HOOK3

Summary

HOOK3 (hook microtubule tethering protein 3, HGNC:23576) is a protein-coding gene on chromosome 8p11.21, encoding Protein Hook homolog 3 (Q86VS8). Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.

Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.

Source: NCBI Gene 84376 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 322 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_032410

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23576
Approved symbol	HOOK3
Name	hook microtubule tethering protein 3
Location	8p11.21
Locus type	gene with protein product
Status	Approved
Aliases	HK3
Ensembl gene	ENSG00000168172
Ensembl biotype	protein_coding
OMIM	607825
Entrez	84376

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000307602, ENST00000524839, ENST00000526882, ENST00000527306, ENST00000533338, ENST00000533539, ENST00000862679, ENST00000862680, ENST00000862681, ENST00000862682, ENST00000947883

RefSeq mRNA: 1 — MANE Select: NM_032410 NM_032410

CCDS: CCDS6139

Canonical transcript exons

ENST00000307602 — 22 exons

Exon	Start	End
ENSE00001170681	43013329	43013400
ENSE00001170688	43013051	43013155
ENSE00001238780	43018358	43030535
ENSE00002189289	42997550	42997637
ENSE00003502575	43007847	43007929
ENSE00003582718	43010305	43010405
ENSE00003596662	43002107	43002141
ENSE00003989982	42959231	42959314
ENSE00003989983	42982627	42982696
ENSE00003989984	42986655	42986795
ENSE00003989985	42966473	42966613
ENSE00003989986	42930122	42930172
ENSE00003989987	42974107	42974194
ENSE00003989988	42896978	42897188
ENSE00003989989	42906173	42906258
ENSE00003989990	42968013	42968214
ENSE00003989991	42925557	42925629
ENSE00003989992	42943313	42943445
ENSE00003989993	42957094	42957156
ENSE00003989994	42973289	42973399
ENSE00003989995	42950388	42950455
ENSE00003989996	42964311	42964474

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 98.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.3821 / max 371.8702, expressed in 1812 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88707	20.2338	1809
88706	0.7440	401
88708	0.4043	205

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.07	gold quality
sural nerve	UBERON:0015488	97.04	gold quality
tendon	UBERON:0000043	96.77	gold quality
tendon of biceps brachii	UBERON:0008188	95.85	gold quality
colonic epithelium	UBERON:0000397	95.75	gold quality
epithelial cell of pancreas	CL:0000083	94.91	gold quality
corpus callosum	UBERON:0002336	94.56	gold quality
endothelial cell	CL:0000115	94.48	gold quality
buccal mucosa cell	CL:0002336	93.51	gold quality
medial globus pallidus	UBERON:0002477	93.24	gold quality
deltoid	UBERON:0001476	92.98	gold quality
adrenal tissue	UBERON:0018303	92.27	gold quality
tibialis anterior	UBERON:0001385	91.81	gold quality
globus pallidus	UBERON:0001875	91.40	gold quality
vastus lateralis	UBERON:0001379	91.26	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.10	gold quality
upper arm skin	UBERON:0004263	90.90	gold quality
visceral pleura	UBERON:0002401	90.79	gold quality
oviduct epithelium	UBERON:0004804	90.74	gold quality
cauda epididymis	UBERON:0004360	90.58	gold quality
quadriceps femoris	UBERON:0001377	90.56	gold quality
bone marrow cell	CL:0002092	90.54	gold quality
amniotic fluid	UBERON:0000173	90.51	gold quality
lower lobe of lung	UBERON:0008949	90.28	gold quality
skeletal muscle tissue	UBERON:0001134	90.17	gold quality
biceps brachii	UBERON:0001507	89.71	gold quality
pancreatic ductal cell	CL:0002079	89.60	gold quality
right lobe of thyroid gland	UBERON:0001119	89.60	gold quality
thyroid gland	UBERON:0002046	89.44	gold quality
mammary duct	UBERON:0001765	88.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

587 targeting HOOK3, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233

Literature-anchored findings (GeneRIF, showing 9)

• Salmonella SpiC targets the function of Hook3, a mammalian protein implicated in cellular trafficking. (PMID:12950921)
• Hook3 interacts with a cytoplasmic domain of scavenger receptor A (PMID:17237231)
• A fusion product between exon 11 of HOOK3 and exon 12 of RET gene was identified by 5’RACE, and the presence of chimeric HOOK3-RET protein of 88 kDa was detected by western blot analysis with an anti-RET antibody. (PMID:17639057)
• Hook3 is recruited to pericentriolar satellites through interaction with pericentriolar material 1 protein PCM1. (PMID:20152126)
• Results found that downregulation of Hook3 expression slows down endosomal transport and increases beta-amyloid production suggesting that Hook3 might play a critical role in pathogenic events exacerbating Alzheimer disease. (PMID:25799409)
• results of our study identify HOOK3 as a strong candidate prognostic marker with a possible role in maintaining genomic integrity in prostate cancer, which may have potential for inclusion into clinical routine assays (PMID:26230842)
• Single-molecule motility assays using total internal reflection fluorescence microscopy indicate that both Hook1 and Hook3 effectively activate cytoplasmic dynein, inducing longer run lengths and higher velocities than the previously characterized dynein activator bicaudal D2 (BICD2). (PMID:27365401)
• This work reveals the structural details of Hook3’s interaction with dynein and offers insight into how cargo adaptors form processive dynein-dynactin motor complexes. (PMID:27482052)
• Study demonstrates that PTPN21 activates KIF1C by binding to the stalk region. This function does not require catalytic activity of the phosphatase, and its N-terminal FERM domain alone is sufficient to stimulate the transport of KIF1C cargoes in cells as well as increasing the landing rate of KIF1C on microtubules in vitro. The cargo adapter Hook3 binds KIF1C in the same region and activates KIF1C in a similar way. (PMID:31217419)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	HOOK3	ENSDARG00000114329
mus_musculus	Hook3	ENSMUSG00000037234
rattus_norvegicus	AABR07026291.1	ENSRNOG00000014275
drosophila_melanogaster	Girdin	FBGN0283724
caenorhabditis_elegans		WBGENE00013082

Paralogs (5): CCDC88C (ENSG00000015133), HOOK2 (ENSG00000095066), CCDC88A (ENSG00000115355), HOOK1 (ENSG00000134709), CCDC88B (ENSG00000168071)

Protein

Protein identifiers

Protein Hook homolog 3 — Q86VS8 (reviewed: Q86VS8)

All UniProt accessions (4): Q86VS8, H0YDK4, H0YDM4, H0YE69

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Predominantly recruits 2 dyneins, which increases both the force and speed of the microtubule motor. Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). May regulate clearance of endocytosed receptors such as MSR1. Participates in defining the architecture and localization of the Golgi complex. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell. (Microbial infection) May serve as a target for the spiC protein from Salmonella typhimurium, which inactivates it, leading to a strong alteration in cellular trafficking.

Subunit / interactions. Self-associates. Component of the FTS/Hook/FHIP complex (FHF complex), composed of AKTIP/FTS, FHIP1B, and one or more members of the Hook family of proteins HOOK1, HOOK2, and HOOK3. May interact directly with AKTIP/FTS, HOOK1 and HOOK2. Associates with several subunits of the homotypic vesicular sorting complex (the HOPS complex) including VPS16 and VPS41; these interactions may be indirect. Interacts with MSR1, and this association is stimulated by ligand binding to MSR1. Interacts with microtubules. Part of a tripartite complex with dynein and dynactin, acts an adapter linking the dynein motor complex and dynactin. Interacts with dynein intermediate chain and dynactin (DCTN1). Interacts with CCDC181. Interacts with LRGUK. (Microbial infection) Interacts with Salmonella typhimurium spiC.

Subcellular location. Cytoplasm. Cytoskeleton. Golgi apparatus.

Similarity. Belongs to the hook family.

RefSeq proteins (1): NP_115786* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001715	CH_dom	Domain
IPR008636	Hook_C	Domain
IPR036872	CH_dom_sf	Homologous_superfamily
IPR043936	HOOK_N	Domain

Pfam: PF05622, PF19047

UniProt features (33 total): helix 12, modified residue 6, region of interest 4, sequence variant 2, turn 2, coiled-coil region 2, chain 1, domain 1, sequence conflict 1, strand 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6B9H	X-RAY DIFFRACTION	1.5
5J8E	X-RAY DIFFRACTION	1.7
9KNS	X-RAY DIFFRACTION	2.7
9KO8	X-RAY DIFFRACTION	3
8QAT	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86VS8-F1	83.01	0.45

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 (6): 3, 6, 238, 693, 707, 1

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 571 (showing top): GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, HORIUCHI_WTAP_TARGETS_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ENDOSOME_ORGANIZATION, TGCGCANK_UNKNOWN, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_MICROTUBULE_ANCHORING, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, MODULE_45

GO Biological Process (14): endosome organization (GO:0007032), lysosome organization (GO:0007040), endosome to lysosome transport (GO:0008333), protein transport (GO:0015031), interkinetic nuclear migration (GO:0022027), cytoskeleton-dependent intracellular transport (GO:0030705), cytoplasmic microtubule organization (GO:0031122), microtubule anchoring at centrosome (GO:0034454), early endosome to late endosome transport (GO:0045022), negative regulation of neurogenesis (GO:0050768), Golgi localization (GO:0051645), protein localization to centrosome (GO:0071539), neuronal stem cell population maintenance (GO:0097150), protein localization to perinuclear region of cytoplasm (GO:1905719)

GO Molecular Function (7): microtubule binding (GO:0008017), dynactin binding (GO:0034452), identical protein binding (GO:0042802), dynein light chain binding (GO:0045503), dynein intermediate chain binding (GO:0045505), dynein light intermediate chain binding (GO:0051959), protein binding (GO:0005515)

GO Cellular Component (10): pericentriolar material (GO:0000242), cytoplasm (GO:0005737), cis-Golgi network (GO:0005801), centrosome (GO:0005813), microtubule (GO:0005874), centriolar satellite (GO:0034451), FHF complex (GO:0070695), Golgi apparatus (GO:0005794), cytoskeleton (GO:0005856), HOPS complex (GO:0030897)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cytoplasm	3
cellular anatomical structure	3
intracellular protein localization	2
centrosome	2
intracellular membrane-bounded organelle	2
endomembrane system organization	1
vesicle organization	1
lytic vacuole organization	1
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
transport	1
establishment of protein localization	1
nuclear migration	1
cell proliferation in forebrain	1
intracellular transport	1
microtubule cytoskeleton organization	1
supramolecular fiber organization	1
microtubule anchoring at microtubule organizing center	1
vesicle-mediated transport between endosomal compartments	1
negative regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
negative regulation of nervous system development	1
organelle localization	1
protein localization to microtubule organizing center	1
stem cell population maintenance	1
tubulin binding	1
cytoskeletal protein binding	1
binding	1
intracellular anatomical structure	1
Golgi apparatus	1
centriole	1
microtubule organizing center	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
protein-containing complex	1
endomembrane system	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1904 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOOK3	BICD2	Q8TD16	842
HOOK3	BICDL1	Q6ZP65	822
HOOK3	FHIP1B	Q8N612	798
HOOK3	RAB11FIP3	O75154	746
HOOK3	NIN	Q8N4C6	736
HOOK3	FHIP2A	Q5W0V3	725
HOOK3	DYNC1LI1	Q9Y6G9	716
HOOK3	NINL	Q9Y2I6	695
HOOK3	PCM1	Q15154	694
HOOK3	BICD1	Q96G01	657
HOOK3	CLN3	Q13286	654
HOOK3	RAB11A	P24410	611
HOOK3	FHIP2B	Q86V87	577
HOOK3	BICDL2	A1A5D9	540
HOOK3	FHIP1A	Q05DH4	539

IntAct

136 interactions, top by confidence:

A	B	Type	Score
RUBCN	BECN1	psi-mi:“MI:0914”(association)	0.920
GFAP	VIM	psi-mi:“MI:0914”(association)	0.830
HOOK3	HOOK1	psi-mi:“MI:0915”(physical association)	0.800
HOOK1	HOOK3	psi-mi:“MI:0915”(physical association)	0.800
KRT31	HGS	psi-mi:“MI:0914”(association)	0.780
HOOK3	AKTIP	psi-mi:“MI:0915”(physical association)	0.750
AKTIP	HOOK3	psi-mi:“MI:0915”(physical association)	0.750
HOOK3	FHIP1A	psi-mi:“MI:0914”(association)	0.710
KRT27	HOOK3	psi-mi:“MI:0915”(physical association)	0.670
FAM9C	NDC80	psi-mi:“MI:0914”(association)	0.670
KRT34	TXLNA	psi-mi:“MI:0914”(association)	0.670
IFT57	IFT56	psi-mi:“MI:0914”(association)	0.640
TNFSF13B	IPO8	psi-mi:“MI:0914”(association)	0.640
RALBP1	JUN	psi-mi:“MI:0914”(association)	0.640
CTIF	HOOK3	psi-mi:“MI:0915”(physical association)	0.560
KRT13	HOOK3	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	HOOK3	psi-mi:“MI:0915”(physical association)	0.560
HOOK3	PNMA5	psi-mi:“MI:0915”(physical association)	0.560
FNTB	BLTP3B	psi-mi:“MI:0914”(association)	0.530
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
DYNC1LI1	DYNC1LI2	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
SDF4	GTPBP6	psi-mi:“MI:0914”(association)	0.530

BioGRID (310): HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), MRE11A (Co-fractionation), HOOK3 (Affinity Capture-MS), HOOK3 (Proximity Label-MS), HOOK3 (Proximity Label-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS)

ESM2 similar proteins: A0PJP4, A0PJT0, A2VDP1, A4IFK7, D3ZUQ0, E9PSL7, O14578, O75665, P0C219, P49025, P97817, Q01850, Q0IHE5, Q14BN4, Q17QG3, Q28623, Q3LGD4, Q3SYW5, Q3URD3, Q3V079, Q4R3X1, Q4R7Y8, Q58A65, Q5DTM8, Q5EBL4, Q5R5R4, Q5VTR2, Q5ZJA3, Q5ZLS3, Q62172, Q62796, Q68CZ1, Q6AYA0, Q6DFC2, Q6DH86, Q6NRH3, Q6ZUS6, Q7Z3E2, Q86VS8, Q8BR07

Diamond homologs: A0A2R8QCI3, A6NC98, B4KE73, F3Y5P4, O61493, P85120, Q3V6T2, Q4QRL3, Q5SNZ0, Q6VGS5, Q7PWT9, Q86VS8, Q8BUK6, Q9P219, B0WPU9, B3MNR6, B3NL60, B4G831, B4I5P7, B4JAL5, B4N1C2, B4PAF2, B4Q9E6, Q17AF4, Q24185, Q29N92, Q5TZ80, Q5ZJ27, Q6GQ73, Q6NRB0, Q7TMK6, B6MFW3, Q8BIL5, Q96ED9, Q9UJC3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HOOK3	down-regulates	MARCO	binding
HOOK3	down-regulates	MSR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 151 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
Aggrephagy	7	19.1×	3e-05
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	10.6×	3e-03
Kinesins	5	9.8×	4e-03
Golgi-to-ER retrograde transport	6	8.8×	2e-03
EML4 and NUDC in mitotic spindle formation	8	8.2×	6e-04
Autophagy	5	8.2×	7e-03
Intra-Golgi and retrograde Golgi-to-ER traffic	7	8.1×	1e-03
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	6	7.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
early endosome to late endosome transport	5	24.9×	5e-04
morphogenesis of an epithelium	6	15.9×	5e-04
intermediate filament organization	7	13.0×	5e-04
lysosome organization	5	11.8×	9e-03
protein ubiquitination	12	3.8×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	247
Likely benign	21
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1703528	GRCh37/hg19 5q32-35.3(chr5:149010383-180719789)	Pathogenic
599519	NM_032410.4(HOOK3):c.225T>G (p.Asn75Lys)	Likely pathogenic

SpliceAI

7753 predictions. Top by Δscore:

Variant	Effect	Δscore
5:176881218:C:CC	acceptor_gain	1.0000
5:176881298:TCACC:T	donor_loss	1.0000
5:176881299:CA:C	donor_loss	1.0000
5:176881300:A:AC	donor_gain	1.0000
5:176881300:ACCGC:A	donor_loss	1.0000
5:176881301:C:CC	donor_gain	1.0000
5:176881301:C:CG	donor_loss	1.0000
5:176881301:CCG:C	donor_gain	1.0000
5:176881536:C:CC	acceptor_gain	1.0000
5:176881544:C:CT	acceptor_gain	1.0000
5:176881544:C:T	acceptor_gain	1.0000
5:176881545:A:T	acceptor_gain	1.0000
5:176881656:C:CA	donor_gain	1.0000
5:176881679:AGG:A	donor_gain	1.0000
5:176882125:TTCC:T	acceptor_loss	1.0000
5:176882128:CTGC:C	acceptor_loss	1.0000
5:176883763:T:TA	donor_gain	1.0000
5:176883764:CCTCA:C	donor_loss	1.0000
5:176883765:CTCAC:C	donor_loss	1.0000
5:176883766:TCAC:T	donor_loss	1.0000
5:176883769:C:A	donor_loss	1.0000
5:176883785:T:C	donor_gain	1.0000
5:176883866:CTGC:C	acceptor_gain	1.0000
5:176883870:C:CC	acceptor_gain	1.0000
5:176884036:TACC:T	donor_loss	1.0000
5:176884038:C:CA	donor_loss	1.0000
5:176884038:CCTGT:C	donor_gain	1.0000
5:176884135:C:CC	acceptor_gain	1.0000
5:176884135:CTG:C	acceptor_loss	1.0000
5:176884136:T:A	acceptor_loss	1.0000

AlphaMissense

4751 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:42906227:G:A	G38R	1.000
8:42906227:G:C	G38R	1.000
8:42906227:G:T	G38W	1.000
8:42906228:G:A	G38E	1.000
8:42906249:T:C	L45P	1.000
8:42943347:C:A	P101H	1.000
8:42943401:T:C	L119P	1.000
8:42943407:T:C	L121P	1.000
8:42943422:C:A	A126D	1.000
8:42950394:T:A	I136N	1.000
8:42950403:T:A	I139N	1.000
8:42950428:A:C	Q147H	1.000
8:42950428:A:T	Q147H	1.000
8:42950436:T:A	V150D	1.000
8:42950439:T:C	M151T	1.000
8:42950440:G:A	M151I	1.000
8:42950440:G:C	M151I	1.000
8:42950440:G:T	M151I	1.000
8:42950444:G:C	A153P	1.000
8:42950448:T:A	I154N	1.000
8:42957095:T:C	L157P	1.000
8:42959304:T:C	L202P	1.000
8:42966579:G:C	A296P	1.000
8:42966589:T:C	L299P	1.000
8:42966610:T:C	L306P	1.000
8:42968072:T:C	L327P	1.000
8:42986672:T:C	L470P	1.000
8:43010397:G:C	A611P	1.000
8:43010398:C:A	A611D	1.000
8:43013052:T:A	V614D	1.000

dbSNP variants (sampled 300 via entrez): RS1000018327 (8:42961127 A>C,G), RS1000021087 (8:42939081 T>C), RS1000044504 (8:42924967 ACT>A), RS1000052696 (8:42967011 A>G), RS1000074315 (8:42954662 T>C), RS1000091116 (8:43024424 T>C), RS1000103350 (8:42966686 A>G), RS1000114219 (8:42926326 C>G), RS1000136099 (8:42979947 G>T), RS1000158419 (8:43026128 A>G), RS1000180383 (8:42992280 G>T), RS1000181190 (8:42904496 A>G), RS1000193770 (8:42907348 C>G,T), RS1000226202 (8:42907554 C>T), RS1000278915 (8:42948988 A>C)

Disease associations

OMIM: gene MIM:607825 | disease phenotypes: MIM:601379, MIM:602629

GenCC curated gene-disease

Mondo (3): Hunter-McAlpine craniosynostosis (MONDO:0011065), long QT syndrome (MONDO:0002442), torsion dystonia 6 (MONDO:0011264)

Orphanet (2): Hunter-McAlpine syndrome (Orphanet:97340), Primary dystonia, DYT6 type (Orphanet:98806)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002934_2	Zinc levels	6.000000e-07
GCST005956_15	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_13	Waist-to-hip ratio adjusted for BMI (age <50)	3.000000e-07
GCST005962_42	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-08
GCST006462_27	Uterine fibroids	3.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C538003	Dystonia 6, torsion (supp.)
C536072	Hunter-McAlpine syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, increases methylation	3
urushiol	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
coumarin	increases phosphorylation	1
cobalt oxide	increases expression	1
dimethylarsinous acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzophenoneidum	increases expression	1
Caffeine	decreases phosphorylation	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	increases expression	1
Thiram	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
Vincristine	decreases expression	1
Aflatoxin M1	decreases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SR61	HAP1 HOOK3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea