DOCK5

Summary

DOCK5 (dedicator of cytokinesis 5, HGNC:23476) is a protein-coding gene on chromosome 8p21.2, encoding Dedicator of cytokinesis protein 5 (Q9H7D0). Guanine nucleotide exchange factor (GEF) for Rho and Rac.

This gene encodes a member of the dedicator of cytokinesis protein family. Members of this family act as guanine nucleotide exchange factors for small Rho family G proteins. The protein encoded by this gene is thought to associate with adaptors CRK and CRKL, and function in regulation of intestinal epithelial cell spreading and migration on collagen IV. Similar proteins in mouse and zebrafish also function in myoblast fusion.

Source: NCBI Gene 80005 — RefSeq curated summary.

At a glance

• GWAS associations: 25
• Clinical variants (ClinVar): 354 total
• Druggable target: yes
• MANE Select transcript: NM_024940

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23476
Approved symbol	DOCK5
Name	dedicator of cytokinesis 5
Location	8p21.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21034
Ensembl gene	ENSG00000147459
Ensembl biotype	protein_coding
OMIM	616904
Entrez	80005

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 retained_intron, 4 protein_coding, 1 nonsense_mediated_decay

ENST00000276440, ENST00000410074, ENST00000444569, ENST00000463457, ENST00000467709, ENST00000478099, ENST00000479547, ENST00000481100, ENST00000481728, ENST00000487948, ENST00000495236, ENST00000521405

RefSeq mRNA: 2 — MANE Select: NM_024940 NM_001322810, NM_024940

CCDS: CCDS6047, CCDS83265

Canonical transcript exons

ENST00000276440 — 52 exons

Exon	Start	End
ENSE00001197834	25411194	25415711
ENSE00001331833	25368571	25368725
ENSE00001364472	25310407	25310532
ENSE00001364856	25300576	25300657
ENSE00001365428	25298944	25299101
ENSE00001365815	25308783	25308925
ENSE00001368623	25304255	25304327
ENSE00001371215	25317007	25317131
ENSE00001371268	25292024	25292172
ENSE00001372801	25320980	25321052
ENSE00001376357	25268845	25268885
ENSE00001376520	25275386	25275441
ENSE00001378095	25278569	25278665
ENSE00001380027	25243674	25243757
ENSE00001381813	25323848	25323951
ENSE00001388006	25319578	25319676
ENSE00001389083	25325364	25325547
ENSE00001390234	25296513	25296648
ENSE00001390250	25302325	25302454
ENSE00001416814	25334096	25334196
ENSE00001418369	25332603	25332692
ENSE00001423173	25336239	25336373
ENSE00001431565	25332251	25332348
ENSE00001861796	25184689	25184951
ENSE00003460951	25373618	25373658
ENSE00003462514	25366870	25366970
ENSE00003468406	25391896	25391980
ENSE00003469782	25390206	25390287
ENSE00003481212	25399911	25399994
ENSE00003489396	25382674	25382778
ENSE00003529550	25340877	25340988
ENSE00003548863	25377305	25377424
ENSE00003561089	25358963	25359061
ENSE00003568274	25380305	25380394
ENSE00003574698	25392796	25392882
ENSE00003580660	25410099	25410202
ENSE00003588628	25341739	25341809
ENSE00003588776	25363047	25363141
ENSE00003589644	25351731	25351826
ENSE00003605493	25345475	25345611
ENSE00003607520	25342401	25342507
ENSE00003610501	25403558	25403724
ENSE00003634067	25368192	25368250
ENSE00003645416	25400929	25401066
ENSE00003647811	25395543	25395719
ENSE00003657064	25374564	25374654
ENSE00003660830	25372559	25372718
ENSE00003666281	25364626	25364704
ENSE00003673025	25389091	25389232
ENSE00003681604	25408802	25408940
ENSE00003687123	25407983	25408154
ENSE00003687270	25369556	25369641

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 97.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.1547 / max 2080.9817, expressed in 1689 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88014	13.3211	1597
88016	8.4276	1567
88015	1.0685	561
88012	0.2625	134
88013	0.0750	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	97.66	gold quality
sural nerve	UBERON:0015488	97.43	gold quality
corpus callosum	UBERON:0002336	97.36	gold quality
inferior vagus X ganglion	UBERON:0005363	96.50	gold quality
blood	UBERON:0000178	93.77	gold quality
pons	UBERON:0000988	93.71	gold quality
germinal epithelium of ovary	UBERON:0001304	93.71	gold quality
medial globus pallidus	UBERON:0002477	93.59	gold quality
globus pallidus	UBERON:0001875	93.47	gold quality
subthalamic nucleus	UBERON:0001906	93.21	gold quality
epithelial cell of pancreas	CL:0000083	92.26	gold quality
superior vestibular nucleus	UBERON:0007227	91.93	gold quality
oviduct epithelium	UBERON:0004804	90.75	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.63	gold quality
lateral globus pallidus	UBERON:0002476	90.56	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.27	gold quality
trigeminal ganglion	UBERON:0001675	90.13	gold quality
ventral tegmental area	UBERON:0002691	89.86	gold quality
jejunal mucosa	UBERON:0000399	89.69	gold quality
tibial nerve	UBERON:0001323	89.68	gold quality
bone marrow cell	CL:0002092	89.35	gold quality
monocyte	CL:0000576	89.04	gold quality
leukocyte	CL:0000738	88.75	gold quality
right lobe of thyroid gland	UBERON:0001119	88.67	gold quality
duodenum	UBERON:0002114	88.55	gold quality
left lobe of thyroid gland	UBERON:0001120	88.36	gold quality
thyroid gland	UBERON:0002046	87.95	gold quality
descending thoracic aorta	UBERON:0002345	87.95	gold quality
dorsal root ganglion	UBERON:0000044	87.85	gold quality
adrenal tissue	UBERON:0018303	87.75	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	2547.98
E-CURD-6	yes	600.10
E-GEOD-76312	yes	350.79
E-HCAD-35	yes	100.90
E-HCAD-25	yes	55.48
E-CURD-119	yes	32.54
E-ANND-3	yes	21.28
E-CURD-46	yes	10.85
E-MTAB-6678	yes	8.39
E-MTAB-9801	yes	7.93
E-HCAD-13	yes	7.01
E-ENAD-27	yes	6.79
E-GEOD-124858	no	1527.66
E-CURD-112	no	2.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

222 targeting DOCK5, 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-4692	100.00	67.32	2066
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960

Literature-anchored findings (GeneRIF, showing 9)

• along with DOCK1, DOCK5 is an important mediator of CrkII/CrkL regulation of Caco-2 spreading and migration on collagen IV. (PMID:19004829)
• the potential role of DOCK5 in human obesity (PMID:22595969)
• our work identifies DOCK5 as a key regulator of epithelial invasion and metastasis, and demonstrates that suppression of DOCK5 by GIT2 represents a previously unappreciated mechanism for coordination of Rho and Rac GTPases. (PMID:27669437)
• Study combined biochemical and structural approaches to characterize the biochemical activity of human DOCK5DHR2 and its inhibition by small molecules C21, a small molecule that inhibits mouse Dock5 in cells and blocks bone degradation in mice models of osteoporosis, and CPYPP, which inhibits both DOCK5 and Trio. C21 uses intramolecular dynamics of DOCK5 and Rac1 to remodel the complex into an unproductive conformation. (PMID:29089502)
• We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss- and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration, and invasion of HPV-negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival. (PMID:29945995)
• Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation. (PMID:32920599)
• ZEB1 represses biogenesis of circ-DOCK5 to facilitate metastasis in esophageal squamous cell carcinoma via a positive feedback loop with TGF-beta. (PMID:34216686)
• PHF5A regulates the expression of the DOCK5 variant to promote HNSCC progression through p38 MAPK activation. (PMID:37434235)
• Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism. (PMID:38161229)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	dock5	ENSDARG00000001968
mus_musculus	Dock5	ENSMUSG00000044447
rattus_norvegicus	Dock5	ENSRNOG00000024703
drosophila_melanogaster	Zir	FBGN0031216
drosophila_melanogaster	Ziz	FBGN0260486
caenorhabditis_elegans		WBGENE00000419
caenorhabditis_elegans	F22G12.5	WBGENE00009065
caenorhabditis_elegans		WBGENE00018520

Paralogs (10): DOCK9 (ENSG00000088387), DOCK3 (ENSG00000088538), DOCK8 (ENSG00000107099), DOCK7 (ENSG00000116641), DOCK4 (ENSG00000128512), DOCK6 (ENSG00000130158), DOCK2 (ENSG00000134516), DOCK10 (ENSG00000135905), DOCK11 (ENSG00000147251), DOCK1 (ENSG00000150760)

Protein

Protein identifiers

Dedicator of cytokinesis protein 5 — Q9H7D0 (reviewed: Q9H7D0)

All UniProt accessions (4): Q9H7D0, B9A015, H0Y7N4, H0YB14

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) for Rho and Rac. GEF proteins activate small GTPases by exchanging bound GDP for free GTP. Along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on type IV collagen.

Subunit / interactions. Interacts with CRK and CRKL. Interacts (via N-terminus) with tensin TNS3 (via N-terminus); the interaction increases DOCK5 guanine nucleotide exchange activity towards Rac. Interacts with ELMO1.

Subcellular location. Cytoplasm. Cell membrane. Cell projection. Podosome.

Domain organisation. The DOCKER domain may mediate some GEF activity.

Similarity. Belongs to the DOCK family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H7D0-1	1	yes
Q9H7D0-2	2

RefSeq proteins (2): NP_001309739, NP_079216* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR026791	DOCK	Family
IPR027007	C2_DOCK-type_domain	Domain
IPR027357	DOCKER_dom	Domain
IPR030717	DHR2_DOCK5	Domain
IPR032376	DOCK_N	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR042455	DOCK_N_sub1	Homologous_superfamily
IPR043161	DOCK_C_lobe_A	Homologous_superfamily
IPR043162	DOCK_C_lobe_C	Homologous_superfamily
IPR046769	DOCKER_Lobe_A	Domain
IPR046770	DOCKER_Lobe_B	Domain
IPR046773	DOCKER_Lobe_C	Domain
IPR047025	DOCK1_5_SH3	Domain
IPR056372	TPR_DOCK	Domain

Pfam: PF00018, PF06920, PF14429, PF16172, PF20421, PF20422, PF23554

UniProt features (29 total): modified residue 10, sequence conflict 5, sequence variant 4, domain 3, compositionally biased region 3, region of interest 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7DPA	ELECTRON MICROSCOPY	3.8
8ZJI	ELECTRON MICROSCOPY	4.23
8ZJJ	ELECTRON MICROSCOPY	4.23
8ZJK	ELECTRON MICROSCOPY	4.23
8ZJL	ELECTRON MICROSCOPY	4.31
8ZJM	ELECTRON MICROSCOPY	4.52
8ZJ2	ELECTRON MICROSCOPY	4.66
8JHK	ELECTRON MICROSCOPY	4.76
8XM7	ELECTRON MICROSCOPY	4.91
9LX0	ELECTRON MICROSCOPY	6.98
9LXH	ELECTRON MICROSCOPY	7.52

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H7D0-F1	79.63	0.41

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 (10): 818, 1756, 1766, 1785, 1789, 1794, 1814, 1834, 1869, 365

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 309 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, BERENJENO_ROCK_SIGNALING_NOT_VIA_RHOA_DN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_SUBSTRATE_ADHESION_DEPENDENT_CELL_SPREADING, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOLDRATH_ANTIGEN_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_REGULATION_OF_SUBSTRATE_ADHESION_DEPENDENT_CELL_SPREADING

GO Biological Process (10): myoblast fusion (GO:0007520), positive regulation of epithelial cell migration (GO:0010634), cell migration (GO:0016477), Rac protein signal transduction (GO:0016601), bone remodeling (GO:0046849), podosome assembly (GO:0071800), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), negative regulation of vascular associated smooth muscle contraction (GO:1904694), positive regulation of vascular associated smooth muscle cell migration (GO:1904754), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (7): podosome (GO:0002102), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	2
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
GTPase regulator activity	2
syncytium formation by cell-cell fusion	1
myotube differentiation	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
cell motility	1
small GTPase-mediated signal transduction	1
tissue remodeling	1
protein-containing complex assembly	1
plasma membrane bounded cell projection assembly	1
positive regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
regulation of vascular associated smooth muscle contraction	1
vascular associated smooth muscle contraction	1
negative regulation of vasoconstriction	1
negative regulation of smooth muscle contraction	1
positive regulation of smooth muscle cell migration	1
vascular associated smooth muscle cell migration	1
regulation of vascular associated smooth muscle cell migration	1
intracellular signaling cassette	1
GTP binding	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
GTPase binding	1
binding	1
actin-based cell projection	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

1348 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOCK5	TNFRSF10D	Q9UBN6	732
DOCK5	CRK	P46108	712
DOCK5	PTK2B	Q14289	664
DOCK5	CRKL	P46109	655
DOCK5	DOCK7	Q96N67	607
DOCK5	DHX8	Q14562	598
DOCK5	DHX37	Q8IY37	597
DOCK5	TNFRSF10A	O00220	578
DOCK5	RUNX2	Q13950	540
DOCK5	ELMO2	Q96JJ3	528
DOCK5	SRC	P12931	522
DOCK5	ELMO1	Q92556	516
DOCK5	COL10A1	Q03692	512
DOCK5	DOCK9	Q9BZ29	509
DOCK5	AKT1	P31749	482

IntAct

54 interactions, top by confidence:

A	B	Type	Score
ELMO1	DOCK1	psi-mi:“MI:0914”(association)	0.940
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
CRK	DOCK5	psi-mi:“MI:0407”(direct interaction)	0.690
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
CRK	ARHGAP42	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
ELMO1	CALML3	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
	MYL12B	psi-mi:“MI:0914”(association)	0.460
	DENR	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
ATXN1	DOCK5	psi-mi:“MI:0915”(physical association)	0.370
Cdc37	STX18	psi-mi:“MI:0914”(association)	0.350
CDCA5	BDP1	psi-mi:“MI:0914”(association)	0.350
CRKL	SOS1	psi-mi:“MI:0914”(association)	0.350
Lgals3bp	CS	psi-mi:“MI:0914”(association)	0.350
Rock1		psi-mi:“MI:0914”(association)	0.350
PPP4R3A	COG4	psi-mi:“MI:0914”(association)	0.350
DOCK5	DSP	psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
	BTAF1	psi-mi:“MI:0914”(association)	0.350
PA	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350

BioGRID (171): DOCK5 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), DOCK5 (Two-hybrid), DOCK5 (Affinity Capture-MS), ELMO2 (Affinity Capture-MS), ZHX2 (Affinity Capture-MS), ATP1A2 (Affinity Capture-MS), DOCK5 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS)

ESM2 similar proteins: A1Z713, A3KGB4, A8XPU7, B2RY04, F4ICD9, F4JIN3, G0S3B8, G5EDN3, O42926, O43150, O94443, P87319, P91133, Q07878, Q08D51, Q09417, Q0IIM8, Q0WT48, Q12150, Q19954, Q1ZXS5, Q21480, Q22706, Q54LB8, Q555C6, Q5F3R2, Q5H8C4, Q5THJ4, Q709C8, Q74ZX0, Q75E74, Q7SIG6, Q7XPJ0, Q7XVN7, Q7YTB0, Q80Y84, Q8BX70, Q91ZU6, Q96RL7, Q9BGZ0

Diamond homologs: B2RY04, E7F1U2, P53281, P59764, Q14185, Q8BUR4, Q8C3J5, Q8CIQ7, Q8IZD9, Q8N1I0, Q92608, Q9H7D0, A1IGU3, A1IGU4, A1IGU5, A4RF61, A5D7F8, A7E3N7, B0BNA1, B1V8A0, E2RP94, F1LXF1, F1M0Z1, G5EC32, M0R4F8, O08641, O13736, O15068, O35179, O35180, O35964, O43307, O43586, O59679, O75791, O75962, O88811, P00527, P10569, P11274

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 71 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
FCGR3A-mediated phagocytosis	5	24.0×	3e-04
Regulation of actin dynamics for phagocytic cup formation	5	23.6×	3e-04
RAC1 GTPase cycle	6	9.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	275
Likely benign	15
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

8075 predictions. Top by Δscore:

Variant	Effect	Δscore
8:25243666:A:AG	acceptor_gain	1.0000
8:25243667:T:G	acceptor_gain	1.0000
8:25243669:TCCA:T	acceptor_loss	1.0000
8:25243670:CCAGC:C	acceptor_loss	1.0000
8:25243671:CAGC:C	acceptor_loss	1.0000
8:25243672:A:AG	acceptor_gain	1.0000
8:25243672:A:G	acceptor_loss	1.0000
8:25243672:AGC:A	acceptor_gain	1.0000
8:25243673:G:GA	acceptor_gain	1.0000
8:25243673:GC:G	acceptor_gain	1.0000
8:25243673:GCG:G	acceptor_gain	1.0000
8:25243673:GCGA:G	acceptor_gain	1.0000
8:25243673:GCGAT:G	acceptor_gain	1.0000
8:25243754:GAGG:G	donor_gain	1.0000
8:25243755:AGGG:A	donor_loss	1.0000
8:25243756:GG:G	donor_gain	1.0000
8:25243757:GG:G	donor_gain	1.0000
8:25243758:G:GG	donor_gain	1.0000
8:25243759:T:TC	donor_loss	1.0000
8:25292022:A:AG	acceptor_gain	1.0000
8:25292023:G:GG	acceptor_gain	1.0000
8:25292173:G:GC	donor_loss	1.0000
8:25292173:G:GG	donor_gain	1.0000
8:25296644:AGAAG:A	donor_loss	1.0000
8:25296645:GAAGG:G	donor_loss	1.0000
8:25296646:AAGG:A	donor_loss	1.0000
8:25296648:GGT:G	donor_loss	1.0000
8:25296649:GT:G	donor_loss	1.0000
8:25298937:T:TA	acceptor_gain	1.0000
8:25298942:A:AG	acceptor_gain	1.0000

AlphaMissense

12422 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:25302446:G:A	G323E	1.000
8:25374578:T:C	L1247P	1.000
8:25380308:T:A	W1314R	1.000
8:25380308:T:C	W1314R	1.000
8:25380310:G:C	W1314C	1.000
8:25380310:G:T	W1314C	1.000
8:25243734:T:A	V35D	0.999
8:25278636:T:A	W98R	0.999
8:25278636:T:C	W98R	0.999
8:25292085:G:C	R128P	0.999
8:25299032:T:A	V232D	0.999
8:25300595:T:A	W262R	0.999
8:25300595:T:C	W262R	0.999
8:25302383:G:C	R302P	0.999
8:25302437:G:C	R320T	0.999
8:25302438:A:C	R320S	0.999
8:25302438:A:T	R320S	0.999
8:25302451:G:C	A325P	0.999
8:25302452:C:A	A325E	0.999
8:25310407:G:A	G398D	0.999
8:25317083:T:A	N465K	0.999
8:25317083:T:G	N465K	0.999
8:25319659:T:A	W509R	0.999
8:25319659:T:C	W509R	0.999
8:25321034:C:G	H533D	0.999
8:25332257:T:C	L637P	0.999
8:25332308:T:C	L654P	0.999
8:25332603:T:C	F668L	0.999
8:25332605:T:A	F668L	0.999
8:25332605:T:G	F668L	0.999

dbSNP variants (sampled 300 via entrez): RS1000022392 (8:25227851 C>A), RS1000028175 (8:25261048 G>C), RS1000031420 (8:25266648 A>G), RS1000035683 (8:25313679 G>A), RS1000037438 (8:25274603 G>A), RS1000039876 (8:25339494 G>A,C), RS1000052004 (8:25411135 A>G), RS1000072615 (8:25339794 T>A), RS1000090895 (8:25222191 A>G), RS1000122960 (8:25283495 G>C,T), RS1000128344 (8:25342140 A>G), RS1000132588 (8:25316703 C>T), RS1000149871 (8:25299878 A>G), RS1000169078 (8:25395169 C>T), RS1000177532 (8:25358269 C>G)

Disease associations

OMIM: gene MIM:616904 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST002726_14	Glucose homeostasis traits	4.000000e-06
GCST003262_620	Post bronchodilator FEV1	3.000000e-06
GCST003262_621	Post bronchodilator FEV1	2.000000e-06
GCST003264_1027	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST003264_1601	Post bronchodilator FEV1/FVC ratio	3.000000e-08
GCST003264_1602	Post bronchodilator FEV1/FVC ratio	3.000000e-08
GCST003264_1627	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST003264_752	Post bronchodilator FEV1/FVC ratio	2.000000e-07
GCST003264_971	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST005171_1	QT interval	3.000000e-07
GCST005194_199	Coronary artery disease	2.000000e-06
GCST006958_3	Length of menstrual cycle	1.000000e-10
GCST010866_130	Coronary artery disease	2.000000e-08
GCST012489_43	Heel bone mineral density x serum urate levels interaction	2.000000e-12
GCST012490_113	Femur bone mineral density x serum urate levels interaction	1.000000e-08
GCST90002385_161	High light scatter reticulocyte count	1.000000e-15
GCST90002386_472	High light scatter reticulocyte percentage of red cells	7.000000e-16
GCST90002389_172	Lymphocyte percentage of white cells	6.000000e-10
GCST90002395_8	Mean platelet volume	2.000000e-11
GCST90002395_9	Mean platelet volume	2.000000e-09
GCST90002401_507	Platelet distribution width	3.000000e-29
GCST90002401_508	Platelet distribution width	1.000000e-16
GCST90002404_312	Red cell distribution width	5.000000e-10
GCST90002405_499	Reticulocyte count	7.000000e-12
GCST90002406_269	Reticulocyte fraction of red cells	2.000000e-12

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0004682	QT interval
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0007986	reticulocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007984	platelet component distribution width
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739705 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.10	IC50	8000	nM	CHEMBL4749280

PubChem BioAssay actives

1 with measured affinity, of 21 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
7-[(3-chlorophenyl)methyl]-2-(4-methoxy-3-methylphenyl)-2,7-diazaspiro[4.4]nonan-1-one	1700461: Inhibition of N-terminal GFP tagged human DOCK5 (1212-1642 residues) expressed in HEK293T cells assessed as reduction in exchange activity incubated for 1 hr by Western blot analysis based Rac-GTP pull-down assay	ic50	8.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	4
arsenite	affects binding, decreases reaction, decreases methylation	2
sodium arsenite	decreases expression, increases abundance	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
butyraldehyde	increases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases 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, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4705283	Binding	Inhibition of N-terminal GFP tagged human DOCK5 (1212-1642 residues) expressed in HEK293T cells assessed as reduction in exchange activity incubated for 1 hr by Western blot analysis based Rac-GTP pull-down assay	Novel 2,7-Diazaspiro[4,4]nonane Derivatives to Inhibit Mouse and Human Osteoclast Activities and Prevent Bone Loss in Ovariectomized Mice without Affecting Bone Formation. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer