DHX8

Summary

DHX8 (DEAH-box helicase 8, HGNC:2749) is a protein-coding gene on chromosome 17q21.31, encoding ATP-dependent RNA helicase DHX8 (Q14562). Involved in pre-mRNA splicing as component of the spliceosome. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

This gene is a member of the DEAH box polypeptide family. The encoded protein contains the DEAH (Asp-Glu-Ala-His) motif which is characteristic of all DEAH box proteins, and is thought to function as an ATP-dependent RNA helicase that regulates the release of spliced mRNAs from spliceosomes prior to their export from the nucleus. This protein may be required for the replication of human immunodeficiency virus type 1 (HIV-1). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1659 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 251 total — 1 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_004941

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2749
Approved symbol	DHX8
Name	DEAH-box helicase 8
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	HRH1, Prp22, PRPF22, Dhr2
Ensembl gene	ENSG00000067596
Ensembl biotype	protein_coding
OMIM	600396
Entrez	1659

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000262415, ENST00000540306, ENST00000587044, ENST00000587574, ENST00000588996, ENST00000589898, ENST00000592258, ENST00000605777, ENST00000650571, ENST00000872044, ENST00000872045, ENST00000958204, ENST00000958205

RefSeq mRNA: 8 — MANE Select: NM_004941 NM_001302623, NM_001322216, NM_001322217, NM_001322218, NM_001322219, NM_001322220, NM_001322221, NM_004941

CCDS: CCDS11464, CCDS77040, CCDS92330

Canonical transcript exons

ENST00000262415 — 23 exons

Exon	Start	End
ENSE00000897775	43489449	43489534
ENSE00001279890	43520130	43520267
ENSE00001279895	43517167	43517322
ENSE00001280005	43483975	43484185
ENSE00001311829	43523628	43525670
ENSE00003460808	43493683	43493886
ENSE00003463253	43498862	43498959
ENSE00003491479	43492183	43492292
ENSE00003503300	43491165	43491250
ENSE00003522870	43499956	43500103
ENSE00003525001	43521369	43521565
ENSE00003545326	43507003	43507197
ENSE00003553570	43513362	43513502
ENSE00003587651	43520751	43520879
ENSE00003587792	43496181	43496268
ENSE00003610513	43490391	43490463
ENSE00003616512	43504644	43504825
ENSE00003617256	43492681	43493040
ENSE00003625838	43508339	43508520
ENSE00003637101	43507503	43507688
ENSE00003639075	43522047	43522226
ENSE00003680781	43493445	43493589
ENSE00003687409	43507809	43508019

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 92.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.9462 / max 299.2983, expressed in 1822 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161084	29.8772	1822
161083	0.0690	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	92.37	gold quality
skin of leg	UBERON:0001511	91.89	gold quality
mucosa of transverse colon	UBERON:0004991	91.66	gold quality
skin of abdomen	UBERON:0001416	91.24	gold quality
ganglionic eminence	UBERON:0004023	91.13	gold quality
ventricular zone	UBERON:0003053	91.12	gold quality
ectocervix	UBERON:0012249	90.66	gold quality
granulocyte	CL:0000094	90.54	gold quality
stromal cell of endometrium	CL:0002255	90.53	gold quality
monocyte	CL:0000576	90.37	gold quality
leukocyte	CL:0000738	90.10	gold quality
adenohypophysis	UBERON:0002196	90.07	gold quality
esophagus mucosa	UBERON:0002469	89.97	gold quality
mononuclear cell	CL:0000842	89.88	gold quality
lower esophagus	UBERON:0013473	89.81	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.81	gold quality
rectum	UBERON:0001052	89.78	gold quality
esophagus	UBERON:0001043	89.70	gold quality
right testis	UBERON:0004534	89.70	gold quality
cortical plate	UBERON:0005343	89.68	gold quality
nerve	UBERON:0001021	89.67	gold quality
tibial nerve	UBERON:0001323	89.67	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.67	gold quality
popliteal artery	UBERON:0002250	89.61	gold quality
left coronary artery	UBERON:0001626	89.60	gold quality
left testis	UBERON:0004533	89.60	gold quality
tibial artery	UBERON:0007610	89.60	gold quality
apex of heart	UBERON:0002098	89.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.51	gold quality
upper lobe of left lung	UBERON:0008952	89.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting DHX8, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-7113-5P	97.88	67.33	1735

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 7)

• Preliminary X-ray diffraction analysis of the crystals of the C-terminal domain of the human DExD/H-box protein hPrp22 at 2.1 A resolution, is reported. (PMID:19724143)
• structural and functional analysis of C-terminal domain of the spliceosomal helicase Prp22 (PMID:23096351)
• cellular complexes comprising cactin, DHX8 and SRRM2 sustain precise chromosome segregation, genome stability and cell proliferation by allowing faithful splicing of specific pre-mRNAs. (PMID:28062851)
• The copy number variation initially recognized as duplication of exon 1-19 of the BRCA1 gene by MLPA analysis is a structural variation with breakpoints in the BRCA1 and DHX8 genes. (PMID:30191368)
• This study provides an in-depth understanding of the activity of DHX8 and contributes insights into the RNA-unwinding mechanisms of the DEAH-box helicase family. (PMID:31409651)
• Spliceosomal helicases DDX41/SACY-1 and PRP22/MOG-5 both contribute to proofreading against proximal 3’ splice site usage. (PMID:38282418)
• Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8. (PMID:38866787)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhx8	ENSDARG00000054707
mus_musculus	Dhx8	ENSMUSG00000034931
rattus_norvegicus	Dhx8	ENSRNOG00000020772
drosophila_melanogaster	pea	FBGN0086895
caenorhabditis_elegans		WBGENE00003393

Paralogs (18): DHX33 (ENSG00000005100), YTHDC2 (ENSG00000047188), DHX29 (ENSG00000067248), DHX32 (ENSG00000089876), DHX35 (ENSG00000101452), DHX40 (ENSG00000108406), DHX15 (ENSG00000109606), HELB (ENSG00000127311), DHX30 (ENSG00000132153), DHX34 (ENSG00000134815), DHX9 (ENSG00000135829), DHX38 (ENSG00000140829), DQX1 (ENSG00000144045), DHX37 (ENSG00000150990), TDRD9 (ENSG00000156414), DHX57 (ENSG00000163214), DHX36 (ENSG00000174953), DHX16 (ENSG00000204560)

Protein

Protein identifiers

ATP-dependent RNA helicase DHX8 — Q14562 (reviewed: Q14562)

Alternative names: DEAH box protein 8, RNA helicase HRH1

All UniProt accessions (5): Q14562, F5H658, K7EJH9, K7END7, K7EQH7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in pre-mRNA splicing as component of the spliceosome. Facilitates nuclear export of spliced mRNA by releasing the RNA from the spliceosome.

Subunit / interactions. Identified in the spliceosome C complex. Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with SRRM2. Interacts with CACTIN.

Subcellular location. Nucleus.

Tissue specificity. Expressed in skin, cervix and nerve. Also expressed in the brain.

Domain organisation. The RS domain confers a nuclear localization signal, and appears to facilitate the interaction with the spliceosome.

Similarity. Belongs to the DEAD box helicase family. DEAH subfamily. DDX8/PRP22 sub-subfamily.

RefSeq proteins (8): NP_001289552, NP_001309145, NP_001309146, NP_001309147, NP_001309148, NP_001309149, NP_001309150, NP_004932* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR002464	DNA/RNA_helicase_DEAH_CS	Conserved_site
IPR003029	S1_domain	Domain
IPR007502	Helicase-assoc_dom	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR011709	DEAD-box_helicase_OB_fold	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR044762	DHX8/Prp22_DEXHc	Domain
IPR048333	HA2_WH	Domain
IPR049588	DHX8_GH2-like	Domain
IPR049621	S1_DHX8_helicase	Domain

Pfam: PF00270, PF00271, PF00575, PF04408, PF07717, PF21010

Enzyme classification (BRENDA):

• EC 3.6.4.13 — RNA helicase (BRENDA: 3 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (105 total): strand 35, helix 35, turn 13, compositionally biased region 6, domain 3, modified residue 2, cross-link 2, sequence variant 2, mutagenesis site 2, region of interest 2, chain 1, binding site 1, short sequence motif 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
3I4U	X-RAY DIFFRACTION	2.1
6HYT	X-RAY DIFFRACTION	2.33
6HYS	X-RAY DIFFRACTION	2.6
8C6J	ELECTRON MICROSCOPY	2.8
6ICZ	ELECTRON MICROSCOPY	3
6HYU	X-RAY DIFFRACTION	3.22
6QDV	ELECTRON MICROSCOPY	3.3
9FMD	ELECTRON MICROSCOPY	3.3
5XJC	ELECTRON MICROSCOPY	3.6
7W59	ELECTRON MICROSCOPY	3.6
7W5A	ELECTRON MICROSCOPY	3.6
7W5B	ELECTRON MICROSCOPY	4.3
5MQF	ELECTRON MICROSCOPY	5.9
2EQS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14562-F1	72.83	0.15

Functional residue map

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

Ligand- & substrate-binding residues (1): 588–595

Post-translational modifications (4): 395, 460, 140, 399

Mutagenesis-validated functional residues (2):

Position	Phenotype
594	in get; inhibition of pre-mrna splicing and nuclear export of unspliced rna.
717	in lat; inhibition of pre-mrna splicing and nuclear export of unspliced rna.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway

MSigDB gene sets: 360 (showing top): GOBP_MEMORY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, FREAC2_01, GOBP_COGNITION, GOBP_BEHAVIOR, DORSAM_HOXA9_TARGETS_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_ASSOCIATIVE_LEARNING, GEORGES_CELL_CYCLE_MIR192_TARGETS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, BROWNE_HCMV_INFECTION_16HR_UP, MODULE_229, GOBP_CELL_CELL_SIGNALING

GO Biological Process (4): mRNA splicing, via spliceosome (GO:0000398), RNA processing (GO:0006396), RNA splicing (GO:0008380), mRNA processing (GO:0006397)

GO Molecular Function (11): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), ATP binding (GO:0005524), ATP-dependent activity, acting on RNA (GO:0008186), ATP hydrolysis activity (GO:0016887), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), cytosol (GO:0005829), nuclear body (GO:0016604), U2-type catalytic step 2 spliceosome (GO:0071007), catalytic step 2 spliceosome (GO:0071013), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
mRNA Splicing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ATP-dependent activity	3
RNA processing	2
binding	2
cellular anatomical structure	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
mRNA metabolic process	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1
U2-type spliceosomal complex	1
U2 snRNP	1
U6 snRNP	1
catalytic step 2 spliceosome	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
protein-containing complex	1

Protein interactions and networks

STRING

3792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHX8	SLU7	O95391	971
DHX8	PRPF18	Q99633	958
DHX8	DOCK9	Q9BZ29	935
DHX8	DOCK1	Q14185	929
DHX8	DOCK4	Q8N1I0	884
DHX8	DOCK11	Q5JSL3	879
DHX8	DOCK10	Q96BY6	864
DHX8	CWC25	Q9NXE8	833
DHX8	CDC42	P21181	827
DHX8	DDX49	Q9Y6V7	823
DHX8	DDX56	Q9NY93	818
DHX8	SNRNP200	O75643	781
DHX8	DDX54	Q8TDD1	777
DHX8	DDX21	Q9NR30	770
DHX8	EFTUD2	Q15029	767

IntAct

128 interactions, top by confidence:

A	B	Type	Score
NKAP	DHX8	psi-mi:“MI:0915”(physical association)	0.720
DHX8	SRPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.690
PNN	CASC3	psi-mi:“MI:0914”(association)	0.640
DHX8	AHCYL1	psi-mi:“MI:0914”(association)	0.640
CHCHD10	CLPX	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
DHX8	ISY1	psi-mi:“MI:0915”(physical association)	0.630
DHX8	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.590
USP12	PHLPP1	psi-mi:“MI:0914”(association)	0.570
DHX8	ZCCHC10	psi-mi:“MI:0915”(physical association)	0.550
H1-6	ZNF724	psi-mi:“MI:0914”(association)	0.530
SNIP1	CASC3	psi-mi:“MI:0914”(association)	0.530
NCBP3	SAP18	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
RNPS1	CASC3	psi-mi:“MI:0914”(association)	0.530
HNRNPC	CASC3	psi-mi:“MI:0914”(association)	0.530
RPL19	ZBTB24	psi-mi:“MI:0914”(association)	0.530
RPL13A	NVL	psi-mi:“MI:0914”(association)	0.530
DHX8	CHERP	psi-mi:“MI:0915”(physical association)	0.510
DHX8	DHX8	psi-mi:“MI:0915”(physical association)	0.510
CHERP	DHX8	psi-mi:“MI:0915”(physical association)	0.510
DHX8		psi-mi:“MI:0915”(physical association)	0.490

BioGRID (412): DHX8 (Affinity Capture-RNA), DHX8 (Affinity Capture-RNA), DHX8 (Affinity Capture-RNA), DHX8 (Affinity Capture-RNA), DHX8 (Affinity Capture-MS), RPL26L1 (Affinity Capture-MS), RPL26 (Affinity Capture-MS), RBM28 (Affinity Capture-MS), FTSJ3 (Affinity Capture-MS), CACTIN (Affinity Capture-MS), SRPK1 (Affinity Capture-MS), SRPK2 (Affinity Capture-MS), RPL10A (Affinity Capture-MS), RPL5 (Affinity Capture-MS), C11orf57 (Affinity Capture-MS)

ESM2 similar proteins: A1Z9L3, A2A4P0, A2QIL2, A3KFM7, A3KMI0, B2RR83, B6ZLK2, D3ZA12, D4A2Z8, E9PZM4, F4IJV4, F4ILR7, F4JY24, F4K2E9, O14646, O14647, O18017, O42643, O45244, O60231, P24384, P34498, P40201, P93008, Q05B79, Q09530, Q10752, Q14562, Q17R09, Q38953, Q4TVV3, Q53RK8, Q54F05, Q5R746, Q5RAZ4, Q5ZI74, Q6P158, Q6P5D3, Q6PGC1, Q767K6

Diamond homologs: A1Z9L3, A2A4P0, B4GEU5, B4JT42, B4K5R2, B4RC48, D4A2Z8, F4HYJ7, F4IE66, F4IJV4, F4ILR7, F4IM84, F4JMJ3, F4JRJ6, F4K2E9, F4KGU4, O17438, O22243, O22899, O35286, O42643, O42945, O43143, O45244, O46072, O51767, O60114, O60231, O70133, O94536, P0C7L7, P0CE10, P15938, P20095, P24384, P34305, P34498, P36009, P37024, P43329

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 137 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
Transport of Mature Transcript to Cytoplasm	7	27.5×	2e-07
mRNA Splicing	20	22.6×	5e-20
RNA Polymerase II Transcription Termination	10	22.6×	9e-10
mRNA 3’-end processing	11	22.3×	1e-10
Processing of Capped Intron-Containing Pre-mRNA	23	19.5×	2e-21
mRNA Splicing - Major Pathway	31	17.5×	5e-28
mRNA Polyadenylation	16	14.5×	1e-12
Transport of Mature mRNA derived from an Intron-Containing Transcript	9	14.1×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	6	38.3×	2e-06
U2-type prespliceosome assembly	5	26.0×	2e-04
mRNA splicing, via spliceosome	25	19.1×	3e-22
ribosomal large subunit biogenesis	5	18.5×	8e-04
regulation of alternative mRNA splicing, via spliceosome	8	16.3×	7e-06
mRNA export from nucleus	5	12.3×	3e-03
RNA splicing	16	11.8×	2e-10
negative regulation of translation	6	9.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	184
Likely benign	10
Benign	15

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1344611	NM_001079675.5(ETV4):c.1244G>A (p.Arg415His)	Likely pathogenic

SpliceAI

5923 predictions. Top by Δscore:

Variant	Effect	Δscore
17:43484179:GACC:G	donor_gain	1.0000
17:43484183:TTGGT:T	donor_loss	1.0000
17:43484186:G:GC	donor_loss	1.0000
17:43484186:G:GG	donor_gain	1.0000
17:43484187:T:A	donor_loss	1.0000
17:43489441:A:AG	acceptor_gain	1.0000
17:43489442:T:G	acceptor_gain	1.0000
17:43489445:GCAGC:G	acceptor_loss	1.0000
17:43489447:A:AG	acceptor_gain	1.0000
17:43489447:AGCT:A	acceptor_gain	1.0000
17:43489448:G:GT	acceptor_gain	1.0000
17:43489448:GC:G	acceptor_gain	1.0000
17:43489448:GCT:G	acceptor_gain	1.0000
17:43489448:GCTG:G	acceptor_gain	1.0000
17:43489448:GCTGA:G	acceptor_gain	1.0000
17:43489531:TACGG:T	donor_loss	1.0000
17:43489532:ACGGT:A	donor_loss	1.0000
17:43489533:CGGTA:C	donor_loss	1.0000
17:43489534:GGTA:G	donor_loss	1.0000
17:43489535:G:GG	donor_gain	1.0000
17:43489535:GTAT:G	donor_loss	1.0000
17:43489536:T:A	donor_loss	1.0000
17:43490387:A:AG	acceptor_gain	1.0000
17:43490387:AAAG:A	acceptor_gain	1.0000
17:43490388:A:G	acceptor_gain	1.0000
17:43490388:AAG:A	acceptor_gain	1.0000
17:43490389:A:G	acceptor_gain	1.0000
17:43490389:AG:A	acceptor_gain	1.0000
17:43490390:G:GG	acceptor_gain	1.0000
17:43490390:GG:G	acceptor_gain	1.0000

AlphaMissense

8033 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:43484138:T:A	V34D	1.000
17:43484150:T:C	L38P	1.000
17:43489449:C:A	A50D	1.000
17:43492985:G:C	G270R	1.000
17:43492986:G:A	G270D	1.000
17:43492992:T:A	V272D	1.000
17:43493009:T:C	F278L	1.000
17:43493010:T:G	F278C	1.000
17:43493011:T:A	F278L	1.000
17:43493011:T:G	F278L	1.000
17:43493012:G:C	G279R	1.000
17:43493012:G:T	G279C	1.000
17:43493013:G:A	G279D	1.000
17:43493013:G:T	G279V	1.000
17:43493015:T:C	C280R	1.000
17:43493017:C:G	C280W	1.000
17:43493018:T:C	F281L	1.000
17:43493020:T:A	F281L	1.000
17:43493020:T:G	F281L	1.000
17:43493022:T:A	V282E	1.000
17:43493458:G:C	G293R	1.000
17:43493459:G:A	G293D	1.000
17:43493462:T:A	L294Q	1.000
17:43493462:T:C	L294P	1.000
17:43493465:T:A	V295E	1.000
17:43493467:C:G	H296D	1.000
17:43493469:C:A	H296Q	1.000
17:43493469:C:G	H296Q	1.000
17:43493473:T:C	S298P	1.000
17:43493474:C:T	S298F	1.000

dbSNP variants (sampled 300 via entrez): RS1000053527 (17:43493996 G>A), RS1000094113 (17:43607968 C>T), RS1000102128 (17:43565327 A>G), RS1000107458 (17:43523129 T>C), RS1000113620 (17:43522615 G>A,T), RS1000120669 (17:43542923 C>A), RS1000138375 (17:43565111 G>A), RS1000169011 (17:43540181 G>T), RS1000198090 (17:43539997 C>A), RS1000203769 (17:43576518 T>C), RS1000225578 (17:43573487 G>A), RS1000262202 (17:43570122 G>A), RS1000270176 (17:43483512 CAA>C), RS1000312983 (17:43496735 G>A), RS1000339385 (17:43587905 C>T)

Disease associations

OMIM: gene MIM:600396 | disease phenotypes: MIM:181500, MIM:610805

GenCC curated gene-disease

Mondo (2): schizophrenia (MONDO:0005090), congenital anomaly of kidney and urinary tract (MONDO:0019719)

Orphanet (2): Renal or urinary tract malformation (Orphanet:93545), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

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

HPO	Term
HP:0100753	Schizophrenia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST003817_2	Mortality in sepsis	7.000000e-07
GCST006021_19	Systolic blood pressure	1.000000e-08
GCST006259_31	Systolic blood pressure	2.000000e-08
GCST006661_65	Male-pattern baldness	2.000000e-09
GCST006979_98	Heel bone mineral density	8.000000e-28
GCST007094_4	Diastolic blood pressure	9.000000e-06
GCST007095_108	Systolic blood pressure	2.000000e-06
GCST007096_238	Pulse pressure	2.000000e-10
GCST007099_174	Systolic blood pressure	3.000000e-13
GCST009368_51	HDL cholesterol levels x long total sleep time interaction (2df test)	1.000000e-13
GCST90020026_154	Hip index	4.000000e-10
GCST90020028_724	Hip circumference adjusted for BMI	5.000000e-11
GCST90020028_770	Hip circumference adjusted for BMI	6.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004352	mortality
EFO:0006335	systolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465306 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
tetrahydropalmatine	increases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bromovanin	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Benztropine	affects cotreatment, decreases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Cannabidiol	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1
Methotrexate	decreases expression	1
Ribonucleotides	affects binding	1
Theophylline	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5338434	Binding	Binding affinity to Dhx8 (unknown origin) at 200 uM preincubated for 2 hrs followed by pronase addition and measured after 30 mins by coomassie blue staining based SDS-PAGE gel analysis	Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans. — J Nat Prod

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety