INTS6

Summary

INTS6 (integrator complex subunit 6, HGNC:14879) is a protein-coding gene on chromosome 13q14.3, encoding Integrator complex subunit 6 (Q9UL03). Component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes. It is a selective cancer dependency (DepMap: 73.9% of cell lines).

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. The protein encoded by this gene is a DEAD box protein that is part of a complex that interacts with the C-terminus of RNA polymerase II and is involved in 3’ end processing of snRNAs. In addition, this gene is a candidate tumor suppressor and is located in the critical region of loss of heterozygosity (LOH). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 26512 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 153 total — 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 73.9% of screened cell lines
• MANE Select transcript: NM_012141

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14879
Approved symbol	INTS6
Name	integrator complex subunit 6
Location	13q14.3
Locus type	gene with protein product
Status	Approved
Aliases	DICE1, HDB, Notchl2, DBI-1, DDX26A, INT6
Ensembl gene	ENSG00000102786
Ensembl biotype	protein_coding
OMIM	604331
Entrez	26512

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 11 protein_coding, 7 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000311234, ENST00000398119, ENST00000442263, ENST00000460868, ENST00000461515, ENST00000466784, ENST00000469430, ENST00000476666, ENST00000483288, ENST00000483441, ENST00000483746, ENST00000485178, ENST00000486195, ENST00000488009, ENST00000490542, ENST00000491189, ENST00000491723, ENST00000491997, ENST00000493153, ENST00000497989, ENST00000912385

RefSeq mRNA: 4 — MANE Select: NM_012141 NM_001039937, NM_001039938, NM_001306091, NM_012141

CCDS: CCDS41890, CCDS45048, CCDS76636, CCDS9428

Canonical transcript exons

ENST00000311234 — 18 exons

Exon	Start	End
ENSE00001901770	51452415	51453036
ENSE00001958085	51361577	51365845
ENSE00003464769	51368939	51369310
ENSE00003469114	51367805	51367898
ENSE00003475524	51374654	51374796
ENSE00003481081	51382029	51382123
ENSE00003496736	51395300	51395483
ENSE00003510529	51451978	51452055
ENSE00003530729	51451025	51451174
ENSE00003543787	51378239	51378454
ENSE00003562574	51389319	51389444
ENSE00003578217	51383329	51383461
ENSE00003609410	51374208	51374439
ENSE00003613474	51379462	51379572
ENSE00003627253	51387386	51387540
ENSE00003645227	51376048	51376174
ENSE00003671828	51383589	51383741
ENSE00003786336	51430294	51430383

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 96.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.1672 / max 1039.2505, expressed in 1819 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137380	42.5867	1815
137375	0.8660	344
137377	0.6712	364
137376	0.2955	120
137374	0.2354	80
137373	0.2165	65
137378	0.1915	61
137379	0.1043	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	96.09	gold quality
calcaneal tendon	UBERON:0003701	96.00	gold quality
tongue squamous epithelium	UBERON:0006919	95.66	gold quality
adrenal tissue	UBERON:0018303	95.00	gold quality
cranial nerve II	UBERON:0000941	94.81	gold quality
right testis	UBERON:0004534	94.81	gold quality
left testis	UBERON:0004533	94.73	gold quality
colonic epithelium	UBERON:0000397	93.92	gold quality
testis	UBERON:0000473	93.04	gold quality
tonsil	UBERON:0002372	91.00	gold quality
body of pancreas	UBERON:0001150	90.94	gold quality
ventricular zone	UBERON:0003053	90.62	gold quality
gingival epithelium	UBERON:0001949	90.61	gold quality
lower esophagus mucosa	UBERON:0035834	90.45	gold quality
stromal cell of endometrium	CL:0002255	90.30	gold quality
tibia	UBERON:0000979	89.71	gold quality
squamous epithelium	UBERON:0006914	89.61	gold quality
esophagus squamous epithelium	UBERON:0006920	89.51	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.38	gold quality
ganglionic eminence	UBERON:0004023	89.25	gold quality
hair follicle	UBERON:0002073	89.17	gold quality
right lobe of liver	UBERON:0001114	89.11	gold quality
pancreas	UBERON:0001264	89.01	gold quality
oral cavity	UBERON:0000167	88.71	gold quality
gingiva	UBERON:0001828	88.47	gold quality
cortical plate	UBERON:0005343	88.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.07	gold quality
sperm	CL:0000019	87.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.87	gold quality
corpus epididymis	UBERON:0004359	87.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	30.78
E-GEOD-135922	yes	28.72
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

214 targeting INTS6, 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-1277-5P	100.00	73.95	5056
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-5011-5P	100.00	83.46	5820
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4668-3P	100.00	68.74	2635
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-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 73.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• Molecular characterization of the tumor suppressor gene in lung carcinoma cells (PMID:11939413)
• Somatic mutations were identified in three patients (3/56, 5%), and one novel polymorphism was identified in 3% of ESCC patients (4/136) and 3% of healthy individuals (6/232). We conclude that DICE1 mutations occur in ESCC but are infrequent. (PMID:12527901)
• DICE1 has a growth-suppressing activity and interferes with anchorage-independent growth of IGF-IR transformed tumor cells dependent upon IGF-I signaling (PMID:15254679)
• Not mutated in human cancer cell lines which demonstratse 13q14 deletions. (PMID:16271964)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• Findings suggest that EBV encoded miR-BART3* miRNA targets DICE1 tumor suppressor to promote cellular growth and transformation in nasopharyngeal cancer(NPC). (PMID:23280823)
• In response to the DNA damage response, INTS3-hSSB1-INTS6 complex relocates to the DNA damage sites. (PMID:23986477)
• DICE1 appears to be involved in prostate cancer progression rather than in the initiation of prostate cancer. (PMID:25660097)
• Findings demonstrate INTS6P1 and INTS6 exert the tumor suppressive roles through competing for oncomiR-17-5p. (PMID:25686840)
• the results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in hepatocellular carcinoma (HCC) patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients. (PMID:28899352)
• Downregulation of Wnt/beta-catenin signaling was observed during the activation period, and the impairment of beta-catenin degradation reversed the tumor suppressor effects of INTS6. (PMID:29895194)
• The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer. (PMID:34004147)
• INTS6 promotes colorectal cancer progression by activating of AKT and ERK signaling. (PMID:34508742)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ints6	ENSDARG00000013025
mus_musculus	Ints6	ENSMUSG00000035161
rattus_norvegicus	Ints6	ENSRNOG00000009873
drosophila_melanogaster	IntS6	FBGN0261383
caenorhabditis_elegans		WBGENE00000994

Paralogs (11): INTS6L (ENSG00000165359), SAGE1 (ENSG00000181433), CT45A5 (ENSG00000228836), CT45A1 (ENSG00000268940), CT45A3 (ENSG00000269096), CT45A10 (ENSG00000269586), CT45A9 (ENSG00000270946), CT45A2 (ENSG00000271449), CT45A7 (ENSG00000273696), CT45A8 (ENSG00000278085), CT45A6 (ENSG00000278289)

Protein

Protein identifiers

Integrator complex subunit 6 — Q9UL03 (reviewed: Q9UL03)

Alternative names: DBI-1, Protein deleted in cancer 1

All UniProt accessions (9): Q9UL03, B3KU90, C9J885, C9JAV7, C9JVX2, C9JXP6, C9K0V7, F8WAV7, G5E9X1

UniProt curated annotations — full annotation on UniProt →

Function. Component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes. The integrator complex provides a quality checkpoint during transcription elongation by driving premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: the complex terminates transcription by (1) catalyzing dephosphorylation of the C-terminal domain (CTD) of Pol II subunit POLR2A and SUPT5H/SPT5, (2) degrading the exiting nascent RNA transcript via endonuclease activity and (3) promoting the release of Pol II from bound DNA. The integrator complex is also involved in terminating the synthesis of non-coding Pol II transcripts, such as enhancer RNAs (eRNAs), small nuclear RNAs (snRNAs), telomerase RNAs and long non-coding RNAs (lncRNAs). Within the integrator complex, INTS6 acts as a molecular adapter that promotes assembly of protein phosphatase 2A (PP2A) subunits to the integrator core complex, promoting recruitment of PP2A to transcription pause-release checkpoint. Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the integrator complex. May have a tumor suppressor role; an ectopic expression suppressing tumor cell growth.

Subunit / interactions. Component of the Integrator complex, composed of core subunits INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L, INTS12, INTS13, INTS14 and INTS15. The core complex associates with protein phosphatase 2A subunits PPP2CA and PPP2R1A, to form the Integrator-PP2A (INTAC) complex.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Widely expressed. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Domain organisation. The inhibitory loop acts as a regulator of protein phosphatase 2A (PP2A) activity: Asp-629 and Glu-630 residues mimic phosphoserine and phosphothreonine residues and bind to the PP2A catalytic subunit PPP2CA active site to block substrate-binding.

Induction. Frequently down-regulated in nonsmall cell lung carcinomas and prostate cancers. Down-regulation in prostate cancer is due to CpG hypermethylation of its promoter. However, some involvement in cancer is unclear.

Similarity. Belongs to the Integrator subunit 6 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UL03-1	1	yes
Q9UL03-2	2
Q9UL03-3	3

RefSeq proteins (4): NP_001035026, NP_001035027, NP_001293020, NP_036273* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR029307	INT_SG_DDX_CT_C	Domain
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR051113	Integrator_subunit6	Family
IPR057413	Beta-barrel_INTS6	Domain

Pfam: PF13519, PF15300, PF25462

UniProt features (62 total): helix 25, strand 22, turn 7, splice variant 3, chain 1, domain 1, short sequence motif 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
7BV7	X-RAY DIFFRACTION	2.4
8RC4	ELECTRON MICROSCOPY	3.1
7CUN	ELECTRON MICROSCOPY	3.5
7PKS	ELECTRON MICROSCOPY	3.6
8RBZ	ELECTRON MICROSCOPY	3.7
8RBX	ELECTRON MICROSCOPY	4.1
8YJB	ELECTRON MICROSCOPY	4.1
7YCX	ELECTRON MICROSCOPY	4.18
9VD9	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UL03-F1	72.80	0.40

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 (1): 804

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6807505	RNA polymerase II transcribes snRNA genes
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 217 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_RNA_SURVEILLANCE, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, CTTTGTA_MIR524, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, GOBP_SNRNA_PROCESSING, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION

GO Biological Process (7): snRNA processing (GO:0016180), regulation of transcription elongation by RNA polymerase II (GO:0034243), snRNA 3’-end processing (GO:0034472), protein localization to chromatin (GO:0071168), RNA polymerase II transcription initiation surveillance (GO:0160240), transcription by RNA polymerase II (GO:0006366), transcription elongation by RNA polymerase II (GO:0006368)

GO Molecular Function (3): transmembrane signaling receptor activity (GO:0004888), protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), actin cytoskeleton (GO:0015629), integrator complex (GO:0032039), INTAC complex (GO:0160232), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
nuclear protein-containing complex	2
RNA processing	1
snRNA metabolic process	1
transcription elongation by RNA polymerase II	1
regulation of DNA-templated transcription elongation	1
snRNA processing	1
RNA 3’-end processing	1
protein localization to chromosome	1
transcription initiation at RNA polymerase II promoter	1
nuclear RNA surveillance	1
DNA-templated transcription	1
DNA-templated transcription elongation	1
transcription by RNA polymerase II	1
signaling receptor activity	1
protein binding	1
molecular adaptor activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoskeleton	1
integrator complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INTS6	INTS11	Q5TA45	945
INTS6	INTS3	Q68E01	934
INTS6	INTS7	Q9NVH2	820
INTS6	INTS1	Q8N201	773
INTS6	INTS4	Q96HW7	744
INTS6	INTS2	Q9H0H0	724
INTS6	INTS5	Q6P9B9	694
INTS6	INTS12	Q96CB8	694
INTS6	INTS9	Q9NV88	637
INTS6	CSTF1	Q05048	631
INTS6	CSTF3	Q12996	603
INTS6	SYMPK	Q92797	594
INTS6	INTS10	Q9NVR2	581
INTS6	CSTF2	P33240	572
INTS6	INTS13	Q9NVM9	570

IntAct

84 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
INTS6	MCM7	psi-mi:“MI:0915”(physical association)	0.630
MCM7	INTS6	psi-mi:“MI:0915”(physical association)	0.630
C7orf25	RANBP2	psi-mi:“MI:0915”(physical association)	0.540
SUPT5H	POLR2D	psi-mi:“MI:0914”(association)	0.530
TKT	POTEF	psi-mi:“MI:0914”(association)	0.530
EZH1	EPOP	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PPP2CA	SMCO3	psi-mi:“MI:0914”(association)	0.420
INTS6	UPF1	psi-mi:“MI:0915”(physical association)	0.400
UPF2	INTS6	psi-mi:“MI:0915”(physical association)	0.400
INTS6	BKLF1	psi-mi:“MI:0915”(physical association)	0.370
PPP2R1A	INTS2	psi-mi:“MI:0914”(association)	0.350
PPP2CB	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
PPP2CA	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
Ints4	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	MYO9A	psi-mi:“MI:0914”(association)	0.350

BioGRID (181): INTS6 (Affinity Capture-RNA), INTS6 (Affinity Capture-RNA), INTS6 (Affinity Capture-RNA), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Co-fractionation), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS), INTS6 (Affinity Capture-MS)

ESM2 similar proteins: A2AQ25, A6H7A8, B0R1D5, B4F7E8, E9PSK7, F1R7R1, O00472, O14795, P12755, P17863, P49140, Q50H33, Q5DTY9, Q5FVG6, Q5R595, Q5R6Y9, Q5RHQ8, Q5ZJK1, Q60698, Q62739, Q62769, Q68DU8, Q6DC03, Q6PCM2, Q6ZWB6, Q7SYD9, Q80U62, Q812A5, Q8BYR5, Q8CID0, Q8N228, Q8N5Y2, Q8R1F1, Q8TEK3, Q8VDD9, Q8VI24, Q91Y53, Q92622, Q96QF0, Q96TA1

Diamond homologs: A6NJ88, P0DMU7, P0DMU8, P0DMU9, P0DMV0, P0DMV1, P0DMV2, Q2TAF4, Q5DJT8, Q5HYN5, Q5JSJ4, Q5U4W6, Q6PCM2, Q7SYD9, Q8BND4, Q8NHU0, Q9NXZ1, Q9UL03, Q54Z23, Q9W485

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
INTS6	“form complex”	“Integrator complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 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
FGFR2 mutant receptor activation	5	50.1×	2e-06
Signaling by FGFR2 IIIa TM	5	39.5×	4e-06
Abortive elongation of HIV-1 transcript in the absence of Tat	6	39.2×	8e-07
Pausing and recovery of Tat-mediated HIV elongation	7	33.9×	3e-07
Tat-mediated HIV elongation arrest and recovery	7	33.9×	3e-07
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	6	32.2×	1e-06
Signaling by FGFR2	6	32.2×	1e-06
RNA Pol II CTD phosphorylation and interaction with CE	6	32.2×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
mRNA export from nucleus	6	17.9×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	123
Likely benign	10
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3773689	NM_012141.3(INTS6):c.682C>G (p.Gln228Glu)	Likely pathogenic

SpliceAI

3264 predictions. Top by Δscore:

Variant	Effect	Δscore
13:51361269:T:A	acceptor_gain	1.0000
13:51361271:T:TA	acceptor_gain	1.0000
13:51361272:G:A	acceptor_gain	1.0000
13:51361273:GTTA:G	acceptor_loss	1.0000
13:51361274:TTAG:T	acceptor_loss	1.0000
13:51361276:A:AG	acceptor_gain	1.0000
13:51361276:A:G	acceptor_loss	1.0000
13:51361277:G:GG	acceptor_gain	1.0000
13:51361362:CAGGT:C	donor_loss	1.0000
13:51361363:AGGT:A	donor_loss	1.0000
13:51361364:GGTA:G	donor_loss	1.0000
13:51361365:G:C	donor_loss	1.0000
13:51361366:T:A	donor_loss	1.0000
13:51361809:GCTCT:G	acceptor_gain	1.0000
13:51365841:TAAAC:T	acceptor_gain	1.0000
13:51365843:AACCT:A	acceptor_loss	1.0000
13:51365844:AC:A	acceptor_gain	1.0000
13:51365845:CC:C	acceptor_gain	1.0000
13:51365845:CCTGT:C	acceptor_loss	1.0000
13:51365846:C:CC	acceptor_gain	1.0000
13:51365846:CT:C	acceptor_loss	1.0000
13:51365847:T:G	acceptor_loss	1.0000
13:51367895:TATT:T	acceptor_gain	1.0000
13:51367897:TT:T	acceptor_gain	1.0000
13:51367899:C:CC	acceptor_gain	1.0000
13:51367900:T:C	acceptor_gain	1.0000
13:51367900:T:TC	acceptor_gain	1.0000
13:51367906:C:CT	acceptor_gain	1.0000
13:51367907:A:T	acceptor_gain	1.0000
13:51368937:A:AC	donor_gain	1.0000

AlphaMissense

5842 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:51365816:A:G	L867P	1.000
13:51365828:A:G	L863P	1.000
13:51365839:T:A	K859N	1.000
13:51365839:T:G	K859N	1.000
13:51365840:T:A	K859I	1.000
13:51365842:A:C	F858L	1.000
13:51365842:A:T	F858L	1.000
13:51365843:A:G	F858S	1.000
13:51365844:A:G	F858L	1.000
13:51365845:C:A	R857S	1.000
13:51365845:C:G	R857S	1.000
13:51367805:C:A	R857M	1.000
13:51367805:C:G	R857T	1.000
13:51367811:G:T	A855E	1.000
13:51367812:C:G	A855P	1.000
13:51368953:C:G	R821P	1.000
13:51374426:T:A	D629V	1.000
13:51374427:C:G	D629H	1.000
13:51374666:C:A	K620N	1.000
13:51374666:C:G	K620N	1.000
13:51374668:T:C	K620E	1.000
13:51374669:A:C	F619L	1.000
13:51374669:A:T	F619L	1.000
13:51374670:A:C	F619C	1.000
13:51374670:A:G	F619S	1.000
13:51374671:A:G	F619L	1.000
13:51374671:A:T	F619I	1.000
13:51374674:G:A	P618S	1.000
13:51374675:G:C	N617K	1.000
13:51374675:G:T	N617K	1.000

dbSNP variants (sampled 300 via entrez): RS1000015856 (13:51438576 T>A), RS1000079703 (13:51394911 G>A), RS1000094974 (13:51406868 C>G), RS1000183831 (13:51449744 T>A,C), RS1000266185 (13:51420975 T>A,G), RS1000277607 (13:51374459 A>C), RS1000297886 (13:51366716 T>A,C), RS1000340859 (13:51413415 A>G,T), RS1000374483 (13:51445093 T>C), RS1000386371 (13:51381567 C>A), RS1000387424 (13:51399853 C>A), RS1000410061 (13:51427739 A>T), RS1000413423 (13:51407081 A>G), RS1000428063 (13:51335631 G>A,T), RS1000502308 (13:51393589 T>C)

Disease associations

OMIM: gene MIM:604331 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): autism spectrum disorder (MONDO:0005258)

Orphanet (1): NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002337_152	Amyotrophic lateral sclerosis (sporadic)	1.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724659 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.82	IC50	1520	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178581: Inhibition of INTS6 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.5200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	3
Arsenic	affects methylation, decreases expression, increases abundance, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	decreases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697311	Binding	Inhibition of INTS6 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder