	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hearing impairment and infertile male syndrome	Strong	AR
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (6): autosomal recessive nonsyndromic hearing loss 32 (MONDO:0012091), ear malformation (MONDO:0007500), sensorineural hearing loss disorder (MONDO:0020678), nonsyndromic genetic hearing loss (MONDO:0019497), (MONDO:0014849), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (2): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic deafness (Orphanet:96210)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0003251	Male infertility
HP:0003577	Congenital onset
HP:0012208	Immotile sperm
HP:0012864	Abnormal sperm morphology

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007876_39	Estimated glomerular filtration rate	7.000000e-09
GCST008058_130	Estimated glomerular filtration rate	6.000000e-16
GCST008059_177	Estimated glomerular filtration rate	4.000000e-13
GCST010426_1	Systolic blood pressure x educational attainment (some college) interaction (2df)	1.000000e-09
GCST012154_1	Fever and diarrhea in mesalamine-treated irritable bowel disease	4.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0006335	systolic blood pressure

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C564609	Deafness, Autosomal Recessive (supp.)
C563884	Deafness, Autosomal Recessive 32 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1772926 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

1 measured of 2 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(4-thiophen-3-ylanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	2900 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

ChEMBL bioactivities

15 potent at pChembl≥5 of 18 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Ki	57.4	nM	CHEMBL5567968
7.05	IC50	90	nM	CHEMBL5567968
7.03	IC50	93	nM	CHEMBL5567968
5.72	IC50	1920	nM	CHEMBL5568076
5.70	IC50	2000	nM	CHEMBL5560702
5.66	IC50	2170	nM	CHEMBL5568214
5.56	IC50	2780	nM	CHEMBL5563039
5.56	IC50	2740	nM	CHEMBL5565218
5.49	IC50	3210	nM	CHEMBL5556755
5.24	Ki	5800	nM	CHEMBL5561438
5.22	IC50	6000	nM	CHEMBL2316907
5.22	IC50	6000	nM	CHEMBL2316902
5.14	IC50	7200	nM	CHEMBL3426913
5.03	IC50	9410	nM	CHEMBL5542122
5.01	IC50	9850	nM	CHEMBL5561438

PubChem BioAssay actives

15 with measured affinity, of 53 total; 12 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
[difluoro-[4-(1-phenylethenyl)dibenzofuran-1-yl]methyl]phosphonic acid	2076963: Reversible competitive inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ki	0.0574	uM
[difluoro-(4-phenyldibenzofuran-1-yl)methyl]phosphonic acid	2076942: Inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ic50	1.9200	uM
[difluoro-[4-[(E)-2-phenylethenyl]dibenzofuran-1-yl]methyl]phosphonic acid	2076942: Inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ic50	2.0000	uM
[difluoro-[4-(4-hydroxyphenyl)dibenzofuran-1-yl]methyl]phosphonic acid	2076942: Inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ic50	2.1700	uM
[difluoro-[4-(2-phenylethynyl)dibenzofuran-1-yl]methyl]phosphonic acid	2076942: Inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ic50	2.7400	uM
[difluoro-[4-[2-fluoro-4-(trifluoromethyl)phenyl]dibenzofuran-1-yl]methyl]phosphonic acid	2076942: Inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ic50	2.7800	uM
[[4-(5-chlorothiophen-2-yl)dibenzofuran-1-yl]-difluoromethyl]phosphonic acid	2076942: Inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ic50	3.2100	uM
[dibenzofuran-1-yl(difluoro)methyl]phosphonic acid	2076948: Competitive inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ki	5.8000	uM
6-hydroxy-2-phenyl-3-[2-[3-(trifluoromethyl)phenyl]ethynyl]-1-benzofuran-5-carboxylic acid	725026: Inhibition of CDC14A (unknown origin) expressed in Escherichia coli using pNPP substrate after 5 mins by spectrophotometric analysis	ic50	6.0000	uM
6-hydroxy-2-phenyl-3-[2-[4-(trifluoromethoxy)phenyl]ethynyl]-1-benzofuran-5-carboxylic acid	725026: Inhibition of CDC14A (unknown origin) expressed in Escherichia coli using pNPP substrate after 5 mins by spectrophotometric analysis	ic50	6.0000	uM
4-[1-(cyclohexylamino)-1-oxohexan-2-yl]oxy-2-hydroxy-5-[2-[2-(trifluoromethoxy)phenyl]ethynyl]benzoic acid	1206775: Inhibition of CDC14A (unknown origin) using pNPP as substrate at pH 7 at 25 degC by spectrophotometric analysis	ic50	7.2000	uM
[(4-bromodibenzofuran-1-yl)-difluoromethyl]phosphonic acid	2076942: Inhibition of human CDC14A using DiFMUP as substrate incubated for 10 mins by fluorescence based assay	ic50	9.4100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	6
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects methylation, decreases expression, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
FR900359	decreases phosphorylation	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
arsenite	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
GW 3965	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	increases methylation	1
Leflunomide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Chelating Agents	increases expression, affects binding	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Deferoxamine	increases expression	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases reaction, affects binding	1

ChEMBL screening assays

19 unique, capped per target: 18 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1070022	Binding	Inhibition of Cdc14A expressed in Escherichia coli assessed as inhibition of p-nitrophenyl phosphate hydrolysis at pH 7 by spectrophotometry	Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). — J Med Chem
CHEMBL4626310	ADMET	Inhibition of CDC14A (unknown origin) expressed in Escherichia coli BL21 using p-nitrophenyl phosphate as substrate measured after 30 mins by UV-vis spectrophotometric method	Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT06431698	Not specified	UNKNOWN	CORRECTION OF EAR DEFORMITIES IN NEWBORNS BY MODELING, COMPARISON OF TWO PROTOCOLS
NCT07154667	Not specified	RECRUITING	Evaluation of the Auryzon™ EAR 2.0 System in Ear Reconstruction
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults