DOCK4

Summary

DOCK4 (dedicator of cytokinesis 4, HGNC:19192) is a protein-coding gene on chromosome 7q31.1, encoding Dedicator of cytokinesis protein 4 (Q8N1I0). Functions as a guanine nucleotide exchange factor (GEF) that promotes the exchange of GDP to GTP, converting inactive GDP-bound small GTPases into their active GTP-bound form.

This gene is a member of the dedicator of cytokinesis (DOCK) family and encodes a protein with a DHR-1 (CZH-1) domain, a DHR-2 (CZH-2) domain and an SH3 domain. This membrane-associated, cytoplasmic protein functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells. Mutations in this gene have been associated with ovarian, prostate, glioma, and colorectal cancers. Alternatively spliced variants which encode different protein isoforms have been described, but only one has been fully characterized.

Source: NCBI Gene 9732 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (Strong, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 395 total — 5 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_001363540

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19192
Approved symbol	DOCK4
Name	dedicator of cytokinesis 4
Location	7q31.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ34238, KIAA0716
Ensembl gene	ENSG00000128512
Ensembl biotype	protein_coding
OMIM	607679
Entrez	9732

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 9 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000417165, ENST00000423057, ENST00000428053, ENST00000428084, ENST00000437129, ENST00000437633, ENST00000445943, ENST00000450156, ENST00000468571, ENST00000469898, ENST00000476846, ENST00000486186, ENST00000492436, ENST00000492532, ENST00000494769, ENST00000658652, ENST00000661654, ENST00000664131

RefSeq mRNA: 2 — MANE Select: NM_001363540 NM_001363540, NM_014705

CCDS: CCDS47688, CCDS87541

Canonical transcript exons

ENST00000428084 — 53 exons

Exon	Start	End
ENSE00000350383	111760181	111760322
ENSE00000716908	111746334	111746417
ENSE00000716949	111755515	111755601
ENSE00000717011	111758624	111758790
ENSE00000717170	111834588	111834686
ENSE00000881833	111739134	111739243
ENSE00000881837	111741094	111741214
ENSE00000881838	111741540	111741661
ENSE00000881839	111742013	111742132
ENSE00000881841	111747267	111747443
ENSE00001230237	111844763	111844897
ENSE00001230244	111846999	111847126
ENSE00001230250	111863372	111863564
ENSE00001230542	111822362	111822456
ENSE00001230595	111739396	111739477
ENSE00001382451	111784097	111784123
ENSE00001631087	112206102	112206399
ENSE00001638950	111726110	111728720
ENSE00003473560	111867984	111868154
ENSE00003474398	111735054	111735167
ENSE00003488343	111778276	111778369
ENSE00003491640	112000494	112000534
ENSE00003496962	111869574	111869655
ENSE00003501900	111788662	111788747
ENSE00003506389	111808821	111808879
ENSE00003518095	111901677	111901801
ENSE00003536835	111782864	111782924
ENSE00003541381	111809301	111809401
ENSE00003542793	111767032	111767118
ENSE00003543825	111783857	111783952
ENSE00003568756	111935540	111935628
ENSE00003582587	111877030	111877186
ENSE00003585828	111900374	111900536
ENSE00003588648	111984306	111984390
ENSE00003589774	111989015	111989163
ENSE00003590466	111977132	111977283
ENSE00003591627	111944811	111944871
ENSE00003592252	111736917	111736989
ENSE00003605211	111895612	111895718
ENSE00003607508	111872269	111872352
ENSE00003625664	112004048	112004131
ENSE00003626017	111998448	111998503
ENSE00003626053	111769529	111769677
ENSE00003626361	111765118	111765222
ENSE00003638119	111915779	111915904
ENSE00003642284	111811874	111811949
ENSE00003644326	111940110	111940242
ENSE00003650609	111945717	111945798
ENSE00003657711	111872467	111872564
ENSE00003667451	111994135	111994231
ENSE00003675501	111732226	111732287
ENSE00003685200	111790457	111790605
ENSE00003690992	111871990	111872090

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.1237 / max 1307.0084, expressed in 1465 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85763	21.4539	1460
85723	0.6445	59
85762	0.5107	209
85727	0.1526	34
85724	0.1212	42
85728	0.0732	17
85726	0.0635	23
85725	0.0421	17
85722	0.0355	11
85754	0.0266	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.44	gold quality
CA1 field of hippocampus	UBERON:0003881	98.21	gold quality
lateral globus pallidus	UBERON:0002476	98.15	gold quality
middle frontal gyrus	UBERON:0002702	97.98	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.72	gold quality
corpus callosum	UBERON:0002336	97.43	gold quality
frontal pole	UBERON:0002795	96.89	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.48	gold quality
entorhinal cortex	UBERON:0002728	96.23	gold quality
postcentral gyrus	UBERON:0002581	96.01	gold quality
superior frontal gyrus	UBERON:0002661	95.89	gold quality
globus pallidus	UBERON:0001875	95.81	gold quality
parietal lobe	UBERON:0001872	95.73	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.70	gold quality
medial globus pallidus	UBERON:0002477	95.48	gold quality
substantia nigra pars compacta	UBERON:0001965	95.19	gold quality
middle temporal gyrus	UBERON:0002771	94.90	gold quality
visceral pleura	UBERON:0002401	94.88	gold quality
subthalamic nucleus	UBERON:0001906	94.64	gold quality
primary visual cortex	UBERON:0002436	94.50	gold quality
inferior vagus X ganglion	UBERON:0005363	94.35	gold quality
occipital lobe	UBERON:0002021	94.30	gold quality
calcaneal tendon	UBERON:0003701	94.20	gold quality
orbitofrontal cortex	UBERON:0004167	93.96	gold quality
germinal epithelium of ovary	UBERON:0001304	93.67	gold quality
lower lobe of lung	UBERON:0008949	93.65	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.40	gold quality
cranial nerve II	UBERON:0000941	93.23	gold quality
right lung	UBERON:0002167	93.18	gold quality
caudate nucleus	UBERON:0001873	93.15	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	5864.01
E-HCAD-25	yes	4941.77
E-HCAD-30	yes	4905.67
E-HCAD-35	yes	4272.78
E-MTAB-6678	yes	42.90
E-CURD-119	yes	39.37
E-ANND-3	yes	11.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

195 targeting DOCK4, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713

Literature-anchored findings (GeneRIF, showing 21)

• Taken together, these results suggest that Dock4 plays an important role in the regulation of cell migration through activation of Rac1, and that RhoG is a key upstream regulator for Dock4. (PMID:17027967)
• DOCK4 may be regulated by PIP(3) to exert its function (PMID:18459162)
• DOCK4 interacts with the beta-catenin degradation complex, consisting of the proteins adenomatosis polyposis coli, Axin and glycogen synthase kinase 3beta. (PMID:18641688)
• Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family (PMID:19401682)
• Cell migration is regulated by platelet-derived growth factor receptor endocytosis, which involves DOCK4. (PMID:19528233)
• Data suggest that exonic deletions of DOCK4 may act as a risk factor for reading impairment. Genomic disruption of both DOCK4 and CNTNAP5 genes may have an additive effect and may result in a more severe autism spectrum phenotype. (PMID:20346443)
• novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region. (PMID:21532034)
• This study revealed ROCK4 as novel schizophrenia candidate genes in the Jewish population. (PMID:21682944)
• The Atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics. (PMID:23720743)
• The study found significant associations between autism and a SNP of the DOCK4 gene. (PMID:24599690)
• activator DOCK4 as a key component of the TGF-beta/Smad pathway that promotes lung ADC cell extravasation and metastasis. (PMID:25644601)
• DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to vascular lumen formation (PMID:26129894)
• These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia (PMID:26578796)
• DOCK4 over expression suppresses selfrenewal and tumorigenicity of glioblastoma (GBM) stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival. (PMID:28925399)
• SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis (PMID:31019307)
• Up-regulated cytotrophoblast DOCK4 contributes to over-invasion in placenta accreta spectrum. (PMID:32576693)
• DOCK4 stimulates MUC2 production through its effect on goblet cell differentiation. (PMID:33559155)
• DOCK4 regulates ghrelin production in gastric X/A-like cells. (PMID:35302184)
• Genetic variations in DOCK4 contribute to schizophrenia susceptibility in a Chinese cohort: A genetic neuroimaging study. (PMID:36822513)
• Integration analysis of lncRNA and mRNA expression data identifies DOCK4 as a potential biomarker for elderly osteoporosis. (PMID:38443923)
• Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly. (PMID:38526744)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	dock4b	ENSDARG00000024874
danio_rerio	dock4	ENSDARG00000076213
mus_musculus	Dock4	ENSMUSG00000035954
rattus_norvegicus	Dock4	ENSRNOG00000004823
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), DOCK6 (ENSG00000130158), DOCK2 (ENSG00000134516), DOCK10 (ENSG00000135905), DOCK11 (ENSG00000147251), DOCK5 (ENSG00000147459), DOCK1 (ENSG00000150760)

Protein

Protein identifiers

Dedicator of cytokinesis protein 4 — Q8N1I0 (reviewed: Q8N1I0)

All UniProt accessions (9): Q8N1I0, A0A590UJ51, A0A590UJM5, C9J637, C9J7D9, C9JDB3, F8WES4, H0Y599, H0Y7H7

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a guanine nucleotide exchange factor (GEF) that promotes the exchange of GDP to GTP, converting inactive GDP-bound small GTPases into their active GTP-bound form. Involved in regulation of adherens junction between cells. Plays a role in cell migration. Has a higher guanine nucleotide exchange factor activity compared to other isoforms.

Subunit / interactions. Interacts with nucleotide-free Rap1; functions as a guanine nucleotide exchange factor (GEF) for Rap1. Interacts (via DOCKER domain) with RAC1; functions as a guanine nucleotide exchange factor (GEF) for RAC1. Interacts with the SH3 domain of CRK. Interacts with FASLG. Interacts with ELMO2 and EPHA2; mediates activation of RAC1 by EPHA2. Interacts with USH1C (via PDZ 1 domain).

Subcellular location. Cell membrane. Cell projection. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed at low level. Highly expressed in skeletal muscle, prostate and ovary. May be specifically expressed in the brain and eye.

Domain organisation. The DOCKER domain mediates interaction with small GTPases like RAC1 and is required for their activation.

Similarity. Belongs to the DOCK family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N1I0-1	1	yes
Q8N1I0-2	2, DOCK4-Ex49
Q8N1I0-3	3
Q8N1I0-4	4

RefSeq proteins (2): NP_001350469, NP_055520 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR026791	DOCK	Family
IPR027007	C2_DOCK-type_domain	Domain
IPR027357	DOCKER_dom	Domain
IPR032376	DOCK_N	Domain
IPR035769	DOCK4_SH3	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037014	DHR2_DOCK4	Domain
IPR037811	C2_Dock-B	Domain
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
IPR056372	TPR_DOCK	Domain

Pfam: PF06920, PF07653, PF14429, PF16172, PF20421, PF20422, PF23554

UniProt features (44 total): sequence variant 15, modified residue 9, compositionally biased region 5, splice variant 4, sequence conflict 4, domain 3, region of interest 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N1I0-F1	76.47	0.37

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 (9): 167, 193, 1599, 1607, 1614, 1618, 1620, 1631, 1769

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 356 (showing top): CREL_01, MYAATNNNNNNNGGC_UNKNOWN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_SYNAPSE_ASSEMBLY, NKX25_02, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, ZHAN_MULTIPLE_MYELOMA_MF_UP, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION, AP4_Q6, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, DARWICHE_PAPILLOMA_PROGRESSION_RISK, GOMF_GTPASE_BINDING

GO Biological Process (5): small GTPase-mediated signal transduction (GO:0007264), cell chemotaxis (GO:0060326), regulation of postsynapse assembly (GO:0150052), negative regulation of vascular associated smooth muscle contraction (GO:1904694), positive regulation of vascular associated smooth muscle cell migration (GO:1904754)

GO Molecular Function (7): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), SH3 domain binding (GO:0017124), PDZ domain binding (GO:0030165), receptor tyrosine kinase binding (GO:0030971), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (12): nucleolus (GO:0005730), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), stereocilium (GO:0032420), stereocilium bundle (GO:0032421), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cell projection (GO:0042995), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	3
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
GTPase regulator activity	2
protein domain specific binding	2
cytoplasm	2
synapse	2
intracellular signaling cassette	1
chemotaxis	1
cell migration	1
cellular response to chemical stimulus	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	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
GTP binding	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
signaling receptor binding	1
protein tyrosine kinase binding	1
GTPase binding	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
stereocilium	1
cluster of actin-based cell projections	1

Protein interactions and networks

STRING

4403 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOCK4	DHX37	Q8IY37	902
DOCK4	DHX8	Q14562	884
DOCK4	ELMO2	Q96JJ3	851
DOCK4	IMMP2L	Q96T52	612
DOCK4	SH3YL1	Q96HL8	582
DOCK4	ZNF277	Q9NRM2	582
DOCK4	RHOG	P35238	509
DOCK4	RABIF	P47224	493
DOCK4	GRB2	P29354	487
DOCK4	ARHGEF16	Q5VV41	477
DOCK4	CTNNB1	P35222	475
DOCK4	SHANK2	Q9UPX8	471
DOCK4	KDR	P35968	462
DOCK4	CDC42	P21181	452
DOCK4	ELMO1	Q92556	449

IntAct

286 interactions, top by confidence:

A	B	Type	Score
ELMO1	DOCK1	psi-mi:“MI:0914”(association)	0.940
STAT1	STAT3	psi-mi:“MI:0914”(association)	0.910
DOCK4	GRB2	psi-mi:“MI:0915”(physical association)	0.800
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
DGCR2	DOCK4	psi-mi:“MI:0915”(physical association)	0.620
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
ERMAP	AP3B1	psi-mi:“MI:0914”(association)	0.530
VSIG8	RPN2	psi-mi:“MI:0914”(association)	0.530
ARRB1	SAG	psi-mi:“MI:0914”(association)	0.530
ELMO1	CALML3	psi-mi:“MI:0914”(association)	0.530
DGCR2	HOXD13	psi-mi:“MI:0914”(association)	0.530
ADAM10	DOCK4	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	FASLG	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI3	DOCK4	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF12	DOCK4	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	NHERF1	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (114): DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Two-hybrid), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), HNRNPL (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-MS), DOCK4 (Affinity Capture-RNA), DOCK4 (Affinity Capture-MS)

ESM2 similar proteins: A2AF47, B0DOB4, B0R034, E9Q8I9, O02697, O15327, O75694, O94915, P37199, P42228, P48736, P59764, Q0VGW0, Q14B46, Q1JQ19, Q2TAF4, Q4QR86, Q4R4D7, Q5JSL3, Q5R8B7, Q5RA60, Q5U1Z0, Q5XGX5, Q62717, Q6AZT6, Q6GLR7, Q80TJ1, Q80TR8, Q86UW7, Q8BMG7, Q8BYR5, Q8BZN6, Q8C147, Q8N1I0, Q8NF50, Q8NFP9, Q8R1A4, Q8R3N6, Q91WS7, Q95JW3

Diamond homologs: B2RY04, E7F1U2, P53281, P59764, Q14185, Q8BUR4, Q8C3J5, Q8CIQ7, Q8IZD9, Q8N1I0, Q92608, Q9H7D0, M0R4F8, Q09822, Q5TCX8, Q62662, Q6XZF7, Q8VDG6, Q91X43, Q922K9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DOCK4	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 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
Ras activation upon Ca2+ influx through NMDA receptor	5	29.7×	7e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	28.3×	7e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	28.3×	7e-05
Assembly and cell surface presentation of NMDA receptors	10	26.4×	8e-10
Dopamine Neurotransmitter Release Cycle	5	25.9×	9e-05
Long-term potentiation	5	24.8×	1e-04
Neurexins and neuroligins	11	22.6×	8e-10
Protein-protein interactions at synapses	7	19.4×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	43.0×	1e-11
receptor clustering	8	37.0×	1e-08
protein localization to synapse	6	34.0×	4e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	6	22.0×	3e-05
bicellular tight junction assembly	5	12.2×	3e-03
regulation of small GTPase mediated signal transduction	8	8.5×	3e-04
protein-containing complex assembly	10	8.4×	4e-05
cell-cell adhesion	10	7.5×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	5
Uncertain significance	284
Likely benign	35
Benign	14

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2627575	NM_001363540.2(DOCK4):c.2945C>T (p.Thr982Ile)	Likely pathogenic
2627576	NM_001363540.2(DOCK4):c.3131T>C (p.Met1044Thr)	Likely pathogenic
2627577	NM_001363540.2(DOCK4):c.3200T>C (p.Ile1067Thr)	Likely pathogenic
545340	Single allele	Likely pathogenic
545341	NC_000007.14:g.(?111777402)(111865491_?)del	Likely pathogenic

SpliceAI

11528 predictions. Top by Δscore:

Variant	Effect	Δscore
7:111747266:C:CT	donor_loss	1.0000
7:111747266:CCT:C	donor_gain	1.0000
7:111747440:CTAC:C	acceptor_gain	1.0000
7:111755600:CT:C	acceptor_gain	1.0000
7:111760151:A:AC	donor_gain	1.0000
7:111760152:C:CC	donor_gain	1.0000
7:111760180:CA:C	donor_gain	1.0000
7:111760186:G:C	donor_gain	1.0000
7:111760320:ATTC:A	acceptor_loss	1.0000
7:111760321:TT:T	acceptor_gain	1.0000
7:111760322:TC:T	acceptor_loss	1.0000
7:111760323:C:CC	acceptor_gain	1.0000
7:111760324:T:A	acceptor_loss	1.0000
7:111760329:A:AC	acceptor_gain	1.0000
7:111760329:A:C	acceptor_gain	1.0000
7:111765114:TTA:T	donor_loss	1.0000
7:111765115:TA:T	donor_loss	1.0000
7:111765116:A:AC	donor_gain	1.0000
7:111765116:ACT:A	donor_gain	1.0000
7:111765117:C:CA	donor_gain	1.0000
7:111765117:CT:C	donor_gain	1.0000
7:111765117:CTC:C	donor_gain	1.0000
7:111765117:CTCT:C	donor_gain	1.0000
7:111765117:CTCTT:C	donor_gain	1.0000
7:111765219:TCAT:T	acceptor_gain	1.0000
7:111765219:TCATC:T	acceptor_loss	1.0000
7:111765220:CAT:C	acceptor_gain	1.0000
7:111765220:CATC:C	acceptor_gain	1.0000
7:111765223:C:CC	acceptor_gain	1.0000
7:111767114:CAACA:C	acceptor_gain	1.0000

AlphaMissense

13078 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:111742056:A:G	L1576P	1.000
7:111742068:A:G	L1572P	1.000
7:111742113:C:T	G1557D	1.000
7:111742114:C:G	G1557R	1.000
7:111742122:A:G	L1554P	1.000
7:111747275:A:C	Y1520D	1.000
7:111747275:A:G	Y1520H	1.000
7:111747286:C:T	G1516D	1.000
7:111747287:C:G	G1516R	1.000
7:111747289:C:T	G1515D	1.000
7:111747295:A:T	V1513D	1.000
7:111747301:G:T	A1511D	1.000
7:111747307:A:T	I1509K	1.000
7:111747313:C:T	G1507E	1.000
7:111747314:C:G	G1507R	1.000
7:111747314:C:T	G1507R	1.000
7:111747319:A:G	L1505P	1.000
7:111747325:A:G	M1503T	1.000
7:111747385:A:G	L1483P	1.000
7:111747418:G:T	A1472E	1.000
7:111747419:C:G	A1472P	1.000
7:111755597:A:G	L1436P	1.000
7:111758627:G:C	F1433L	1.000
7:111758627:G:T	F1433L	1.000
7:111758628:A:C	F1433C	1.000
7:111758628:A:G	F1433S	1.000
7:111758629:A:G	F1433L	1.000
7:111758667:C:G	R1420P	1.000
7:111758679:A:G	F1416S	1.000
7:111758781:A:T	I1382K	1.000

dbSNP variants (sampled 300 via entrez): RS1000001236 (7:112097582 T>C), RS1000004683 (7:111850033 T>C), RS1000006741 (7:111922145 C>G), RS1000028308 (7:112042203 C>T), RS1000030397 (7:111792016 T>C), RS1000035600 (7:112177770 G>GT), RS1000043697 (7:111761102 C>T), RS1000076370 (7:112051054 G>A,C), RS1000079276 (7:112007528 C>G), RS1000082655 (7:112145154 T>C,G), RS1000084060 (7:112170595 T>A), RS1000085159 (7:112090371 T>G), RS1000085830 (7:112205558 G>C), RS1000088117 (7:112085472 G>A), RS1000103358 (7:111828993 G>A,T)

Disease associations

OMIM: gene MIM:607679 | disease phenotypes: MIM:181500, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies	Strong	Autosomal dominant

Mondo (5): neurodevelopmental disorder (MONDO:0700092), autism spectrum disorder (MONDO:0005258), schizophrenia (MONDO:0005090), autism (MONDO:0005260), neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (MONDO:0060490)

Orphanet (2): NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia
HP:0000717	Autism

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001605_3	C-reactive protein and white blood cell count	7.000000e-11
GCST001632_6	Response to fenofibrate	1.000000e-07
GCST002337_133	Amyotrophic lateral sclerosis (sporadic)	3.000000e-06
GCST002692_2	Body mass index (change over time)	5.000000e-06
GCST003720_7	Migraine	2.000000e-08
GCST007158_10	Refractive astigmatism	2.000000e-06
GCST009204_8	Total intracranial volume	7.000000e-06
GCST010002_260	Refractive error	3.000000e-11
GCST90026416_15	Mild age-related type 2 diabetes	7.000000e-06
GCST90093092_2	DHEAS levels	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0005937	longitudinal BMI measurement
EFO:0004886	intracranial volume measurement
EFO:0007001	dehydroepiandrosterone sulphate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs61399156	DOCK4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, decreases expression	7
Valproic Acid	affects cotreatment, increases expression, affects expression	4
Aflatoxin B1	increases expression, affects expression, decreases expression, decreases methylation	4
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Doxorubicin	affects response to substance, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases methylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
kojic acid	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium bichromate	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice