HTT

Summary

HTT (huntingtin, HGNC:4851) is a protein-coding gene on chromosome 4p16.3, encoding Huntingtin (P42858). May play a role in microtubule-mediated transport or vesicle function.

Huntingtin is a disease gene linked to Huntington’s disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological. The huntingtin locus is large, spanning 180 kb and consisting of 67 exons. The huntingtin gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript of approximately 10.3 kb is more widely expressed. The genetic defect leading to Huntington’s disease may not necessarily eliminate transcription, but may confer a new property on the mRNA or alter the function of the protein. One candidate is the huntingtin-associated protein-1, highly expressed in brain, which has increased affinity for huntingtin protein with expanded polyglutamine repeats. This gene contains an upstream open reading frame in the 5’ UTR that inhibits expression of the huntingtin gene product through translational repression.

Source: NCBI Gene 3064 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Huntington disease (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 784 total — 6 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 165 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001388492

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4851
Approved symbol	HTT
Name	huntingtin
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	IT15
Ensembl gene	ENSG00000197386
Ensembl biotype	protein_coding
OMIM	613004
Entrez	3064

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 10 retained_intron, 5 protein_coding, 4 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000355072, ENST00000506137, ENST00000508321, ENST00000509043, ENST00000509618, ENST00000509751, ENST00000510626, ENST00000512068, ENST00000512909, ENST00000513326, ENST00000513639, ENST00000513806, ENST00000647962, ENST00000648150, ENST00000649131, ENST00000649900, ENST00000650588, ENST00000650595, ENST00000680239, ENST00000680291, ENST00000680360, ENST00000680956, ENST00000681528

RefSeq mRNA: 2 — MANE Select: NM_001388492 NM_001388492, NM_002111

CCDS: CCDS43206

Canonical transcript exons

ENST00000355072 — 67 exons

Exon	Start	End
ENSE00000854943	3086939	3087022
ENSE00000854944	3099274	3099394
ENSE00000854945	3103824	3103883
ENSE00000854946	3105357	3105436
ENSE00000854947	3107285	3107423
ENSE00000854948	3115304	3115445
ENSE00000854953	3125549	3125629
ENSE00000854954	3127264	3127604
ENSE00000854955	3129924	3130047
ENSE00000854956	3130305	3130423
ENSE00000854981	3187651	3187886
ENSE00000854982	3188951	3189093
ENSE00000854987	3207281	3207357
ENSE00000854988	3208773	3208911
ENSE00001251499	3074681	3075088
ENSE00001506818	3122889	3122936
ENSE00001506819	3121228	3121432
ENSE00002026783	3239846	3243957
ENSE00003460831	3154293	3154419
ENSE00003467481	3235565	3235778
ENSE00003472889	3209827	3209949
ENSE00003475088	3131638	3131775
ENSE00003476697	3225661	3225743
ENSE00003479441	3211929	3212142
ENSE00003490959	3222387	3222487
ENSE00003494967	3116085	3116263
ENSE00003501297	3236149	3236254
ENSE00003503216	3228880	3229009
ENSE00003512853	3148005	3148207
ENSE00003512984	3212564	3212709
ENSE00003522087	3174721	3174799
ENSE00003522768	3177332	3177387
ENSE00003543993	3223406	3223560
ENSE00003548126	3238818	3238978
ENSE00003558932	3172320	3172397
ENSE00003559384	3204007	3204148
ENSE00003571103	3132562	3132720
ENSE00003574493	3180515	3180651
ENSE00003581669	3186597	3186719
ENSE00003584863	3145152	3145228
ENSE00003589182	3233163	3233353
ENSE00003596776	3206496	3206675
ENSE00003597650	3160282	3160392
ENSE00003603422	3217765	3217952
ENSE00003607438	3136226	3136326
ENSE00003613725	3199732	3199939
ENSE00003615800	3182354	3182470
ENSE00003620583	3146797	3146948
ENSE00003635707	3140510	3140656
ENSE00003639044	3215110	3215211
ENSE00003644432	3228615	3228745
ENSE00003648724	3132814	3132911
ENSE00003651248	3223992	3224131
ENSE00003657059	3135904	3135967
ENSE00003658160	3157072	3157199
ENSE00003658909	3142766	3142886
ENSE00003659509	3172908	3173131
ENSE00003665848	3178298	3178446
ENSE00003669528	3220182	3220308
ENSE00003671014	3174946	3175107
ENSE00003673769	3134401	3134540
ENSE00003678629	3238447	3238609
ENSE00003679310	3213958	3214135
ENSE00003681950	3131286	3131397
ENSE00003685801	3229887	3230042
ENSE00003689364	3206807	3206983
ENSE00003691918	3235284	3235398

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 95.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.8293 / max 398.7661, expressed in 1820 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46672	31.8293	1820

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.04	gold quality
body of pancreas	UBERON:0001150	92.59	gold quality
colonic epithelium	UBERON:0000397	91.95	gold quality
granulocyte	CL:0000094	91.03	gold quality
adrenal tissue	UBERON:0018303	90.74	gold quality
stromal cell of endometrium	CL:0002255	90.59	gold quality
calcaneal tendon	UBERON:0003701	90.29	gold quality
pancreas	UBERON:0001264	90.21	gold quality
ventricular zone	UBERON:0003053	90.06	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.58	gold quality
cortical plate	UBERON:0005343	89.53	gold quality
skin of leg	UBERON:0001511	89.42	gold quality
skin of abdomen	UBERON:0001416	88.69	gold quality
right frontal lobe	UBERON:0002810	88.26	gold quality
islet of Langerhans	UBERON:0000006	88.10	gold quality
prefrontal cortex	UBERON:0000451	87.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.86	gold quality
gastrocnemius	UBERON:0001388	87.85	gold quality
muscle of leg	UBERON:0001383	87.73	gold quality
cerebellar hemisphere	UBERON:0002245	87.54	gold quality
cerebellar cortex	UBERON:0002129	87.52	gold quality
upper lobe of left lung	UBERON:0008952	87.21	gold quality
anterior cingulate cortex	UBERON:0009835	87.07	gold quality
ganglionic eminence	UBERON:0004023	87.02	gold quality
cingulate cortex	UBERON:0003027	86.99	gold quality
leukocyte	CL:0000738	86.96	gold quality
bone marrow cell	CL:0002092	86.94	gold quality
left lobe of thyroid gland	UBERON:0001120	86.90	gold quality
monocyte	CL:0000576	86.80	gold quality
right lobe of thyroid gland	UBERON:0001119	86.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

140 targeting HTT, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-221-5P	99.86	65.45	1052

Literature-anchored findings (GeneRIF, showing 40)

• wild type huntingtin reduces the cellular toxicity of mutant huntingtin in mammalian cell models of Huntington’s disease (PMID:11432963)
• Normal huntingtin has an important role in neuronal cell survival, and loss of function of the normal protein may contribute to HD as well as gain of function of the abnormal huntingtin. (PMID:11642542)
• In human fibroblasts from normal and HD patients, huntingtin localized diffusely in the nucleus and in subnuclear compartments identified as speckles, promyelocytic leukemia protein bodies, and nucleoli (PMID:11739372)
• Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. (PMID:11792860)
• arfaptin 2 is involved in regulating huntingtin protein aggregation (PMID:11854752)
• Huntingtin is found in the perinuclear region along with microtubules, and in the centrosomal region along with gamma-tubulin. Inclusions are found in perinuclear locations because the beta-tubulin binding property of huntingtin brings it there. (PMID:11870213)
• These results suggest that medium-sized spiny striatal neurons are more vulnerable to NR2B-subtype NMDAR-mediated cell death in a transgenic mouse model of HD expressing full-length mutant huntingtin, compared with wild-type mice. (PMID:11906693)
• findings suggest that altered gene expression may result from the interactions of soluble mutant huntingtin with nuclear transcription factors, rather than from the depletion of transcription factors by nuclear inclusions (PMID:11971872)
• huntingtin interacts with Sp1 and TAFII130; transcriptional activity of SP1 and TAFII130 disrupted in early Huntingtin’s Disease (PMID:11988536)
• mutant huntingtin containing an expanded polyglutamine stretch induces neuronal death. (PMID:12062094)
• Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation in transgenic mice (PMID:12135980)
• Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. (PMID:12191472)
• An upstream open reading frame impedes translation of the huntingtin gene (PMID:12466534)
• Role of huntingtin in human health and disease [review] (PMID:12569151)
• Context-dependent neurodegeneration in huntington disease may be mediated by different N-terminal huntingtin fragments (PMID:12657678)
• In cases where the mother is known to be not a carrier, early Huntington disease prenatal diagnosis is possible by semiquantitative fluorescent-PCR of trace fetal dna in maternal blood samples (PMID:12682342)
• may function as a transcriptional coactivator of nuclear hormone receptors. (PMID:12799135)
• HD mutation is accompanied by a dramatic decline in Ca2+-triggered exocytosis of neurotransmitter and the decline in neurotransmitter release is a direct consequence of complexin II depletion. (PMID:12807877)
• polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N-methyl-D-aspartate receptors (PMID:12810713)
• Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. (PMID:12873381)
• Regulated expression of huntingtin (Huntington disease) induced reversible striatal neuropathology typical for Huntington disease. (PMID:12952868)
• theories differ with respect to subcellular distribution of HD at initiation of toxicity in Huntington’s diease: nuclear if cleaved and cytoplasmic in the absence of cleavage (PMID:14527999)
• Here we show dramatic mutation length increases (gains of up to 1000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathological cell loss. (PMID:14570710)
• huntingtin has a role in regulating cysteine string protein inhibition of N-type calcium channels (PMID:14570907)
• modeling framework based on a key analogy of the physicochemical properties of the huntingtin exon1 fragment to block copolymers (PMID:14617779)
• genome-wide screens were performed in yeast to identify genes that enhance the toxicity of mutant huntingtin;the genes clustered in the functionally related cellular processes of response to stress, protein folding & ubiquitin-dependent protein catabolism (PMID:14657499)
• A patient with triosephosphate isomerase (TPI) deficiency exhibited worsening of abnormal involuntary movements of the dystonic type and developed psychiatric symptoms while on selegiline. (PMID:14743370)
• Nonnuclear events induced by cytoplasmic huntingtin aggregation play a central role in the progressive neurodegeneration observed in Huntington’s disease. (PMID:14978262)
• Inhibiting the interaction of calmodulin with transglutaminase and huntingtin protein could decrease cross-linking and diminish huntingtin aggregate formation in the HD brain (PMID:14985437)
• Rapid clearance through the ubiquitin-proteasome pathway slows huntingtin aggregate formation, yet increases cellular toxicity. Polyglutamine neurotoxicity may be triggered by non-aggregated protein and aggregate formation may be a defense mechanism (PMID:15140195)
• Our findings using htt exon 1 suggest that the process of mutant htt aggregation rather than the resulting inclusion body is critical for neuronal cell death (PMID:15140196)
• the mutant huntingtin protein significantly decreased the Ca2+ threshold necessary to trigger MPT pore opening which accompanied by a significant release of cytochrome c (PMID:15163634)
• Causes huntingti0n disase when transfected into mice. (PMID:15240759)
• In Huntington’s disease, expansion occurs in the huntingtin protein. (review) (PMID:15261377)
• Time course of striatal degeneration produced by expanded huntingtin (Exp-Htt)occurs rapidly: at 48 h post-transfection, 60% of cultured striatal neurons expressing Exp-Htt have apoptotic characteristics including fragmented DNA and neuritic retraction. (PMID:15312898)
• unusual infantile onset of the disease in a little girl who presented with a history of seizures and psychomotor regression starting at the age of 3 years (PMID:15338298)
• is involved in fast axonal trafficking (PMID:15340079)
• siRNA is not directly linked to DNA methylation at the target huntingtin genomic locus in human cells (PMID:15351733)
• Growing evidence discussed in this review suggests that mutant huntingtin mediates multiple pathological pathways causing selective neurodegeneration in brains of Huntington’s disease patients. (PMID:15359012)
• Here we report the purification of huntingtin aggregates from postmortem Huntington’s disease brains. (PMID:15496672)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	htt	ENSDARG00000052866
mus_musculus	Htt	ENSMUSG00000029104
rattus_norvegicus	Htt	ENSRNOG00000011073
drosophila_melanogaster	htt	FBGN0027655
caenorhabditis_elegans		WBGENE00009027

Protein

Protein identifiers

Huntingtin — P42858 (reviewed: P42858)

Alternative names: Huntington disease protein

All UniProt accessions (8): A0A3B3ISR3, A0A3B3IU25, A0A7P0TA78, A0A7P0TAC5, A0A7P0TAN5, A0A7P0Z417, P42858, H0YA07

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in microtubule-mediated transport or vesicle function. Promotes the formation of autophagic vesicles.

Subunit / interactions. Interacts with PFN1. Interacts through its N-terminus with PRPF40A. Interacts with PQBP1. Interacts with SETD2. Interacts with SH3GLB1. Interacts with SYVN. Interacts with TPR; the interaction is inhibited by forms of Huntingtin with expanded polyglutamine stretch. Interacts with ZDHHC13 (via ANK repeats). Interacts with ZDHHC17 (via ANK repeats). Interacts with F8A1/F8A2/F8A3. Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A.

Subcellular location. Cytoplasm. Nucleus. Early endosome Cytoplasmic vesicle. Autophagosome.

Tissue specificity. Expressed in the brain cortex (at protein level). Widely expressed with the highest level of expression in the brain (nerve fibers, varicosities, and nerve endings). In the brain, the regions where it can be mainly found are the cerebellar cortex, the neocortex, the striatum, and the hippocampal formation.

Post-translational modifications. Cleaved by caspases downstream of the polyglutamine stretch. The resulting N-terminal fragments are cytotoxic and provokes apoptosis. Forms with expanded polyglutamine expansion are specifically ubiquitinated by SYVN1, which promotes their proteasomal degradation. Phosphorylation at Ser-1179 and Ser-1199 by CDK5 in response to DNA damage in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Myristoylated at Gly-551, following proteolytic cleavage at Asp-550.

Disease relevance. Huntington disease (HD) [MIM:143100] A neurodegenerative disorder characterized by involuntary movements (chorea), general motor impairment, psychiatric disorders and dementia. Onset of the disease occurs usually in the third or fourth decade of life. Onset and clinical course depend on the degree of poly-Gln repeat expansion, longer expansions resulting in earlier onset and more severe clinical manifestations. Neuropathology of Huntington disease displays a distinctive pattern with loss of neurons, especially in the caudate and putamen. The disease is caused by variants affecting the gene represented in this entry. Lopes-Maciel-Rodan syndrome (LOMARS) [MIM:617435] An autosomal recessive neurodevelopmental disorder characterized by developmental regression in infancy, delayed psychomotor development, severe intellectual disability, and cerebral and cerebellar atrophy. Additional features include swallowing problems, dystonia, bradykinesia, and continuous manual stereotypies without chorea. Some patients manifest seizures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal Gln-rich and Pro-rich domain has great conformational flexibility and is likely to exist in a fluctuating equilibrium of alpha-helical, random coil, and extended conformations.

Polymorphism. The poly-Gln region of HTT is highly polymorphic (10 to 35 repeats) in the normal population and is expanded to about 36-120 repeats in Huntington disease patients. The repeat length usually increases in successive generations, but also contracts on occasion. The adjacent poly-Pro region is also polymorphic and varies between 7-12 residues. Polyglutamine expansion leads to elevated susceptibility to apopain cleavage and likely result in accelerated neuronal apoptosis.

Similarity. Belongs to the huntingtin family.

RefSeq proteins (2): NP_001375421, NP_002102 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000091	Huntingtin	Family
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR024613	Huntingtin_N_HEAT_rpt-2	Repeat
IPR028426	Huntingtin_fam	Family
IPR048411	Htt_N_HEAT_rpt-1	Repeat
IPR048412	Htt_bridge	Repeat
IPR048413	Htt_C-HEAT_rpt	Repeat

Pfam: PF12372, PF20925, PF20926, PF20927

UniProt features (281 total): helix 146, turn 35, strand 31, modified residue 15, sequence variant 15, mutagenesis site 10, region of interest 8, compositionally biased region 6, repeat 5, site 5, chain 2, short sequence motif 1, lipid moiety-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

31 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9PMW	ELECTRON MICROSCOPY	2.1
9PN0	ELECTRON MICROSCOPY	2.3
9YR6	ELECTRON MICROSCOPY	2.3
4RAV	X-RAY DIFFRACTION	2.5
3LRH	X-RAY DIFFRACTION	2.6
6X9O	ELECTRON MICROSCOPY	2.6
8VLX	ELECTRON MICROSCOPY	2.6
8W15	ELECTRON MICROSCOPY	2.72
4FEB	X-RAY DIFFRACTION	2.8
4FED	X-RAY DIFFRACTION	2.81
4FE8	X-RAY DIFFRACTION	3
4FEC	X-RAY DIFFRACTION	3
8SAH	ELECTRON MICROSCOPY	3.2
8R2O	X-RAY DIFFRACTION	3.23
3IOT	X-RAY DIFFRACTION	3.5
3IOW	X-RAY DIFFRACTION	3.5
3IOR	X-RAY DIFFRACTION	3.6
7DXJ	ELECTRON MICROSCOPY	3.6
3IO4	X-RAY DIFFRACTION	3.63
3IO6	X-RAY DIFFRACTION	3.7
3IOU	X-RAY DIFFRACTION	3.7
3IOV	X-RAY DIFFRACTION	3.7
6EZ8	ELECTRON MICROSCOPY	4
7DXK	ELECTRON MICROSCOPY	4.1
6RMH	ELECTRON MICROSCOPY	9.6
8YAE	ELECTRON MICROSCOPY	10.08
6YEJ	ELECTRON MICROSCOPY	18.2
8YAO	ELECTRON MICROSCOPY	20.8
2LD0	SOLUTION NMR
2LD2	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for P42858 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Antibody-complex structures (SAbDab): 2 — 3LRH, 4RAV

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 511–512 (cleavage; by caspase-3); 528–529 (cleavage; by caspase-3); 550–551 (cleavage; by caspase-3); 584–585 (cleavage; by caspase-6); 587–588 (cleavage; by caspase-3)

Post-translational modifications (16): 9, 176, 234, 343, 411, 417, 419, 432, 442, 640, 643, 1179, 1199, 1870, 1874, 551

Mutagenesis-validated functional residues (10):

Position	Phenotype
495	inhibits interaction with zdhhc13 and zdhhc17.
498–499	abolishes interaction with zdhhc17.
498	inhibits interaction with zdhhc13 and zdhhc17.
499	inhibits interaction with zdhhc13 and zdhhc17.
511	loss of proteolytic cleavage.
528	no effect on proteolytic cleavage.
550	loss of proteolytic cleavage. loss of myristoylation.
551	loss of myristoylation.
584	loss of proteolytic cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9022692	Regulation of MECP2 expression and activity

MSigDB gene sets: 443 (showing top): GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_COGNITION, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_VESICLE_LOCALIZATION, GOBP_SPINDLE_LOCALIZATION, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ORGANELLE_TRANSPORT_ALONG_MICROTUBULE, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION

GO Biological Process (22): establishment of mitotic spindle orientation (GO:0000132), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), apoptotic process (GO:0006915), Golgi organization (GO:0007030), central nervous system development (GO:0007417), neurogenesis (GO:0022008), obsolete positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity (GO:0031587), protein destabilization (GO:0031648), vocal learning (GO:0042297), positive regulation of apoptotic process (GO:0043065), positive regulation of cilium assembly (GO:0045724), vesicle transport along microtubule (GO:0047496), synaptic vesicle transport (GO:0048489), positive regulation of mitophagy (GO:1901526), positive regulation of lipophagy (GO:1904504), regulation of CAMKK-AMPK signaling cascade (GO:1905289), positive regulation of CAMKK-AMPK signaling cascade (GO:1905291), positive regulation of aggrephagy (GO:1905337), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), microtubule-based process (GO:0007017), regulation of signal transduction (GO:0009966), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (11): p53 binding (GO:0002039), phosphoprotein phosphatase activity (GO:0004721), profilin binding (GO:0005522), kinase binding (GO:0019900), heat shock protein binding (GO:0031072), dynactin binding (GO:0034452), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), dynein intermediate chain binding (GO:0045505), beta-tubulin binding (GO:0048487), protein binding (GO:0005515)

GO Cellular Component (21): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), early endosome (GO:0005769), late endosome (GO:0005770), autophagosome (GO:0005776), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), centriole (GO:0005814), cytosol (GO:0005829), inclusion body (GO:0016234), axon (GO:0030424), dendrite (GO:0030425), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471), presynaptic cytosol (GO:0099523), postsynaptic cytosol (GO:0099524), endosome (GO:0005768), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transcriptional Regulation by MECP2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	6
cytoplasm	5
cellular anatomical structure	4
positive regulation of macroautophagy	3
intracellular membrane-bounded organelle	3
endomembrane system	3
nervous system development	2
cellular process	2
CAMKK-AMPK signaling cascade	2
intracellular anatomical structure	2
endosome	2
neuron projection	2
cytoplasmic vesicle	2
cytosol	2
mitotic cell cycle	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
Golgi vesicle transport	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
endomembrane system organization	1
system development	1
cell differentiation	1
regulation of protein stability	1
auditory behavior	1
imitative learning	1
learned vocalization behavior or vocal learning	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
cilium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of cilium assembly	1
positive regulation of organelle assembly	1
organelle transport along microtubule	1
vesicle cytoskeletal trafficking	1
transport	1
establishment of vesicle localization	1

Protein interactions and networks

STRING

5850 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTT	HAP1	P54257	997
HTT	OPTN	Q96CV9	990
HTT	TP53	P04637	989
HTT	GAPDH	P00354	987
HTT	ZDHHC17	Q8IUH5	986
HTT	SNCA	P37840	983
HTT	CREBBP	Q92793	982
HTT	F8A2	P23610	974
HTT	PRPF40A	O75400	971
HTT	HYPK	Q9NX55	965
HTT	HSPA4	P34932	955
HTT	KAT2B	Q92831	949
HTT	TAF4	O00268	948
HTT	RASD2	Q96D21	946
HTT	HIP1R	O75146	945
HTT	SH3GL3	Q99963	945

IntAct

6699 interactions, top by confidence:

A	B	Type	Score
HTT	HTT	psi-mi:“MI:0407”(direct interaction)	0.890
HTT	HTT	psi-mi:“MI:0915”(physical association)	0.890
HTT	BECN1	psi-mi:“MI:0915”(physical association)	0.770
BECN1	HTT	psi-mi:“MI:0914”(association)	0.770
HTT	DYNC1H1	psi-mi:“MI:0915”(physical association)	0.770
HTT	SQSTM1	psi-mi:“MI:0915”(physical association)	0.770
DNALI1	HTT	psi-mi:“MI:0915”(physical association)	0.740
TP53	HTT	psi-mi:“MI:0915”(physical association)	0.710
ULK1	MTOR	psi-mi:“MI:0914”(association)	0.700
HTT	ZMAT2	psi-mi:“MI:0915”(physical association)	0.700
FTL	HTT	psi-mi:“MI:0915”(physical association)	0.700
XRCC6	HTT	psi-mi:“MI:0915”(physical association)	0.700
NME4	HTT	psi-mi:“MI:0915”(physical association)	0.680
HTT	ARFGAP3	psi-mi:“MI:0915”(physical association)	0.680
MBD4	HTT	psi-mi:“MI:0915”(physical association)	0.680
HNRNPC	HTT	psi-mi:“MI:0915”(physical association)	0.680
HTT	MEOX1	psi-mi:“MI:0915”(physical association)	0.680
HTT	VDAC2	psi-mi:“MI:0915”(physical association)	0.670
HTT	SKIC8	psi-mi:“MI:0915”(physical association)	0.670
HTT	COPS3	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (607): HTT (Affinity Capture-Western), SQSTM1 (Affinity Capture-Western), HTT (Affinity Capture-Western), HTT (Affinity Capture-Western), HTT (Two-hybrid), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS), SQSTM1 (Affinity Capture-Western), ULK1 (Affinity Capture-Western), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS)

ESM2 similar proteins: A0A078CGE6, A2QHV0, A7KAX9, A7SNN5, A9RVK2, B0XPE7, B5X564, D0Z5N4, F4HYG2, F4I114, F4IRW0, F4J394, F4J6F6, F4JY37, O00444, O13839, O24527, O43065, P0CP71, P13185, P38623, P42858, P50526, Q03407, Q0CL79, Q0WPH8, Q14693, Q19192, Q2KHT3, Q2QAV0, Q4WJI7, Q5B4Z3, Q5R9Z7, Q60DG4, Q6GPD0, Q6H647, Q756Z0, Q75CH3, Q75DK7, Q75QN6

Diamond homologs: P42858, P42859, P51111, P51112

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
SGK1	down-regulates	HTT	phosphorylation
CDK5	up-regulates	HTT	phosphorylation
AKT1	unknown	HTT	phosphorylation
TBK1	“up-regulates activity”	HTT	phosphorylation
AKT	unknown	HTT	phosphorylation
PRKACA	“down-regulates quantity by destabilization”	HTT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 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
CD28 dependent PI3K/Akt signaling	5	16.0×	7e-03
Regulation of TP53 Degradation	6	14.3×	3e-03
Autodegradation of the E3 ubiquitin ligase COP1	5	10.8×	9e-03
Vif-mediated degradation of APOBEC3G	5	10.3×	9e-03
AUF1 (hnRNP D0) binds and destabilizes mRNA	5	10.1×	9e-03
Negative regulation of NOTCH4 signaling	5	9.7×	1e-02
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	6	9.6×	7e-03
Degradation of CDH1	6	9.6×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein localization to plasma membrane	6	10.9×	1e-02
negative regulation of apoptotic process	18	4.2×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	7
Uncertain significance	265
Likely benign	330
Benign	81

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1393012	NM_001388492.1(HTT):c.2710C>T (p.Gln904Ter)	Pathogenic
1464611	NM_001388492.1(HTT):c.2085del (p.Gly697fs)	Pathogenic
1494729	NM_001388492.1(HTT):c.5821_5833del (p.Ser1941fs)	Pathogenic
1808621	GRCh37/hg19 4p16.3-15.33(chr4:1-12785001)x1	Pathogenic
409	NC_000004.11:g.3076606GCA[40_?]	Pathogenic
417745	NM_001388492.1(HTT):c.8150T>A (p.Phe2717Tyr)	Pathogenic
1357041	NM_001388492.1(HTT):c.8110-1G>A	Likely pathogenic
1375718	NM_001388492.1(HTT):c.1403-1G>C	Likely pathogenic
1687507	NM_001388492.1(HTT):c.54GCA[40] (p.Gln18_Gln38dup)	Likely pathogenic
3779748	NM_001388492.1(HTT):c.99_102del (p.Gln33fs)	Likely pathogenic
3779749	NM_001388492.1(HTT):c.99del (p.Gln33fs)	Likely pathogenic
3897713	NM_001388492.1:c.52CAG[55_59]	Likely pathogenic
4845680	NM_001388492.1(HTT):c.6921C>G (p.Leu2307=)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

20487 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:3103864:T:C	L170P	1.000
4:3105406:T:C	L193P	1.000
4:3107302:T:C	L209P	1.000
4:3174965:T:A	I1422N	1.000
4:3174986:T:A	V1429D	1.000
4:3175064:T:C	L1455P	1.000
4:3175083:T:A	N1461K	1.000
4:3175083:T:G	N1461K	1.000
4:3175084:T:C	Y1462H	1.000
4:3175091:T:C	L1464P	1.000
4:3175094:T:A	L1465Q	1.000
4:3175094:T:C	L1465P	1.000
4:3175096:G:C	D1466H	1.000
4:3175097:A:T	D1466V	1.000
4:3178345:T:C	L1504P	1.000
4:3180524:C:A	A1541D	1.000
4:3180527:T:C	L1542P	1.000
4:3180548:T:C	L1549P	1.000
4:3222389:T:A	W2458R	1.000
4:3222389:T:C	W2458R	1.000
4:3222419:T:A	W2468R	1.000
4:3222419:T:C	W2468R	1.000
4:3086992:T:A	I106K	0.999
4:3099309:C:A	A128D	0.999
4:3099365:G:C	A147P	0.999
4:3099366:C:A	A147D	0.999
4:3099378:T:C	L151P	0.999
4:3103858:T:C	L168P	0.999
4:3103871:G:C	K172N	0.999
4:3103871:G:T	K172N	0.999

dbSNP variants (sampled 300 via entrez): RS1000020655 (4:3193594 T>C), RS10000252 (4:3214757 C>T), RS1000034843 (4:3113244 T>A), RS1000048838 (4:3237517 T>C), RS1000101527 (4:3165489 A>G), RS1000142891 (4:3086684 A>G), RS1000153510 (4:3155479 C>G,T), RS1000166324 (4:3131872 T>C), RS1000167788 (4:3204420 A>G), RS1000170412 (4:3170726 C>T), RS10002065 (4:3112774 T>C), RS1000216512 (4:3075551 G>A), RS1000251797 (4:3092352 A>G,T), RS1000255058 (4:3119500 A>T), RS1000272117 (4:3138185 G>A,T)

Disease associations

OMIM: gene MIM:613004 | disease phenotypes: MIM:617435, MIM:143100

GenCC curated gene-disease

Disease	Classification	Inheritance
Huntington disease	Definitive	Autosomal dominant
Lopes-Maciel-Rodan syndrome	Strong	Autosomal recessive
juvenile Huntington disease	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Huntington disease	Definitive	AD

Mondo (4): Lopes-Maciel-Rodan syndrome (MONDO:0054573), cerebral palsy (MONDO:0006497), Huntington disease (MONDO:0007739), juvenile Huntington disease (MONDO:0016621)

Orphanet (2): Juvenile Huntington disease (Orphanet:248111), Huntington disease (Orphanet:399)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0100021	Cerebral palsy

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D006816	Huntington Disease	C10.228.140.079.545; C10.228.140.380.278; C10.228.662.262.249.750; C10.574.500.497; C16.320.400.430; F03.615.250.400; F03.615.400.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4296121 (PROTEIN-PROTEIN INTERACTION), CHEMBL5514 (SINGLE PROTEIN), CHEMBL6193806 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

165 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 722,971 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1057	FLUORESCEIN	4	329,940
CHEMBL1089641	TRYPAN BLUE FREE ACID	4	113
CHEMBL1116	RALOXIFENE HYDROCHLORIDE	4	28,574
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1185568	DITHIAZANINE	4	123
CHEMBL1200348	SULCONAZOLE NITRATE	4	3,129
CHEMBL1200471	PYRITHIONE ZINC	4	24,834
CHEMBL1200474	DEMECLOCYCLINE HYDROCHLORIDE	4	1,867
CHEMBL1200596	CHLOROXINE	4	1,792
CHEMBL1200600	FLUOROMETHOLONE	4	24,094
CHEMBL1200612	DIBUCAINE HYDROCHLORIDE	4	7,397
CHEMBL1200848	HYDROXYPROGESTERONE CAPROATE	4	16,548
CHEMBL1201001	MECHLORETHAMINE HYDROCHLORIDE	4	22,478
CHEMBL1201049	ECONAZOLE NITRATE	4	3,918
CHEMBL1201124	KETOROLAC TROMETHAMINE	4	18,700
CHEMBL1201153	ISOETHARINE MESYLATE	4	854
CHEMBL1201284	CINACALCET	4	5,917
CHEMBL1237135	MAPROTILINE HYDROCHLORIDE	4
CHEMBL1276308	MIFEPRISTONE	4
CHEMBL12856	INAMRINONE	4
CHEMBL1319139	BROMHEXINE HYDROCHLORIDE	4
CHEMBL1334033	PERHEXILINE MALEATE	4
CHEMBL1401	NITAZOXANIDE	4
CHEMBL1423	PIMOZIDE	4
CHEMBL1448	NICLOSAMIDE	4
CHEMBL1454910	NITROXOLINE	4
CHEMBL1489	AZACITIDINE	4

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs362267	Efficacy	3	risperidone	Schizophrenia
rs362272	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs362306	Efficacy	3	risperidone	Schizophrenia

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs362272	HTT	3	0.00	1	methylphenidate
rs362267	HTT, MSANTD1	3	0.00	1	risperidone
rs362306	HTT, MSANTD1	3	0.00	1	risperidone

Binding affinities (BindingDB)

216 measured of 230 human assays (247 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2,5-bis(chloranyl)-3-[2-(dimethylamino)-1,3-thiazol-5-yl]-6-pyrrolidin-1-yl-cyclohexa-2,5-diene-1,4-dione	EC50	210 nM
cid_7497069	IC50	450 nM
cid_5928270	IC50	452 nM
SMR001282215	IC50	462 nM
methyl 3-[(2E)-2-(1-cyano-2-oxo-2-phenylethylidene)hydrazinyl]-5-methylsulfanyl-4-propan-2-ylsulfonylthiophene-2-carboxylate	IC50	561 nM
3-[2-furanyl(oxo)methyl]-4-hydroxy-1-(6-methyl-1,3-benzothiazol-2-yl)-2-(5-methyl-2-furanyl)-2H-pyrrol-5-one;oxalic acid	IC50	624 nM
methyl 2-[4-hydroxy-3-(5-methylfuran-2-carbonyl)-2-(4-nitrophenyl)-5-oxo-2H-pyrrol-1-yl]-4-methyl-1,3-thiazole-5-carboxylate	IC50	636 nM
6-chloranyl-N-[2-(2-chlorophenyl)ethyl]-5-methyl-7-oxidanylidene-1H-pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	796 nM
N-[(5Z)-5-[(4,5-dimethoxy-2-nitrophenyl)methylidene]-4-oxo-2-thiazolyl]benzenesulfonamide	IC50	848 nM
MLS000516399	IC50	1010 nM
cid_2807878	IC50	1060 nM
SMR000260936	IC50	1120 nM
(6Z)-5-imino-6-(1H-indol-3-ylmethylene)-3-(methylsulfonyl)-5,6-dihydro-7H-[1,2,4]thiadiazolo[4,5-a]pyrimidin-7-one	IC50	1180 nM
3-(1-benzofuran-2-ylcarbonyl)-2-(3-chlorophenyl)-1-(5-methyl-1,2-oxazol-3-yl)-4-oxidanyl-2H-pyrrol-5-one	IC50	1190 nM
sodium;(6R,7R)-3-(acetyloxymethyl)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	IC50	1200 nM
5-(butylcarbamoyl)-3-(naphthalen-1-ylsulfanylmethyl)-1,2-oxazole-4-carboxylic acid	IC50	1210 nM
MLS002252338	IC50	1240 nM
5-(4-methylnaphthalen-1-yl)-N-(4-methylphenyl)sulfonyl-furan-2-carboxamide	IC50	1340 nM
1-[1-(4-chlorophenyl)cyclobutanecarbonyl]-2-methyl-N-naphthalen-2-ylsulfonylazetidine-2-carboxamide	IC50	1370 nM
N-[3-[bis(fluoranyl)methoxy]phenyl]sulfonyl-2-[4-(naphthalen-2-yloxymethyl)-1,2,3-triazol-1-yl]ethanamide	IC50	1450 nM
MLS001147241	IC50	1480 nM
SMR000459203	IC50	1520 nM
cid_2354951	IC50	1550 nM
3-methyl-1-(3-methylphenyl)-6-thiophen-2-yl-4-pyrazolo[3,4-b]pyridinecarboxylic acid	IC50	1600 nM
cid_24789603	IC50	1620 nM
2-({[(3,4-dichlorophenyl)amino]carbonyl}amino)benzoic acid	EC50	1670 nM
SMR001550649	IC50	1670 nM
MLS001179702	IC50	1670 nM
N-(4-fluorophenyl)-2-[2-[(Z)-(4-oxidanylidene-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]phenoxy]ethanamide	IC50	1690 nM
MLS001180600	IC50	1730 nM
cid_49790522	IC50	1780 nM
4-(4-propan-2-ylphenyl)-2-(thiophen-2-ylcarbonylamino)thiophene-3-carboxylic acid	IC50	1840 nM
N-[[[3-(4-fluorophenyl)-1H-pyrazol-5-yl]carbonylamino]carbamothioyl]-5-methyl-3-phenyl-1,2-oxazole-4-carboxamide	IC50	1840 nM
MLS003127993	IC50	1850 nM
2-[[[4-[[2-(4-methoxyphenoxy)-1-oxoethyl]amino]phenyl]-oxomethyl]amino]benzoic acid	IC50	1870 nM
SMR000211931	IC50	1900 nM
2-[2-(4-chloroanilino)-4-thiophen-2-yl-5-thiazolyl]acetic acid	IC50	1900 nM
(2Z)-5-amino-2-(2-furfurylidene)-7-(2-furyl)-3-keto-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitrile	IC50	1920 nM
4-[[(E)-3-(1,3-diphenyl-4-pyrazolyl)-1-oxoprop-2-enyl]amino]benzoic acid	IC50	1950 nM
2-(4-chloro-3-methylphenoxy)-N-(4-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]sulfonyl}phenyl)acetamide	IC50	1950 nM
cid_2334017	IC50	1970 nM
2-Benzoylamino-5-phenyl-thiophene-3-carboxylic acid	IC50	2000 nM
SMR000814574	IC50	2010 nM
2-(3,4-dimethoxyphenyl)-3-(furan-2-carbonyl)-4-hydroxy-1-(6-methoxy-1,3-benzothiazol-2-yl)-2H-pyrrol-5-one	IC50	2040 nM
5-(3-chlorophenyl)-3-[4-(2H-1,2,3,4-tetrazol-5-yl)phenyl]-1,2,4-oxadiazole	IC50	2060 nM
cid_5965423	IC50	2090 nM
SMR000248556	IC50	2140 nM
methyl 2-(naphthalen-2-ylsulfonylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate	IC50	2150 nM
cid_4880464	IC50	2150 nM
(5E)-1-butyl-5-[(E)-3-(2-furanyl)prop-2-enylidene]-2-sulfanylidene-1,3-diazinane-4,6-dione	IC50	2180 nM

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	Potency	1	nM	CHEMBL1307475
9.00	Potency	1	nM	KENPAULLONE
8.96	Potency	1.1	nM	CHEMBL1460806
8.89	Potency	1.3	nM	CHEMBL1314987
8.80	IC50	1.6	nM	CHEMBL4875017
8.77	IC50	1.7	nM	CHEMBL4878942
8.68	IC50	2.1	nM	CHEMBL4863336
8.68	IC50	2.1	nM	CHEMBL4847156
8.66	IC50	2.2	nM	CHEMBL4867927
8.66	Potency	2.2	nM	CHEMBL1374893
8.66	Potency	2.2	nM	CHEMBL1485295
8.64	IC50	2.3	nM	CHEMBL4859053
8.60	Potency	2.5	nM	CHEMBL1531569
8.60	Potency	2.5	nM	CHEMBL1522262
8.55	Potency	2.8	nM	CHEMBL1427457
8.55	Potency	2.8	nM	CHEMBL1366201
8.55	Potency	2.8	nM	CHEMBL1453691
8.55	Potency	2.8	nM	CHEMBL1313778
8.49	Potency	3.2	nM	CHEMBL1373983
8.35	Potency	4.5	nM	CHEMBL1442568
8.35	Potency	4.5	nM	CHEMBL1543244
8.30	Potency	5	nM	CHEMBL1321101
8.20	Potency	6.3	nM	CHEMBL1527550
8.20	Potency	6.3	nM	CHEMBL1580359
8.15	Potency	7.1	nM	CHEMBL1406095
8.10	IC50	8	nM	CHEMBL5179682
8.05	Potency	8.9	nM	CHEMBL1601713
8.00	Potency	10	nM	CHEMBL1602321
7.85	Potency	14.1	nM	CHEMBL1509005
7.85	Potency	14.1	nM	CHEMBL1433254
7.80	Potency	15.8	nM	CHEMBL1427501
7.80	Potency	15.8	nM	CHEMBL1400505
7.75	Potency	17.8	nM	VINCRISTINE
7.70	Potency	20	nM	TRYPAN BLUE FREE ACID
7.60	Potency	25.1	nM	CHEMBL1380650
7.60	Potency	25.1	nM	CHEMBL1461196
7.60	Potency	25.1	nM	CHEMBL1573026
7.55	Potency	28.2	nM	CHEMBL1516718
7.55	Potency	28.2	nM	CHEMBL1444064
7.55	Potency	28.2	nM	CHEMBL3199116
7.55	Potency	28.2	nM	CHEMBL1587526
7.55	Potency	28.2	nM	CHEMBL1413448
7.55	Potency	28.2	nM	CHEMBL1322179
7.50	Potency	31.6	nM	CHEMBL1437881
7.50	Potency	31.6	nM	CHEMBL1359386
7.50	Potency	31.6	nM	CHEMBL473735
7.50	Potency	31.6	nM	CHEMBL1455655
7.50	Potency	31.6	nM	CHEMBL1600349
7.50	Potency	31.6	nM	CHEMBL1535191
7.50	Potency	31.6	nM	CHEMBL1612884

PubChem BioAssay actives

35 with measured affinity, of 180 total; 31 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-(7-fluoro-2-methylindazol-5-yl)-2-[3-[3-(hydroxymethyl)piperazin-1-yl]-1,2,4-triazin-6-yl]phenol	1782623: Inhibition of endogenous Huntingtin protein (unknown origin) incubated for overnight in presence of MW1/MAB2166 monoclonal antibody by ELISA-based MSD electrochemiluminescence assay	ic50	0.0016	uM
2-[3-[(3S)-3-cyclopropylpiperazin-1-yl]-1,2,4-triazin-6-yl]-5-(2-methyltriazolo[4,5-b]pyridin-6-yl)phenol	1782623: Inhibition of endogenous Huntingtin protein (unknown origin) incubated for overnight in presence of MW1/MAB2166 monoclonal antibody by ELISA-based MSD electrochemiluminescence assay	ic50	0.0017	uM
2-[3-[(3S)-3-cyclopropylpiperazin-1-yl]-1,2,4-triazin-6-yl]-5-(5-fluoro-1H-pyrazol-4-yl)phenol	1782623: Inhibition of endogenous Huntingtin protein (unknown origin) incubated for overnight in presence of MW1/MAB2166 monoclonal antibody by ELISA-based MSD electrochemiluminescence assay	ic50	0.0021	uM
5-(7-fluoro-2-methylindazol-5-yl)-2-[3-(3-methylpiperazin-1-yl)-1,2,4-triazin-6-yl]phenol	1782623: Inhibition of endogenous Huntingtin protein (unknown origin) incubated for overnight in presence of MW1/MAB2166 monoclonal antibody by ELISA-based MSD electrochemiluminescence assay	ic50	0.0021	uM
2-[3-(3-ethylpiperazin-1-yl)-1,2,4-triazin-6-yl]-5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)phenol	1782623: Inhibition of endogenous Huntingtin protein (unknown origin) incubated for overnight in presence of MW1/MAB2166 monoclonal antibody by ELISA-based MSD electrochemiluminescence assay	ic50	0.0022	uM
5-(2-methylimidazo[1,2-a]pyrazin-6-yl)-2-[3-[(3S)-3-propan-2-ylpiperazin-1-yl]-1,2,4-triazin-6-yl]phenol	1782623: Inhibition of endogenous Huntingtin protein (unknown origin) incubated for overnight in presence of MW1/MAB2166 monoclonal antibody by ELISA-based MSD electrochemiluminescence assay	ic50	0.0023	uM
7-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(1-ethylpiperidin-4-yl)-5-fluorocinnoline	1874417: Inhibition of HTT (unknown origin)	ic50	0.0080	uM
4-[3-hydroxy-4-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenyl]-1H-pyridin-2-one	1874417: Inhibition of HTT (unknown origin)	ic50	0.0400	uM
7-(1-ethylpiperidin-4-yl)-9-methyl-2-(2-methylindazol-5-yl)pyrido[1,2-a]pyrimidin-4-one	1874417: Inhibition of HTT (unknown origin)	ic50	0.0800	uM
N-(3-aminopropyl)-N-[(1R)-1-(3-benzyl-7-iodo-4H-quinazolin-2-yl)-2-methylpropyl]-4-methylbenzamide	1922361: Binding affinity to mutant HTT (unknown origin) mediated HD exon 1-72Q aggregation assessed as dissociation constant	kd	0.1000	uM
(3Z)-3-[(3,5-dibromo-4-hydroxyphenyl)methylidene]-5-iodo-1H-indol-2-one	1922361: Binding affinity to mutant HTT (unknown origin) mediated HD exon 1-72Q aggregation assessed as dissociation constant	kd	0.1000	uM
4-[2-[(6-chloroquinazolin-4-yl)amino]ethyl]phenol	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	0.7100	uM
4-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-6-chloroquinazoline	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	1.0700	uM
4-[2-[(6-bromoquinazolin-4-yl)amino]ethyl]phenol	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	1.1100	uM
methyl 4-[[6-(phenylcarbamoyl)-1,3-benzothiazol-2-yl]carbamoyl]benzoate	729971: Inhibition of HD exon 1 fusion protein with 51 glutamine residues (unknown origin) aggregation expressed in Escherichia coli SURE after 16 hrs by Western blotting analysis	ic50	1.2000	uM
6-bromo-4-(4-methylpiperazin-1-yl)quinazoline	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	1.3100	uM
(2-amino-1,3-thiazol-4-yl)-[3-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-3aH-indazol-2-yl]methanone	1922358: Inhibition of HTT (unknown origin)	ic50	1.8000	uM
6-bromo-4-(4-ethylpiperazin-1-yl)quinazoline	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	2.2100	uM
6-bromo-4-piperazin-1-ylquinazoline	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	2.7400	uM
6-chloro-N-[2-(4-chlorophenyl)ethyl]quinazolin-4-amine	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	3.4400	uM
6-chloro-4-(4-ethylpiperazin-1-yl)quinazoline	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	3.6300	uM
ethyl 2-[4-[2-[(6-chloroquinazolin-4-yl)amino]ethyl]phenoxy]acetate	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	4.4800	uM
3-aminospiro[6H-benzo[h]quinazoline-5,1’-cyclopentane]-4-one	1922359: Inhibition of mutant HTT (unknown origin)	ec50	4.9000	uM
(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-4-oxobutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-3-methylpentanoyl]amino]-3-phenylpropanoyl]amino]butanedioic acid	2098552: Inhibition of HTT (unknown origin) by ELISA method	ic50	5.0000	uM
N-(4-anilinophenyl)-2-(2-methylphenoxy)acetamide	1922358: Inhibition of HTT (unknown origin)	ic50	5.0000	uM
4-(4-ethylpiperazin-1-yl)-6-fluoroquinazoline	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	5.2600	uM
6-bromo-N-prop-2-enylquinazolin-4-amine	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	5.3600	uM
N-benzyl-6-bromoquinazolin-4-amine	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	6.1300	uM
4-[2-[(6-fluoroquinazolin-4-yl)amino]ethyl]phenol	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	6.3800	uM
N-(4-anilinophenyl)-2-(3-methylphenoxy)acetamide	1922358: Inhibition of HTT (unknown origin)	ic50	7.5000	uM
6-bromo-N-propylquinazolin-4-amine	419008: Inhibition of Huntingtin protein aggregation by cell based assay	ic50	8.1300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases abundance	2
Aflatoxin B1	decreases methylation, increases methylation	2
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
geldanamycin	affects binding, decreases reaction	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cypermethrin	increases expression	1
manganese chloride	increases abundance, decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
formic acid	affects binding, decreases reaction	1
corosolic acid	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Benzophenoneidum	increases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Copper	affects binding, increases reaction, increases reduction	1
Dexamethasone	decreases expression, affects cotreatment	1
Endosulfan	decreases expression	1

ChEMBL screening assays

77 unique, capped per target: 72 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4187717	Binding	Induction of IAP-huntingtin interaction-mediated huntingtin protein degradation in fibroblasts derived from Huntington’s disease patient incubated for 24 hrs by Western blot method	Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative. — Bioorg Med Chem Lett
CHEMBL1613918	Functional	PUBCHEM_BIOASSAY: qHTS Multiplex Assay to Identify Dual Action Probes in a Cell Model of Huntington: Aggregate Formation (GFP). (Class of assay: confirmatory) [Related pubchem assays: 1482, 1471 ]	PubChem BioAssay data set

Cellosaurus cell lines

248 cell lines: 131 induced pluripotent stem cell, 41 finite cell line, 35 transformed cell line, 19 cancer cell line, 16 embryonic stem cell, 4 conditionally immortalized cell line, 2 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1H81	GM04022	Finite cell line	Female
CVCL_1H82	GM04023	Transformed cell line	Female
CVCL_1I60	GM04854	Transformed cell line	Male
CVCL_1I61	GM04855	Finite cell line	Male
CVCL_1I62	GM04856	Transformed cell line	Female
CVCL_1I63	GM04857	Finite cell line	Female
CVCL_1I94	GM05538	Transformed cell line	Male
CVCL_1I95	GM05539	Finite cell line	Male
CVCL_1J70	GM13503	Transformed cell line	Female
CVCL_1J71	GM13504	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00652457	PHASE4	COMPLETED	Study of Memantine to Treat Huntington’s Disease
NCT01834911	PHASE4	COMPLETED	Effect of Tetrabenazine on Stroop Interference in HD
NCT02509793	PHASE4	UNKNOWN	A Pilot Study Assessing Impulsivity in Patients With Huntington’s Disease on Xenazine (Tetrabenazine)
NCT07601516	PHASE4	COMPLETED	Real World Effectiveness and Safety of Deutetrabenazine in Adult Chinese Patients With Huntington’s Disease (HD) Chorea in China
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00146211	PHASE3	COMPLETED	TREND-HD - A Trial of Ethyl-EPA (Miraxion™) in Treating Mild to Moderate Huntington’s Disease
NCT00219804	PHASE3	COMPLETED	Efficacy and Safety of Tetrabenazine in Chorea
NCT00277602	PHASE3	COMPLETED	Riluzole in Huntington’s Disease
NCT00608881	PHASE3	TERMINATED	Coenzyme Q10 in Huntington’s Disease (HD)
NCT00632645	PHASE3	COMPLETED	Neuroleptic and Huntington Disease Comparison of : Olanzapine, la Tetrabenazine and Tiapride
NCT00665223	PHASE3	COMPLETED	A Study of Treatment With Pridopidine (ACR16) in Participants With Huntington’s Disease
NCT00712426	PHASE3	TERMINATED	Creatine Safety, Tolerability, & Efficacy in Huntington’s Disease (CREST-E)
NCT00920946	PHASE3	COMPLETED	A Safety and Efficacy Study of Dimebon in Patients With Huntington Disease
NCT01085266	PHASE3	TERMINATED	An Extension of the HORIZON Protocol Evaluating the Safety of Dimebon (Latrepirdine) in Subjects With Huntington Disease
NCT03842969	PHASE3	COMPLETED	An Open-Label Extension Study to Evaluate Long-Term Safety and Tolerability of RO7234292 (RG6042) in Huntington’s Disease Participants Who Participated in Prior Roche and Genentech Sponsored Studies
NCT03854019	PHASE3	COMPLETED	Evaluating the Efficacy of Dextromethorphan/Quinidine in Treating Irritability in Huntington’s Disease
NCT04556656	PHASE3	COMPLETED	PRidopidine’s Outcome On Function in Huntington Disease, PROOF- HD
NCT04826692	PHASE3	COMPLETED	TEsting METformin Against Cognitive Decline in HD
NCT05655520	PHASE3	TERMINATED	A Study to Evaluate the Safety and Tolerability of SAGE-718 in Participants With Huntington’s Disease
NCT06097780	PHASE3	UNKNOWN	Efficacy and Safety of NestaCell® in Huntington’s Disease
NCT07326709	PHASE3	RECRUITING	A Study to Investigate the Efficacy, Safety and Tolerability of Votoplam in Participants With Huntington’s Disease
NCT07609108	PHASE3	NOT_YET_RECRUITING	PRidopidine Phase 3 Study to Establish Clinical Impact and Safety in Huntington’s Disease
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy