DOCK6

Summary

DOCK6 (dedicator of cytokinesis 6, HGNC:19189) is a protein-coding gene on chromosome 19p13.2, encoding Dedicator of cytokinesis protein 6 (Q96HP0). Acts as a guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases.

This gene encodes a member of the dedicator of cytokinesis (DOCK) family of atypical guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with small GTPases and are components of intracellular signaling networks. The encoded protein is a group C DOCK protein and plays a role in actin cytoskeletal reorganization by activating the Rho GTPases Cdc42 and Rac1. Mutations in this gene are associated with Adams-Oliver syndrome 2.

Source: NCBI Gene 57572 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Adams-Oliver syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 22
• Clinical variants (ClinVar): 1,718 total — 53 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 78
• MANE Select transcript: NM_020812

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19189
Approved symbol	DOCK6
Name	dedicator of cytokinesis 6
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1395, ZIR1
Ensembl gene	ENSG00000130158
Ensembl biotype	protein_coding
OMIM	614194
Entrez	57572

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 retained_intron, 6 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000294618, ENST00000585609, ENST00000585904, ENST00000586482, ENST00000586702, ENST00000587572, ENST00000587656, ENST00000587734, ENST00000588429, ENST00000588666, ENST00000590452, ENST00000590680, ENST00000591750, ENST00000592403, ENST00000592463, ENST00000592550

RefSeq mRNA: 2 — MANE Select: NM_020812 NM_001367830, NM_020812

CCDS: CCDS45975, CCDS92518

Canonical transcript exons

ENST00000294618 — 48 exons

Exon	Start	End
ENSE00000893963	11208911	11209103
ENSE00000893967	11211993	11212151
ENSE00000893969	11213176	11213328
ENSE00000893971	11214275	11214409
ENSE00000893973	11214553	11214649
ENSE00000893974	11215387	11215471
ENSE00000893975	11215801	11215927
ENSE00000893981	11222109	11222248
ENSE00000893983	11222735	11222905
ENSE00000893984	11222993	11223106
ENSE00000893986	11228940	11229035
ENSE00000893989	11236346	11236577
ENSE00000893999	11238045	11238115
ENSE00000894009	11243059	11243152
ENSE00000894013	11245563	11245712
ENSE00000954150	11204200	11204331
ENSE00000954152	11202394	11202483
ENSE00001061174	11208686	11208829
ENSE00001131396	11217231	11217391
ENSE00001131403	11221851	11222020
ENSE00001131413	11233203	11233366
ENSE00001131425	11235598	11235759
ENSE00001131446	11238187	11238304
ENSE00001131454	11242045	11242207
ENSE00001131464	11243258	11243385
ENSE00001131478	11252119	11252248
ENSE00001131484	11252482	11252550
ENSE00001260083	11243557	11243710
ENSE00001260090	11243802	11243882
ENSE00001260102	11245812	11245878
ENSE00001260107	11248066	11248151
ENSE00001260112	11250874	11251086
ENSE00001662719	11211776	11211876
ENSE00001699947	11204081	11204095
ENSE00001738249	11202584	11202709
ENSE00002807729	11262397	11262524
ENSE00003481088	11201889	11202125
ENSE00003530923	11237641	11237779
ENSE00003541099	11252783	11252958
ENSE00003548962	11236793	11236879
ENSE00003554499	11237456	11237557
ENSE00003558282	11253639	11253726
ENSE00003569666	11199295	11199539
ENSE00003575558	11200716	11200822
ENSE00003586704	11200909	11201052
ENSE00003641989	11200308	11200469
ENSE00003677534	11216914	11217096
ENSE00003785211	11227337	11227477

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 97.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.0907 / max 20.6754, expressed in 1104 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179205	2.0560	1090
179204	0.0206	5
179202	0.0140	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	97.72	gold quality
right lung	UBERON:0002167	97.54	gold quality
apex of heart	UBERON:0002098	97.02	gold quality
upper lobe of left lung	UBERON:0008952	96.36	gold quality
right lobe of thyroid gland	UBERON:0001119	96.13	gold quality
left lobe of thyroid gland	UBERON:0001120	96.13	gold quality
lower esophagus mucosa	UBERON:0035834	95.99	gold quality
metanephros cortex	UBERON:0010533	95.44	gold quality
upper lobe of lung	UBERON:0008948	95.35	gold quality
thyroid gland	UBERON:0002046	95.10	gold quality
omental fat pad	UBERON:0010414	94.90	gold quality
peritoneum	UBERON:0002358	94.84	gold quality
skin of leg	UBERON:0001511	94.79	gold quality
skin of abdomen	UBERON:0001416	94.44	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.38	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.31	gold quality
lower esophagus	UBERON:0013473	93.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.21	gold quality
mucosa of stomach	UBERON:0001199	93.18	gold quality
sural nerve	UBERON:0015488	93.06	gold quality
body of uterus	UBERON:0009853	93.01	gold quality
transverse colon	UBERON:0001157	92.91	gold quality
ectocervix	UBERON:0012249	92.81	gold quality
body of stomach	UBERON:0001161	92.79	gold quality
stromal cell of endometrium	CL:0002255	92.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.70	gold quality
right atrium auricular region	UBERON:0006631	92.63	gold quality
adipose tissue	UBERON:0001013	92.59	gold quality
heart left ventricle	UBERON:0002084	92.54	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting DOCK6, 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-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-5094	98.63	67.11	1062

Literature-anchored findings (GeneRIF, showing 11)

• A homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1, was identified. (PMID:21820096)
• DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies (PMID:25824905)
• this study demonstrates that miR-142-3p is a key regulator of the TGFbeta-mediated contractile phenotype of VSMCs that acts through inhibiting cell migration through targeting DOCK6. (PMID:25832008)
• acute knockdown of the Adams-Oliver syndrome (AOS) gene DOCK6, coding for a RAC1/CDC42 guanine nucleotide exchange factor, results in strikingly different phenotypes to those generated by genomic DOCK6 disruption. (PMID:27693507)
• DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. (PMID:28287327)
• Dock6 was over-expressed in GC tissues, and its positive expression was associated with GC metastasis and indicated poor prognosis of GC patients. (PMID:29587866)
• Results identified c.4106rC and c.3063 C>G mutations in the DOCK6 gene in a 5-year-old Chinese girl with the phenotype of Adams-Oliver syndrome (AOS). When caused by mutations in the DOCK6 gene, the AOS inheritance pattern is autosomal recessive. The two mutations carried by the patient were inherited from the father and mother respectively, generating compound heterozygosity in the patient. (PMID:30898718)
• Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype. (PMID:31654484)
• Overexpression of DOCK6 in oral squamous cell cancer promotes cellular migration and invasion and is associated with poor prognosis. (PMID:34742001)
• Attenuated clinical and osteoclastic phenotypes of Paget’s disease of bone linked to the p.Pro392Leu/SQSTM1 mutation by a rare variant in the DOCK6 gene. (PMID:35241069)
• Associations of ANGPTL6, DOCK6, FABP1, and PCSK9 single-nucleotide variants with hypercholesterolemia in the Polish population: a cross-sectional study. (PMID:36601873)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dock6	ENSDARG00000035706
mus_musculus	Dock6	ENSMUSG00000032198
rattus_norvegicus	Dock6	ENSRNOG00000010652
caenorhabditis_elegans		WBGENE00000419

Paralogs (10): DOCK9 (ENSG00000088387), DOCK3 (ENSG00000088538), DOCK8 (ENSG00000107099), DOCK7 (ENSG00000116641), DOCK4 (ENSG00000128512), DOCK2 (ENSG00000134516), DOCK10 (ENSG00000135905), DOCK11 (ENSG00000147251), DOCK5 (ENSG00000147459), DOCK1 (ENSG00000150760)

Protein

Protein identifiers

Dedicator of cytokinesis protein 6 — Q96HP0 (reviewed: Q96HP0)

All UniProt accessions (6): Q96HP0, K7EKT0, K7EP20, K7EP51, K7ERK2, K7ESB7

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases. Through its activation of CDC42 and RAC1, may regulate neurite outgrowth.

Subcellular location. Cytoplasm. Perinuclear region.

Tissue specificity. Widely expressed. Expressed at low level in spleen, cerebellum, hippocampus and in substantia nigra.

Disease relevance. Adams-Oliver syndrome 2 (AOS2) [MIM:614219] A disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. The disease is caused by variants affecting the gene represented in this entry.

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

Similarity. Belongs to the DOCK family.

RefSeq proteins (2): NP_001354759, NP_065863* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021816	DOCK_C/D_N	Domain
IPR026791	DOCK	Family
IPR027007	C2_DOCK-type_domain	Domain
IPR027357	DOCKER_dom	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037808	C2_Dock-C	Domain
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

Pfam: PF06920, PF11878, PF14429, PF20421, PF20422

UniProt features (29 total): compositionally biased region 7, modified residue 7, sequence variant 6, region of interest 6, domain 2, chain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9VM2	ELECTRON MICROSCOPY	3.94
9VM4	ELECTRON MICROSCOPY	4.2
9VM6	ELECTRON MICROSCOPY	4.27
9VM3	ELECTRON MICROSCOPY	4.52
9VM5	ELECTRON MICROSCOPY	5.32
9VM7	ELECTRON MICROSCOPY	6.85
9VM8	ELECTRON MICROSCOPY	7.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HP0-F1	77.78	0.30

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 (7): 178, 865, 872, 880, 884, 1308, 2036

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 294 (showing top): GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, CAGCTG_AP4_Q5, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, DOUGLAS_BMI1_TARGETS_UP, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, PARENT_MTOR_SIGNALING_UP, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, chr19p13, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, HEB_Q6, GOMF_ENZYME_REGULATOR_ACTIVITY, VERHAAK_GLIOBLASTOMA_CLASSICAL, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A, PID_RAC1_REG_PATHWAY

GO Biological Process (2): small GTPase-mediated signal transduction (GO:0007264), regulation of Rho protein signal transduction (GO:0035023)

GO Molecular Function (2): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

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	3
cytoplasm	2
intracellular signaling cassette	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

864 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOCK6	EOGT	Q5NDL2	712
DOCK6	ARHGAP31	Q2M1Z3	694
DOCK6	DOCK1	Q14185	616
DOCK6	DHX8	Q14562	606
DOCK6	DHX37	Q8IY37	593
DOCK6	LRCH1	Q9Y2L9	563
DOCK6	CDC42	P21181	517
DOCK6	MOB1B	Q7L9L4	515
DOCK6	ANGPTL8	Q6UXH0	508
DOCK6	LRCH3	Q96II8	464
DOCK6	MCF2	P10911	436
DOCK6	RBPJ	Q06330	416
DOCK6	IRS2	Q9Y4H2	414
DOCK6	DOCK8	Q8NF50	408
DOCK6	DOCK3	Q8IZD9	373

IntAct

66 interactions, top by confidence:

A	B	Type	Score
MOB1B	LATS1	psi-mi:“MI:0914”(association)	0.840
DOCK8	LRCH2	psi-mi:“MI:0914”(association)	0.740
LRCH3	DOCK6	psi-mi:“MI:0914”(association)	0.730
MOB1A	LATS1	psi-mi:“MI:0914”(association)	0.670
DOCK8	LRCH4	psi-mi:“MI:0914”(association)	0.620
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
CLU	CANX	psi-mi:“MI:0914”(association)	0.530
ZNF331	USP9Y	psi-mi:“MI:0914”(association)	0.530
LRCH3	LRCH2	psi-mi:“MI:0914”(association)	0.530
DOCK7	LRCH2	psi-mi:“MI:0914”(association)	0.530
LRCH4	DOCK6	psi-mi:“MI:0915”(physical association)	0.500
MOB1B	PPP6C	psi-mi:“MI:2364”(proximity)	0.480
MOB1A	ANKRD28	psi-mi:“MI:0914”(association)	0.420
MOB1B	ANKRD28	psi-mi:“MI:0914”(association)	0.420
MOB1A	PPP6C	psi-mi:“MI:2364”(proximity)	0.420
MOB1A	PPP6C	psi-mi:“MI:0914”(association)	0.420
DOCK6	FLNC	psi-mi:“MI:0915”(physical association)	0.400
DOCK6	HNRNPA1L2	psi-mi:“MI:0915”(physical association)	0.400
DOCK6	HYOU1	psi-mi:“MI:0915”(physical association)	0.400
Cep135		psi-mi:“MI:0914”(association)	0.350
Kifc5b	KPNA3	psi-mi:“MI:0914”(association)	0.350
MYH6	ELOC	psi-mi:“MI:0914”(association)	0.350
Msn	ELOC	psi-mi:“MI:0914”(association)	0.350
Smad3		psi-mi:“MI:0914”(association)	0.350
KIF7	TBC1D31	psi-mi:“MI:0914”(association)	0.350

BioGRID (88): DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS)

ESM2 similar proteins: A1A4J7, A2A9C3, A2BID5, B1WC10, E7FAW3, E7FCN8, O02696, O15360, O75153, O75800, O95248, Q08D69, Q1JPG0, Q3U6Q4, Q499Q5, Q5BLE2, Q5SW28, Q5SW45, Q5T011, Q5U1Z0, Q5U249, Q5UE93, Q5ZIB8, Q6AXZ5, Q6GLY5, Q6GR21, Q6PGF3, Q6ZNJ1, Q6ZQA0, Q7L4E1, Q8BK03, Q8BM55, Q8BMG7, Q8C3S2, Q8CJF7, Q8ND04, Q8QZV7, Q8TC57, Q8VDR9, Q8VE18

Diamond homologs: A2AF47, B0R034, Q5JSL3, Q63603, Q8BIK4, Q8BZN6, Q8C147, Q8NF50, Q8R1A4, Q8VDR9, Q96BY6, Q96HP0, Q96N67, Q9BZ29

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
AKT1	“up-regulates activity”	DOCK6	phosphorylation
AKT	“up-regulates activity”	DOCK6	phosphorylation
PP2CA_R1A_R2A	“down-regulates activity”	DOCK6	phosphorylation
PPP2CA	“down-regulates activity”	DOCK6	phosphorylation
DOCK6	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”
DOCK6	“up-regulates activity”	CDC42	“guanine nucleotide exchange factor”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1718 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	53
Likely pathogenic	40
Uncertain significance	708
Likely benign	689
Benign	106

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1174785	NM_020812.4(DOCK6):c.4751+1G>A	Pathogenic
1206321	NM_020812.4(DOCK6):c.3190_3191del (p.Leu1064fs)	Pathogenic
1319693	NM_020812.4(DOCK6):c.5100C>G (p.Tyr1700Ter)	Pathogenic
1320059	NM_020812.4(DOCK6):c.1396C>T (p.Arg466Ter)	Pathogenic
1320060	NM_020812.4(DOCK6):c.1300del (p.Gln434fs)	Pathogenic
1322760	NM_020812.4(DOCK6):c.5783_5790del (p.Lys1928fs)	Pathogenic
1322762	NM_020812.4(DOCK6):c.4106+1G>A	Pathogenic
1453588	NM_020812.4(DOCK6):c.3745_3752del (p.Ser1249fs)	Pathogenic
1455847	NC_000019.9:g.(?11319342)(11328087_?)del	Pathogenic
1708249	NM_020812.4(DOCK6):c.5616dup (p.Lys1873Ter)	Pathogenic
1912499	NM_020812.4(DOCK6):c.3997C>T (p.Gln1333Ter)	Pathogenic
1939973	NM_020812.4(DOCK6):c.616_617dup (p.Leu207fs)	Pathogenic
2001390	NM_020812.4(DOCK6):c.3975del (p.Leu1326fs)	Pathogenic
2023705	NM_020812.4(DOCK6):c.49del (p.Val17fs)	Pathogenic
2069357	NM_020812.4(DOCK6):c.616_617del (p.Leu206fs)	Pathogenic
2098760	NM_020812.4(DOCK6):c.5997C>A (p.Tyr1999Ter)	Pathogenic
2108027	NM_020812.4(DOCK6):c.1282_1285dup (p.Arg429fs)	Pathogenic
2124323	NM_020812.4(DOCK6):c.3392del (p.Leu1131fs)	Pathogenic
2164601	NM_020812.4(DOCK6):c.667C>T (p.Arg223Ter)	Pathogenic
2426619	NC_000019.9:g.(?11373053)(11373116_?)del	Pathogenic
253046	NM_020812.4(DOCK6):c.788T>A (p.Val263Asp)	Pathogenic
253047	NM_020812.4(DOCK6):c.5939+2T>C	Pathogenic
2576806	NM_020812.4(DOCK6):c.5231G>A (p.Trp1744Ter)	Pathogenic
2845857	NM_020812.4(DOCK6):c.1054dup (p.Ser352fs)	Pathogenic
285860	NM_020812.4(DOCK6):c.4194_4197dup (p.Val1400fs)	Pathogenic
2860384	NM_020812.4(DOCK6):c.5663_5673dup (p.Cys1892fs)	Pathogenic
2874238	NM_020812.4(DOCK6):c.2437_2440del (p.Ser813fs)	Pathogenic
31128	NM_020812.4(DOCK6):c.1245dup (p.Asp416Ter)	Pathogenic
3377288	NM_020812.4(DOCK6):c.4457dup (p.Tyr1486Ter)	Pathogenic
3649519	NM_020812.4(DOCK6):c.5494dup (p.Tyr1832fs)	Pathogenic

SpliceAI

8510 predictions. Top by Δscore:

Variant	Effect	Δscore
19:11200467:CAT:C	acceptor_gain	1.0000
19:11200470:C:CC	acceptor_gain	1.0000
19:11200694:T:TA	donor_gain	1.0000
19:11200710:GCCTA:G	donor_loss	1.0000
19:11200711:CCTAC:C	donor_loss	1.0000
19:11200712:CTAC:C	donor_loss	1.0000
19:11200713:TACT:T	donor_loss	1.0000
19:11200714:A:AC	donor_gain	1.0000
19:11200714:ACT:A	donor_loss	1.0000
19:11200714:ACTT:A	donor_gain	1.0000
19:11200715:C:CT	donor_gain	1.0000
19:11200715:CT:C	donor_gain	1.0000
19:11200715:CTT:C	donor_gain	1.0000
19:11200715:CTTC:C	donor_gain	1.0000
19:11200717:T:TA	donor_gain	1.0000
19:11200728:T:TA	donor_gain	1.0000
19:11200821:CC:C	acceptor_gain	1.0000
19:11200822:CC:C	acceptor_gain	1.0000
19:11200822:CCT:C	acceptor_loss	1.0000
19:11200823:C:CC	acceptor_gain	1.0000
19:11200823:CT:C	acceptor_loss	1.0000
19:11200824:T:C	acceptor_loss	1.0000
19:11200932:AGC:A	donor_gain	1.0000
19:11200960:AG:A	donor_gain	1.0000
19:11200961:G:C	donor_gain	1.0000
19:11200973:T:TA	donor_gain	1.0000
19:11201048:ACCGT:A	acceptor_gain	1.0000
19:11201049:CCGT:C	acceptor_gain	1.0000
19:11201049:CCGTC:C	acceptor_gain	1.0000
19:11201050:CGT:C	acceptor_gain	1.0000

AlphaMissense

13318 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:11209060:A:G	W1599R	1.000
19:11209060:A:T	W1599R	1.000
19:11211785:A:G	L1581P	1.000
19:11215848:A:T	I1325N	1.000
19:11243629:A:G	W396R	1.000
19:11243629:A:T	W396R	1.000
19:11200743:C:G	R1971P	0.999
19:11200746:A:C	L1970W	0.999
19:11200746:A:G	L1970S	0.999
19:11200796:A:C	F1953L	0.999
19:11200796:A:T	F1953L	0.999
19:11200797:A:G	F1953S	0.999
19:11200798:A:G	F1953L	0.999
19:11200806:G:T	A1950D	0.999
19:11200940:A:G	L1934P	0.999
19:11200994:A:G	L1916P	0.999
19:11201027:G:T	A1905D	0.999
19:11202588:A:G	L1786P	0.999
19:11202591:C:G	R1785P	0.999
19:11202634:A:C	Y1771D	0.999
19:11202678:A:G	F1756S	0.999
19:11202687:C:G	R1753P	0.999
19:11204231:A:G	L1730P	0.999
19:11208706:C:G	A1690P	0.999
19:11209058:C:A	W1599C	0.999
19:11209058:C:G	W1599C	0.999
19:11209065:A:G	L1597P	0.999
19:11209071:A:G	L1595P	0.999
19:11209098:G:T	A1586D	0.999
19:11211842:A:G	L1562P	0.999

dbSNP variants (sampled 300 via entrez): RS1000036199 (19:11241128 C>A), RS1000037382 (19:11231090 GC>G,GCC), RS1000043542 (19:11220096 G>A), RS1000060124 (19:11223771 C>T), RS1000168459 (19:11246434 T>G), RS1000404052 (19:11231585 C>A,G), RS1000414116 (19:11231924 A>C,G), RS1000498878 (19:11245318 C>T), RS1000529967 (19:11258832 C>G), RS1000587933 (19:11263878 G>A), RS1000722380 (19:11226490 C>A,G), RS1000729310 (19:11236290 A>C,G), RS1000736723 (19:11230275 C>A,G), RS1000792710 (19:11224559 G>T), RS1000903662 (19:11241798 C>A,T)

Disease associations

OMIM: gene MIM:614194 | disease phenotypes: MIM:614219, MIM:212140, MIM:607748, MIM:100300, MIM:236600, MIM:143890, MIM:167250

GenCC curated gene-disease

Disease	Classification	Inheritance
Adams-Oliver syndrome 2	Strong	Autosomal recessive
Adams-Oliver syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Adams-Oliver syndrome	Definitive	AR

Mondo (10): Adams-Oliver syndrome 2 (MONDO:0013635), systemic primary carnitine deficiency disease (MONDO:0008919), hypercholanemia, familial 1 (MONDO:0031446), Adams-Oliver syndrome (MONDO:0007034), hydrocephalus, nonsyndromic, autosomal recessive 1 (MONDO:0009360), hypercholesterolemia, familial, 1 (MONDO:0007750), Adams-Oliver syndrome 1 (MONDO:0024506), intellectual disability (MONDO:0001071), bone Paget disease (MONDO:0005382), microcephaly (MONDO:0001149)

Orphanet (7): Adams-Oliver syndrome (Orphanet:974), Systemic primary carnitine deficiency (Orphanet:158), Familial hypercholanemia (Orphanet:238475), Congenital hydrocephalus (Orphanet:2185), Homozygous familial hypercholesterolemia (Orphanet:391665), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Paget disease of bone (Orphanet:280110)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000568	Microphthalmia
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0000965	Cutis marmorata
HP:0001057	Aplasia cutis congenita
HP:0001156	Brachydactyly
HP:0001171	Split hand
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001276	Hypertonia
HP:0001321	Cerebellar hypoplasia
HP:0001362	Calvarial skull defect

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000755_23	HDL cholesterol	3.000000e-09
GCST000974_11	HDL cholesterol	5.000000e-06
GCST001904_5	HDL cholesterol	3.000000e-09
GCST003302_3	Cholesterol, total	8.000000e-09
GCST005196_234	Coronary artery disease	2.000000e-08
GCST007441_4	Total cholesterol levels	1.000000e-08
GCST007441_9	Total cholesterol levels	7.000000e-09
GCST007931_48	Medication use (HMG CoA reductase inhibitors)	1.000000e-09
GCST009367_35	HDL cholesterol levels x short total sleep time interaction (2df test)	5.000000e-34
GCST009368_73	HDL cholesterol levels x long total sleep time interaction (2df test)	2.000000e-36
GCST009919_4	Total cholesterol levels	8.000000e-10
GCST010173_122	Triglyceride levels	2.000000e-11
GCST010241_151	Apolipoprotein A1 levels	2.000000e-91
GCST010242_513	HDL cholesterol levels	1.000000e-66
GCST010244_325	Triglyceride levels	2.000000e-14
GCST010245_171	LDL cholesterol levels	6.000000e-16
GCST010867_46	Coronary artery disease	1.000000e-11
GCST011348_55	High density lipoprotein cholesterol levels	8.000000e-09
GCST012020_53	Serum metabolite levels	1.000000e-12
GCST012020_54	Serum metabolite levels	6.000000e-11
GCST90002397_186	Mean spheric corpuscular volume	2.000000e-13
GCST90002404_562	Red cell distribution width	3.000000e-13

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004530	triglyceride measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0009188	Red cell distribution width

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C538225	Adams Oliver syndrome (supp.)
C564336	Hypercholanemia, Familial (supp.)
C536778	Systemic carnitine deficiency (supp.)

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
rs12979813	DOCK6		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
arsenite	affects binding, decreases reaction, decreases methylation	2
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
aflatoxin B2	increases methylation	1
corosolic acid	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Methotrexate	increases expression	1
Thimerosal	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01904396	PHASE4	UNKNOWN	Identification of Carnitine-Responsive Cardiomyopathy
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT00668200	PHASE4	COMPLETED	Impact on Reducing the Incidence of Low Serum Calcium by Providing Educational Materials on the Need to Take Daily Supplemental Calcium and Vitamin D to Patients With Paget’s Disease Treated With Reclast®
NCT00740129	PHASE4	COMPLETED	Re-treatment of Participants With Paget’s Disease Using Zoledronic Acid
NCT00774020	PHASE4	COMPLETED	Efficacy and Safety of Single Dose of 5 mg Zoledronic Acid in Chinese Patients With Paget’s Disease of Bone (PDB)
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00051636	PHASE3	COMPLETED	Safety and Efficacy Trial With Zoledronic Acid for the Treatment of Paget’s Disease of Bone, Including an Extended Observation Period
NCT00103740	PHASE3	COMPLETED	Safety and Efficacy Trial With Zoledronic Acid for the Treatment of Paget’s Disease of Bone, Including an Extended Observation Period
NCT00480662	PHASE3	COMPLETED	A Research Study to Test the Effectiveness of MK0217 in Patients With Paget’s Bone Disease (0217-206)(COMPLETED)
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00515307	PHASE1	COMPLETED	Bone Marrow Stem Cells as a Source of Allogenic Hepatocyte Transplantation in Homozygous Familial Hypercholesterolemia
NCT01583647	PHASE1	TERMINATED	A Study of Extended-release (ER) Niacin/Laropiprant in Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0524A-158)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT07201714	EARLY_PHASE1	RECRUITING	Oral Carnitine in Heart Failure Patients
NCT00187733	Not specified	COMPLETED	Influence of OCTN2 Variants on Carnitine Status and Plasma Triglycerides
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan