LLGL1

Summary

LLGL1 (LLGL scribble cell polarity complex component 1, HGNC:6628) is a protein-coding gene on chromosome 17p11.2, encoding Lethal(2) giant larvae protein homolog 1 (Q15334). Cortical cytoskeleton protein found in a complex involved in maintaining cell polarity and epithelial integrity.

This gene encodes a protein that is similar to a tumor suppressor in Drosophila. The protein is part of a cytoskeletal network and is associated with nonmuscle myosin II heavy chain and a kinase that specifically phosphorylates this protein at serine residues. The gene is located within the Smith-Magenis syndrome region on chromosome 17.

Source: NCBI Gene 3996 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tourette syndrome (No Known Disease Relationship, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 188 total
• Phenotypes (HPO): 14
• MANE Select transcript: NM_004140

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6628
Approved symbol	LLGL1
Name	LLGL scribble cell polarity complex component 1
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	Lgl1, Mgl1
Ensembl gene	ENSG00000131899
Ensembl biotype	protein_coding
OMIM	600966
Entrez	3996

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000316843, ENST00000479155, ENST00000711517, ENST00000855605, ENST00000855606, ENST00000855607, ENST00000855608, ENST00000855609, ENST00000855610, ENST00000855611, ENST00000855612, ENST00000855613, ENST00000855614

RefSeq mRNA: 1 — MANE Select: NM_004140 NM_004140

CCDS: CCDS32586

Canonical transcript exons

ENST00000316843 — 23 exons

Exon	Start	End
ENSE00000902661	18232495	18232576
ENSE00000902662	18232672	18232802
ENSE00000902663	18233778	18233936
ENSE00000902669	18235470	18235537
ENSE00000902672	18236835	18236939
ENSE00000946115	18236607	18236760
ENSE00001214327	18241885	18241999
ENSE00001214334	18241451	18241715
ENSE00001214341	18240578	18240873
ENSE00001236584	18237481	18237773
ENSE00001357139	18225635	18225763
ENSE00001425511	18243908	18244875
ENSE00002340732	18229941	18230038
ENSE00003493866	18235089	18235312
ENSE00003517418	18242508	18242628
ENSE00003531054	18238456	18238609
ENSE00003545028	18234273	18234408
ENSE00003577999	18242743	18242822
ENSE00003587512	18234013	18234175
ENSE00003603910	18234649	18234703
ENSE00003646593	18242166	18242278
ENSE00003665841	18238067	18238214
ENSE00003674696	18234839	18234993

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 95.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5347 / max 185.6341, expressed in 1752 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164144	54.2257	1742
159802	11.2182	1732
159803	0.9395	470
164133	0.6612	203
159801	0.6154	333
164145	0.3904	121
164146	0.1977	83
164151	0.1580	40
164140	0.1483	59
164143	0.1456	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	95.60	gold quality
ventricular zone	UBERON:0003053	94.92	gold quality
ganglionic eminence	UBERON:0004023	93.27	gold quality
substantia nigra	UBERON:0002038	92.94	gold quality
Ammon’s horn	UBERON:0001954	91.28	gold quality
temporal lobe	UBERON:0001871	90.85	gold quality
amygdala	UBERON:0001876	90.78	gold quality
putamen	UBERON:0001874	90.00	gold quality
stromal cell of endometrium	CL:0002255	89.68	gold quality
caudate nucleus	UBERON:0001873	89.10	gold quality
hypothalamus	UBERON:0001898	88.84	gold quality
nucleus accumbens	UBERON:0001882	88.50	gold quality
primary visual cortex	UBERON:0002436	88.46	gold quality
right frontal lobe	UBERON:0002810	88.42	gold quality
cerebral cortex	UBERON:0000956	88.08	gold quality
frontal cortex	UBERON:0001870	88.00	gold quality
prefrontal cortex	UBERON:0000451	87.93	gold quality
corpus callosum	UBERON:0002336	87.60	gold quality
brain	UBERON:0000955	87.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.41	gold quality
lower esophagus mucosa	UBERON:0035834	87.38	gold quality
anterior cingulate cortex	UBERON:0009835	87.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.65	gold quality
cortical plate	UBERON:0005343	86.50	gold quality
right adrenal gland cortex	UBERON:0035827	86.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.93	gold quality
left adrenal gland cortex	UBERON:0035825	85.90	gold quality
left adrenal gland	UBERON:0001234	85.79	gold quality
right adrenal gland	UBERON:0001233	85.76	gold quality
esophagus mucosa	UBERON:0002469	84.88	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-98556	no	158.46
E-MTAB-7037	no	8.03
E-ANND-3	no	2.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXC8

miRNA regulators (miRDB)

54 targeting LLGL1, 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-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-24-3P	99.59	69.97	1934

Literature-anchored findings (GeneRIF, showing 23)

• Hugl-1 can act as a tumour suppressor in Drosophila and thus is the functional homologue of lgl (PMID:15467749)
• downregulation of Hugl-1 contributes to colorectal cancer progression (PMID:15735678)
• loss of Hugl-1 expression contributes to melanoma progression (PMID:16170365)
• aPKCzeta cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia (PMID:17369850)
• loss of Hugl-1 expression in endometrial cancer may contribute to lymph node metastasis and it can be a factor of poor prognosis. (PMID:18074678)
• Results provide the first evidence that Hugl-1 mRNA is frequently mutated by aberrant splicing exclusively in HCC, which may be involved in HCC progression. (PMID:19447873)
• Preservation of HUGL-1 expression in pancreatic adenocarcinoma is a good prognostic factor that contributes to a better overall survival (PMID:22843887)
• Hugl1 and Hugl2 play an essential role in the maintenance of breast epithelial polarity and differentiated cell morphology, as well as growth control. (PMID:23110097)
• inactivation of Llgl1 enhances hematopoietic stem cells self-renewal and fitness and is associated with unfavorable outcome in human acute myeloid leukemia (PMID:23277453)
• Suggest that Hugl-1 induces growth suppression and apoptosis in a human esophageal squamous cell carcinoma cell line both in vitro and in vivo. (PMID:23864775)
• PTEN loss leads to the phosphorylation and inactivation of Lgl by atypical protein kinase C in glioblastoma cells. (PMID:23907540)
• Lgl1 has a role in inhibiting glioblastoma (PMID:25426552)
• Our results support the growing appreciation that the tumour regulatory functions of Scribble, and other polarity protein family members, are context dependent. (PMID:25982280)
• this study provides the evidence that Hugl-1 inhibits glioma cell growth in intracranial model of nude mice, suggesting that Hugl-1 might be a potential tumor target for glioma therapy. (PMID:26341367)
• Reduced expression of Hugl 1 predicts poor survival in lung SqCC patients. The expression of Hugl 1 was inversely correlated with both overall survival rate and tumor stage. (PMID:26662669)
• these results revealed that miR-652-3p execute a tumor-promoter function in non-small cell lung cancer through direct binding and regulating the expression of Lgl1 (PMID:26934648)
• loss of Llgl1 results in EGFR mislocalization, promoting pre-neoplastic changes (PMID:27542214)
• Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2-IgG or LGI1-IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1-IgG. (PMID:28628235)
• LLGL1 is coexpressed with E-cadherin; loss of expression of either protein is associated with diffuse gastric cancer and peritoneal metastases. (PMID:31058107)
• [MiR-665 Promotes the Biological Behavior of Small Cell Lung Cancer by Targeting LLGL1]. (PMID:32222154)
• LLGL1 Regulates Gemcitabine Resistance by Modulating the ERK-SP1-OSMR Pathway in Pancreatic Ductal Adenocarcinoma. (PMID:32615164)
• Scribble, Lgl1, and myosin II form a complex in vivo to promote directed cell migration. (PMID:32697665)
• Hepatocyte polarity establishment and apical lumen formation are organized by Par3, Cdc42, and aPKC in conjunction with Lgl. (PMID:34717957)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	llgl1	ENSDARG00000009693
mus_musculus	Llgl1	ENSMUSG00000020536
rattus_norvegicus	Llgl1	ENSRNOG00000003948
drosophila_melanogaster	l(2)gl	FBGN0002121
caenorhabditis_elegans		WBGENE00018987

Paralogs (3): LLGL2 (ENSG00000073350), STXBP5L (ENSG00000145087), STXBP5 (ENSG00000164506)

Protein

Protein identifiers

Lethal(2) giant larvae protein homolog 1 — Q15334 (reviewed: Q15334)

Alternative names: DLG4, Hugl-1, Human homolog to the D-lgl gene protein

All UniProt accessions (2): A0AAA9YHJ2, Q15334

UniProt curated annotations — full annotation on UniProt →

Function. Cortical cytoskeleton protein found in a complex involved in maintaining cell polarity and epithelial integrity. Involved in the regulation of mitotic spindle orientation, proliferation, differentiation and tissue organization of neuroepithelial cells. Involved in axonogenesis through RAB10 activation thereby regulating vesicular membrane trafficking toward the axonal plasma membrane.

Subunit / interactions. Associated with nonmuscle myosin II heavy chain. Interacts with PRKCI/aPKC, PARD6B/Par-6 and PARD6A. Interacts with STX4A. Interacts with RAB10 (GDP-bound form); the interaction is direct and promotes RAB10 association with membranes and activation through competition with the Rab inhibitor GDI1. Interacts with DCAF1.

Subcellular location. Early endosome membrane. Golgi apparatus. trans-Golgi network membrane. Golgi apparatus membrane. Cell projection. Axon. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in brain, kidney, and muscle but is barely seen in heart and placenta. Down-regulated or lost in all cell lines and in most of the tumor samples analyzed. Loss was associated with advanced stage of the disease.

Post-translational modifications. Phosphorylated at least at Ser-663 by PRKCI.

Miscellaneous. Down-regulation of LLGL1 is associated with the progression of colorectal cancer and melanoma. Located within the Smith-Magenis syndrome region on chromosome 17; deleted in patients with this syndrome. Expression increases cell adhesion and decreases cell migration. Substitutes for Drosophila l(2)gl tumor suppressor function in vivo.

Similarity. Belongs to the WD repeat L(2)GL family.

RefSeq proteins (1): NP_004131* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000664	Lethal2_giant	Family
IPR001680	WD40_rpt	Repeat
IPR013577	LLGL2	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF08366

UniProt features (48 total): sequence conflict 26, repeat 14, modified residue 4, sequence variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8R3Y	ELECTRON MICROSCOPY	3.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15334-F1	80.46	0.61

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 (4): 663, 958, 967, 985

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 494 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, REACTOME_IONOTROPIC_ACTIVITY_OF_KAINATE_RECEPTORS, GOBP_COGNITION, MODULE_274, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, PEREZ_TP63_TARGETS, GOBP_VESICLE_ORGANIZATION, GOBP_SPINDLE_LOCALIZATION, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_RESPONSE_TO_POTASSIUM_ION

GO Biological Process (9): exocytosis (GO:0006887), Golgi to plasma membrane transport (GO:0006893), axonogenesis (GO:0007409), regulation of Notch signaling pathway (GO:0008593), cortical actin cytoskeleton organization (GO:0030866), regulation of establishment or maintenance of cell polarity (GO:0032878), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), establishment of spindle orientation (GO:0051294), protein-containing complex assembly (GO:0065003)

GO Molecular Function (5): GTPase activator activity (GO:0005096), structural molecule activity (GO:0005198), protein kinase binding (GO:0019901), myosin II binding (GO:0045159), protein binding (GO:0005515)

GO Cellular Component (14): Golgi cis cisterna (GO:0000137), Golgi membrane (GO:0000139), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), adherens junction (GO:0005912), axon (GO:0030424), cortical actin cytoskeleton (GO:0030864), early endosome membrane (GO:0031901), trans-Golgi network membrane (GO:0032588), endosome (GO:0005768), Golgi apparatus (GO:0005794), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
endomembrane system	2
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
post-Golgi vesicle-mediated transport	1
vesicle-mediated transport to the plasma membrane	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
Notch signaling pathway	1
regulation of signal transduction	1
actin cytoskeleton organization	1
cortical cytoskeleton organization	1
establishment or maintenance of cell polarity	1
regulation of cellular process	1
establishment or maintenance of apical/basal cell polarity	1
establishment of cell polarity	1
establishment of spindle localization	1
cellular component assembly	1
protein-containing complex organization	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
molecular_function	1
kinase binding	1
myosin binding	1
binding	1
Golgi cisterna	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
cell-cell junction	1
neuron projection	1
actin cytoskeleton	1
cortical cytoskeleton	1
early endosome	1

Protein interactions and networks

STRING

950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LLGL1	FLII	Q13045	836
LLGL1	DLG1	Q12959	765
LLGL1	CLEC10A	Q8IUN9	743
LLGL1	DLG3	Q92796	706
LLGL1	COPS3	Q9UNS2	691
LLGL1	MPP3	Q13368	680
LLGL1	NT5M	Q9NPB1	671
LLGL1	KCNA3	P22001	648
LLGL1	SCRIB	Q14160	634
LLGL1	RNF112	Q9ULX5	568
LLGL1	NUMB	P49757	561
LLGL1	NUMBL	Q9Y6R0	555
LLGL1	KCNAB1	Q14722	549
LLGL1	PARD3	Q8TEW0	542
LLGL1	PRKCZ	Q05513	541

IntAct

94 interactions, top by confidence:

A	B	Type	Score
PARD6B	PRKCI	psi-mi:“MI:0914”(association)	0.960
PARD6A	PRKCI	psi-mi:“MI:0914”(association)	0.950
PRKCZ	PRKCI	psi-mi:“MI:0914”(association)	0.890
PRKCI	LLGL1	psi-mi:“MI:0914”(association)	0.790
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
PRKCZ	NIPSNAP2	psi-mi:“MI:0914”(association)	0.730
PARD6G	PRKCI	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GABARAPL2	IPO5	psi-mi:“MI:0914”(association)	0.690
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
LLGL1	DNAJA2	psi-mi:“MI:0914”(association)	0.640
PARD3	PRKCI	psi-mi:“MI:0914”(association)	0.620
GABARAPL1	IPO5	psi-mi:“MI:0914”(association)	0.590
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
PARD6B	ZZEF1	psi-mi:“MI:0914”(association)	0.530
PRKCI	NIPSNAP2	psi-mi:“MI:0914”(association)	0.530
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480

BioGRID (209): LLGL1 (Affinity Capture-MS), LLGL1 (Affinity Capture-MS), LLGL1 (Affinity Capture-MS), PRKCI (Co-fractionation), LLGL1 (Affinity Capture-MS), LLGL1 (Proximity Label-MS), ALDH1B1 (Affinity Capture-MS), COPB1 (Affinity Capture-MS), HTT (Affinity Capture-MS), LLGL1 (Affinity Capture-MS), LLGL1 (Affinity Capture-MS), PRKCI (Affinity Capture-MS), STX3 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TIMM13 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A0A1L8HX76, A6QR40, O08764, O60294, O95382, P10938, P70218, P97452, Q12851, Q14137, Q15334, Q16586, Q28686, Q32P44, Q3TJ91, Q499N3, Q499U2, Q4KLI9, Q561R2, Q562C2, Q5RBH8, Q5RCX2, Q61161, Q6AY79, Q6F5E8, Q6P1M3, Q6V7V2, Q7SZE3, Q7TMC8, Q80Y17, Q8BYZ7, Q8C3I8, Q8C6B2, Q8CHW4, Q8K4K5, Q8MKF0, Q8N0W3, Q8VC03, Q91WI7

Diamond homologs: P08111, Q08470, Q15334, Q3TJ91, Q5RCX2, Q6P1M3, Q7SZE3, Q80Y17, Q8K4K5, Q8MKF0

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
LLGL1	“form complex”	Scribble_complex_DLG3-LLGL1_variant	binding
LLGL1	“form complex”	Scribble_complex_DLG5-LLGL1_variant	binding
LLGL1	“form complex”	Scribble_complex_DLG4-LLGL1_variant	binding
LLGL1	“form complex”	Scribble_complex_DLG2-LLGL1_variant	binding
LLGL1	“form complex”	Scribble_complex_DLG1-LLGL1_variant	binding
PRKCI	“up-regulates activity”	LLGL1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 100 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
Tight junction interactions	5	26.7×	5e-04
Macroautophagy	7	11.7×	5e-04
KEAP1-NFE2L2 pathway	5	8.7×	5e-03
Clathrin-mediated endocytosis	6	7.4×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	7	46.8×	8e-08
mitophagy	8	29.2×	1e-07
establishment or maintenance of cell polarity	5	23.1×	3e-04
autophagosome maturation	5	20.2×	5e-04
autophagosome assembly	5	12.9×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	152
Likely benign	10
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

4055 predictions. Top by Δscore:

Variant	Effect	Δscore
17:18225761:AAGG:A	donor_loss	1.0000
17:18225763:GGTG:G	donor_loss	1.0000
17:18225764:G:GG	donor_gain	1.0000
17:18232667:ACCAG:A	acceptor_gain	1.0000
17:18232797:TGCC:T	donor_gain	1.0000
17:18233776:A:AG	acceptor_gain	1.0000
17:18233776:AGT:A	acceptor_gain	1.0000
17:18233777:G:GC	acceptor_gain	1.0000
17:18233777:GT:G	acceptor_gain	1.0000
17:18233777:GTG:G	acceptor_gain	1.0000
17:18233777:GTGC:G	acceptor_gain	1.0000
17:18233777:GTGCT:G	acceptor_gain	1.0000
17:18233934:CAGGT:C	donor_loss	1.0000
17:18233935:AGGT:A	donor_loss	1.0000
17:18233936:GGT:G	donor_loss	1.0000
17:18233937:G:GG	donor_gain	1.0000
17:18233937:GT:G	donor_loss	1.0000
17:18233938:T:A	donor_loss	1.0000
17:18234008:CACA:C	acceptor_loss	1.0000
17:18234011:A:AG	acceptor_gain	1.0000
17:18234011:AGC:A	acceptor_gain	1.0000
17:18234011:AGCGT:A	acceptor_gain	1.0000
17:18234012:G:GC	acceptor_gain	1.0000
17:18234012:GC:G	acceptor_gain	1.0000
17:18234012:GCG:G	acceptor_gain	1.0000
17:18234012:GCGT:G	acceptor_gain	1.0000
17:18234012:GCGTG:G	acceptor_gain	1.0000
17:18234174:AGG:A	donor_loss	1.0000
17:18234176:GTAT:G	donor_gain	1.0000
17:18234177:T:G	donor_loss	1.0000

AlphaMissense

6905 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:18236632:T:A	W460R	1.000
17:18236632:T:C	W460R	1.000
17:18236935:G:A	G536D	1.000
17:18237571:T:A	W568R	1.000
17:18237571:T:C	W568R	1.000
17:18237716:G:A	G616D	1.000
17:18237728:G:A	G620D	1.000
17:18238133:G:C	K657N	1.000
17:18238133:G:T	K657N	1.000
17:18238143:C:A	R661S	1.000
17:18238153:T:C	F664S	1.000
17:18240601:T:A	W744R	1.000
17:18240601:T:C	W744R	1.000
17:18240608:G:A	G746D	1.000
17:18240620:G:A	G750D	1.000
17:18240722:T:C	L784P	1.000
17:18240727:C:G	H786D	1.000
17:18240851:T:A	I827N	1.000
17:18240857:C:A	S829Y	1.000
17:18240857:C:T	S829F	1.000
17:18240863:A:T	E831V	1.000
17:18240873:G:C	K834N	1.000
17:18240873:G:T	K834N	1.000
17:18241490:A:G	K848E	1.000
17:18241492:G:C	K848N	1.000
17:18241492:G:T	K848N	1.000
17:18241597:C:A	N883K	1.000
17:18241597:C:G	N883K	1.000
17:18241602:G:A	G885D	1.000
17:18241602:G:T	G885V	1.000

dbSNP variants (sampled 300 via entrez): RS1000140560 (17:18236393 G>T), RS1000265507 (17:18227218 G>T), RS1000506511 (17:18225645 C>A,T), RS1000638116 (17:18243275 T>A), RS1000789030 (17:18227474 C>G), RS1001031596 (17:18225795 G>C,T), RS1001456408 (17:18236881 A>G), RS1001608454 (17:18231993 C>G), RS1001865147 (17:18238300 G>A), RS1001940528 (17:18230739 G>A,C), RS1002080028 (17:18226327 G>A), RS1002094945 (17:18227629 T>C), RS1002479784 (17:18243468 C>A), RS1002483027 (17:18236148 C>T), RS1002532923 (17:18225588 G>C,T)

Disease associations

OMIM: gene MIM:600966 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Tourette syndrome	No Known Disease Relationship	Unknown

Mondo (1): Tourette syndrome (MONDO:0007661)

Orphanet (0):

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000486	Strabismus
HP:0000729	Autistic behavior
HP:0001065	Striae distensae
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001382	Joint hypermobility
HP:0001519	Disproportionate tall stature
HP:0001763	Pes planus
HP:0002650	Scoliosis
HP:0003593	Infantile onset
HP:0006855	Cerebellar vermis atrophy
HP:0012771	Increased arm span

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006612_99	LDL cholesterol	3.000000e-09
GCST90000025_124	Appendicular lean mass	3.000000e-09
GCST90020025_1405	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020027_33	Waist-hip index	9.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004980	appendicular lean mass
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases abundance	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic	decreases expression, increases abundance	1
Cannabinoids	affects methylation, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
Tacrolimus	increases expression	1
Antirheumatic Agents	increases expression	1
Lactic Acid	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	PHASE2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	PHASE2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	PHASE2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	PHASE2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome
NCT02679079	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Children and Adolescents With Tourette Syndrome
NCT02879578	PHASE2	COMPLETED	Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With Tourette Syndrome
NCT03066193	PHASE2	COMPLETED	Efficacy of a Therapeutic Combination of Dronabinol and PEA for Tourette Syndrome
NCT03247244	PHASE2	TERMINATED	Safety and Efficacy of Cannabis in Tourette Syndrome
NCT03325010	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
NCT03444038	PHASE2	COMPLETED	Open-Label Safety and Tolerability Study of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome