DHX30

Summary

DHX30 (DExH-box helicase 30, HGNC:16716) is a protein-coding gene on chromosome 3p21.31, encoding ATP-dependent RNA helicase DHX30 (Q7L2E3). RNA-dependent helicase. It is a selective cancer dependency (DepMap: 14.6% of cell lines).

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The family member encoded by this gene is a mitochondrial nucleoid protein that associates with mitochondrial DNA. It has also been identified as a component of a transcriptional repressor complex that functions in retinal development, and it is required to optimize the function of the zinc-finger antiviral protein. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 22907 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with severe motor impairment and absent language (Definitive, ClinGen)
• Clinical variants (ClinVar): 327 total — 10 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 14.6% of screened cell lines
• MANE Select transcript: NM_138615

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16716
Approved symbol	DHX30
Name	DExH-box helicase 30
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0890, FLJ11214
Ensembl gene	ENSG00000132153
Ensembl biotype	protein_coding
OMIM	616423
Entrez	22907

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 25 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000348968, ENST00000395745, ENST00000415400, ENST00000441384, ENST00000445061, ENST00000457607, ENST00000461905, ENST00000470959, ENST00000471082, ENST00000472718, ENST00000474183, ENST00000476446, ENST00000492893, ENST00000619982, ENST00000876607, ENST00000876608, ENST00000876609, ENST00000876610, ENST00000876611, ENST00000876612, ENST00000876613, ENST00000876614, ENST00000876615, ENST00000876616, ENST00000876617, ENST00000923018, ENST00000923019, ENST00000923020, ENST00000954987, ENST00000954988, ENST00000954989, ENST00000954990, ENST00000954991, ENST00000954992, ENST00000954993

RefSeq mRNA: 3 — MANE Select: NM_138615 NM_001330990, NM_014966, NM_138615

CCDS: CCDS2759, CCDS87074

Canonical transcript exons

ENST00000445061 — 22 exons

Exon	Start	End
ENSE00001394371	47805326	47805420
ENSE00001730891	47803138	47803212
ENSE00001749460	47849867	47850193
ENSE00003461654	47810657	47810711
ENSE00003491347	47847432	47847536
ENSE00003493567	47827347	47827477
ENSE00003494509	47849192	47849349
ENSE00003496265	47845700	47845852
ENSE00003500943	47848180	47848386
ENSE00003507300	47848469	47848550
ENSE00003509004	47829024	47829134
ENSE00003510564	47849630	47849769
ENSE00003519771	47841617	47841737
ENSE00003532123	47848920	47849079
ENSE00003549630	47847273	47847348
ENSE00003558934	47847781	47847956
ENSE00003580980	47848624	47848817
ENSE00003622206	47818022	47818117
ENSE00003629381	47849451	47849554
ENSE00003669522	47840877	47841178
ENSE00003679320	47843106	47843255
ENSE00003693039	47846165	47847001

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 96.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.0438 / max 309.0581, expressed in 1821 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36552	23.6674	1803
36548	19.2893	1798
36551	1.9743	1198
36546	0.5951	355
202750	0.2825	113
36547	0.2064	58
36549	0.0288	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	96.69	gold quality
right testis	UBERON:0004534	96.58	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.55	gold quality
cerebellar hemisphere	UBERON:0002245	95.27	gold quality
cerebellar cortex	UBERON:0002129	95.14	gold quality
testis	UBERON:0000473	95.07	gold quality
adenohypophysis	UBERON:0002196	94.50	gold quality
ganglionic eminence	UBERON:0004023	94.50	gold quality
ventricular zone	UBERON:0003053	94.38	gold quality
pituitary gland	UBERON:0000007	94.36	gold quality
cerebellum	UBERON:0002037	94.32	gold quality
cortical plate	UBERON:0005343	94.04	gold quality
right frontal lobe	UBERON:0002810	94.03	gold quality
right lobe of thyroid gland	UBERON:0001119	93.47	gold quality
right uterine tube	UBERON:0001302	93.44	gold quality
body of uterus	UBERON:0009853	93.43	gold quality
left ovary	UBERON:0002119	93.27	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.22	gold quality
left uterine tube	UBERON:0001303	93.17	gold quality
right ovary	UBERON:0002118	93.17	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.16	gold quality
metanephros cortex	UBERON:0010533	93.14	gold quality
lower esophagus	UBERON:0013473	93.14	gold quality
prefrontal cortex	UBERON:0000451	93.11	gold quality
sperm	CL:0000019	93.02	gold quality
apex of heart	UBERON:0002098	92.99	gold quality
left lobe of thyroid gland	UBERON:0001120	92.97	gold quality
granulocyte	CL:0000094	92.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.90	gold quality
endocervix	UBERON:0000458	92.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.62
E-MTAB-4850	no	568.36

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FASTKD2	Repression

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• Here, we provide evidence that overexpression of an RNA helicase named DHX30 enhances HIV-1 gene expression, but leads to the generation of viruses that package significantly low levels of viral RNA and exhibit severely decreased infectivity. (PMID:18022663)
• Identifies DHX30 as a nucleoid protein. (PMID:18063578)
• Provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder. (PMID:29100085)
• A double-stranded RNA is required for the interaction between a host restriction factor DHX30 and the NS1 protein of influenza A virus. (PMID:31754723)
• Nutlin-Induced Apoptosis Is Specified by a Translation Program Regulated by PCBP2 and DHX30. (PMID:32234473)
• Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders. (PMID:34020708)
• De novo pathogenic DHX30 variants in two cases. (PMID:34180050)
• Conformational change of RNA-helicase DHX30 by ALS/FTD-linked FUS induces mitochondrial dysfunction and cytosolic aggregates. (PMID:36163369)
• DHX30-Associated Neurodevelopmental Disorder with Severe Motor Impairment and Absent Language: First Korean Case in Two Siblings and Literature Review. (PMID:37094863)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhx30	ENSDARG00000077839
mus_musculus	Dhx30	ENSMUSG00000032480
rattus_norvegicus	Dhx30	ENSRNOG00000029194

Paralogs (18): DHX33 (ENSG00000005100), YTHDC2 (ENSG00000047188), DHX29 (ENSG00000067248), DHX8 (ENSG00000067596), DHX32 (ENSG00000089876), DHX35 (ENSG00000101452), DHX40 (ENSG00000108406), DHX15 (ENSG00000109606), HELB (ENSG00000127311), 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 DHX30 — Q7L2E3 (reviewed: Q7L2E3)

Alternative names: DEAH box protein 30

All UniProt accessions (3): Q7L2E3, F6R0H4, H7BXY3

UniProt curated annotations — full annotation on UniProt →

Function. RNA-dependent helicase. Plays an important role in the assembly of the mitochondrial large ribosomal subunit. Required for optimal function of the zinc-finger antiviral protein ZC3HAV1. Associates with mitochondrial DNA. Involved in nervous system development and differentiation through its involvement in the up-regulation of a number of genes which are required for neurogenesis, including GSC, NCAM1, neurogenin, and NEUROD.

Subunit / interactions. Identified in a complex with TFAM and SSBP1. Interacts with AGO1 and AGO2. Interacts (via N-terminus) with ZC3HAV1 (via N-terminal domain) in an RNA-independent manner. Found in a complex with GRSF1, DDX28, FASTKD2 and FASTKD5.

Subcellular location. Cytoplasm. Mitochondrion. Mitochondrion matrix. Mitochondrion nucleoid.

Post-translational modifications. Phosphorylated on Ser-15.

Disease relevance. Neurodevelopmental disorder with variable motor and language impairment (NEDMIAL) [MIM:617804] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, intellectual disability, speech impairment and gait abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DEAD box helicase family. DEAH subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7L2E3-1	1	yes
Q7L2E3-2	2
Q7L2E3-3	3

RefSeq proteins (3): NP_001317919, NP_055781, NP_619520* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR002464	DNA/RNA_helicase_DEAH_CS	Conserved_site
IPR007502	Helicase-assoc_dom	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR011709	DEAD-box_helicase_OB_fold	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR056755	DSRM_2	Domain

Pfam: PF00270, PF00271, PF07717, PF21010, PF24995

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (34 total): sequence variant 6, modified residue 4, helix 4, strand 4, domain 3, splice variant 3, sequence conflict 2, region of interest 2, compositionally biased region 2, chain 1, turn 1, short sequence motif 1, binding site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2DB2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L2E3-F1	81.09	0.49

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): 457–464

Post-translational modifications (4): 6, 226, 380, 15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 307 (showing top): RRAGTTGT_UNKNOWN, GOBP_RIBOSOME_BIOGENESIS, AAGTCCA_MIR422B_MIR422A, CMYB_01, GOBP_RIBOSOME_ASSEMBLY, GGAMTNNNNNTCCY_UNKNOWN, EFC_Q6, GOBP_RIBOSOMAL_LARGE_SUBUNIT_ASSEMBLY, MODULE_285, KLEIN_PRIMARY_EFFUSION_LYMPHOMA_UP, ZIC1_01, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_ORGANELLE_ASSEMBLY, GGCKCATGS_UNKNOWN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN

GO Biological Process (3): central nervous system development (GO:0007417), mitochondrial large ribosomal subunit assembly (GO:1902775), ribosome biogenesis (GO:0042254)

GO Molecular Function (13): G-quadruplex RNA binding (GO:0002151), DNA helicase activity (GO:0003678), chromatin binding (GO:0003682), RNA binding (GO:0003723), RNA helicase activity (GO:0003724), double-stranded RNA binding (GO:0003725), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), ribonucleoprotein granule (GO:0035770), mitochondrial nucleoid (GO:0042645)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
RNA binding	2
helicase activity	2
ATP-dependent activity	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
mitochondrion	2
intracellular membraneless organelle	2
nervous system development	1
system development	1
ribosomal large subunit assembly	1
mitochondrial ribosome assembly	1
ribonucleoprotein complex biogenesis	1
ATP-dependent activity, acting on DNA	1
nucleic acid binding	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
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 anatomical structure	1
intracellular organelle lumen	1
supramolecular complex	1
mitochondrial matrix	1
nucleoid	1

Protein interactions and networks

STRING

3380 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHX30	DDX28	Q9NUL7	792
DHX30	POLRMT	O00411	775
DHX30	PTCD3	Q96EY7	703
DHX30	GRSF1	Q12849	692
DHX30	FASTKD2	Q9NYY8	682
DHX30	FASTKD3	Q14CZ7	670
DHX30	DDX6	P26196	619
DHX30	SSBP1	Q04837	611
DHX30	NR2E3	Q9Y5X4	603
DHX30	TRMT10C	Q7L0Y3	599
DHX30	MRRF	Q96E11	591
DHX30	SUPV3L1	Q8IYB8	578
DHX30	ZC3HAV1	Q7Z2W4	561
DHX30	DDX59	Q5T1V6	534
DHX30	DDX54	Q8TDD1	508

IntAct

339 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
FBL	NOP56	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PTK2	TGFB1I1	psi-mi:“MI:0914”(association)	0.680
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
DHX30	H1-5	psi-mi:“MI:0915”(physical association)	0.560
TEFM	POLRMT	psi-mi:“MI:0914”(association)	0.560
RPS6	IPO7	psi-mi:“MI:0914”(association)	0.530
DHX30	CFTR	psi-mi:“MI:0915”(physical association)	0.520
FUS	DDX3X	psi-mi:“MI:0914”(association)	0.430
Sgo2a	RPL36A	psi-mi:“MI:0915”(physical association)	0.400
Ybx1	MRPS18B	psi-mi:“MI:0915”(physical association)	0.400
Snu13		psi-mi:“MI:0915”(physical association)	0.400
S100A9	DHX30	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
Srp72		psi-mi:“MI:0914”(association)	0.350
NOP56	C12orf43	psi-mi:“MI:0914”(association)	0.350
IBTK	POP7	psi-mi:“MI:0914”(association)	0.350
HNRNPU		psi-mi:“MI:0914”(association)	0.350
Eif3i	CBX4	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
DUX4		psi-mi:“MI:0914”(association)	0.350

BioGRID (645): DHX30 (Affinity Capture-RNA), DHX30 (Affinity Capture-RNA), DHX30 (Affinity Capture-RNA), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DHX30 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2K1Q8, B2RX12, E9PU17, E9PX95, F1MWM0, O00329, O15438, O35600, O75899, O88563, O88871, O94911, O95477, P41233, P55205, P58428, P78363, Q09427, Q09428, Q09429, Q2NKY8, Q5BJS0, Q5R607, Q5ZI74, Q6TL19, Q7L2E3, Q7TNJ2, Q80T41, Q84M24, Q8CF82, Q8IUA7, Q8K440, Q8K441, Q8K442, Q8K448, Q8K449, Q8LPK0, Q8N139, Q8NCL4, Q8R420

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

2 interactions.

A	Effect	B	Mechanism
DHX30	“down-regulates quantity by repression”	FASTKD2	“transcriptional regulation”
DHX30	up-regulates	Stress_granules

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 237 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
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	15	10.5×	3e-09
SRP-dependent cotranslational protein targeting to membrane	17	10.1×	5e-10
Eukaryotic Translation Termination	14	10.0×	1e-08
Peptide chain elongation	13	9.8×	5e-08
Viral mRNA Translation	13	9.8×	5e-08
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	13	9.7×	5e-08
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	16	9.3×	3e-09
Selenocysteine synthesis	13	9.3×	8e-08

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mRNA processing	5	20.5×	8e-04
cytoplasmic translation	16	13.7×	2e-11
negative regulation of viral genome replication	6	10.4×	4e-03
translation	20	9.5×	2e-11
ribosomal small subunit biogenesis	8	8.4×	1e-03
negative regulation of translation	9	8.2×	4e-04
rRNA processing	11	7.2×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	7
Uncertain significance	199
Likely benign	75
Benign	3

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1330305	NM_138615.3(DHX30):c.2345G>A (p.Arg782Gln)	Pathogenic
2443976	NM_138615.3(DHX30):c.2389C>T (p.Arg797Ter)	Pathogenic
2571616	NM_138615.3(DHX30):c.1930-1G>T	Pathogenic
3340667	NM_138615.3(DHX30):c.1613G>A (p.Gly538Asp)	Pathogenic
375373	NM_138615.3(DHX30):c.2344C>T (p.Arg782Trp)	Pathogenic
375374	NM_138615.3(DHX30):c.1478G>A (p.Arg493His)	Pathogenic
402130	NM_138615.3(DHX30):c.1685A>G (p.His562Arg)	Pathogenic
4240216	NM_138615.3(DHX30):c.1861del (p.His621fs)	Pathogenic
453269	NM_138615.3(DHX30):c.2342G>A (p.Gly781Asp)	Pathogenic
801964	NM_138615.3(DHX30):c.1390A>G (p.Thr464Ala)	Pathogenic
1712157	NM_138615.3(DHX30):c.3214C>T (p.Arg1072Ter)	Likely pathogenic
2430361	NM_138615.3(DHX30):c.2929+2T>C	Likely pathogenic
2444127	NM_138615.3(DHX30):c.2345G>C (p.Arg782Pro)	Likely pathogenic
2575537	NM_138615.3(DHX30):c.25A>T (p.Lys9Ter)	Likely pathogenic
2576175	NM_138615.3(DHX30):c.2359C>T (p.Gln787Ter)	Likely pathogenic
3376258	NM_138615.3(DHX30):c.3545C>G (p.Pro1182Arg)	Likely pathogenic
3767593	NM_138615.3(DHX30):c.3028GAG[3] (p.Glu1013del)	Likely pathogenic

SpliceAI

3659 predictions. Top by Δscore:

Variant	Effect	Δscore
3:47805417:TAAGG:T	donor_loss	1.0000
3:47805419:AGG:A	donor_loss	1.0000
3:47805420:GGTA:G	donor_loss	1.0000
3:47805421:G:C	donor_loss	1.0000
3:47805422:T:A	donor_loss	1.0000
3:47827345:A:AG	acceptor_gain	1.0000
3:47827346:G:GG	acceptor_gain	1.0000
3:47827346:GC:G	acceptor_gain	1.0000
3:47827346:GCTTC:G	acceptor_gain	1.0000
3:47827474:AAAGG:A	donor_loss	1.0000
3:47827475:AAGGT:A	donor_loss	1.0000
3:47827476:AGGTA:A	donor_loss	1.0000
3:47827477:GG:G	donor_loss	1.0000
3:47827478:GTAA:G	donor_loss	1.0000
3:47829020:CCA:C	acceptor_loss	1.0000
3:47829021:CA:C	acceptor_loss	1.0000
3:47829022:A:AG	acceptor_gain	1.0000
3:47829023:G:GG	acceptor_gain	1.0000
3:47829023:GA:G	acceptor_gain	1.0000
3:47829023:GAA:G	acceptor_gain	1.0000
3:47829023:GAAA:G	acceptor_gain	1.0000
3:47843101:TGTAG:T	acceptor_loss	1.0000
3:47843103:TAG:T	acceptor_loss	1.0000
3:47843104:A:AG	acceptor_gain	1.0000
3:47843105:G:A	acceptor_loss	1.0000
3:47843105:G:GG	acceptor_gain	1.0000
3:47843105:GA:G	acceptor_gain	1.0000
3:47843105:GAAC:G	acceptor_gain	1.0000
3:47843252:GAAG:G	donor_gain	1.0000
3:47843253:AAGGT:A	donor_loss	1.0000

AlphaMissense

7724 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:47827370:T:C	F50L	1.000
3:47827372:C:A	F50L	1.000
3:47827372:C:G	F50L	1.000
3:47827392:T:A	L57H	1.000
3:47827392:T:C	L57P	1.000
3:47829034:T:C	L89P	1.000
3:47829045:T:A	W93R	1.000
3:47829045:T:C	W93R	1.000
3:47829047:G:C	W93C	1.000
3:47829047:G:T	W93C	1.000
3:47829048:C:T	P94S	1.000
3:47829118:C:A	A117D	1.000
3:47829120:T:C	C118R	1.000
3:47843155:T:C	L280P	1.000
3:47843166:T:A	W284R	1.000
3:47843166:T:C	W284R	1.000
3:47843251:T:C	L312P	1.000
3:47846457:G:A	G462E	1.000
3:47846559:C:A	A496D	1.000
3:47846747:G:C	D559H	1.000
3:47846748:A:C	D559A	1.000
3:47846748:A:T	D559V	1.000
3:47846751:A:T	E560V	1.000
3:47847446:T:C	F674L	1.000
3:47847448:C:A	F674L	1.000
3:47847448:C:G	F674L	1.000
3:47847456:G:A	G677E	1.000
3:47847853:T:A	V728D	1.000
3:47847858:G:C	A730P	1.000
3:47847862:C:T	T731I	1.000

dbSNP variants (sampled 300 via entrez): RS1000011158 (3:47836553 CTG>C), RS1000061658 (3:47816390 G>T), RS1000075713 (3:47827877 CA>C), RS1000206952 (3:47808386 C>G), RS1000240245 (3:47809219 T>G), RS1000312939 (3:47834718 C>T), RS1000322488 (3:47847671 A>G), RS1000387872 (3:47801389 A>G), RS1000388541 (3:47848865 G>T), RS1000475325 (3:47840430 G>T), RS1000543577 (3:47842396 G>A,C), RS1000598827 (3:47835745 T>C), RS1000667331 (3:47834279 T>C,G), RS1000792413 (3:47802732 G>A,T), RS1000826688 (3:47842047 C>A)

Disease associations

OMIM: gene MIM:616423 | disease phenotypes: MIM:617804, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with severe motor impairment and absent language	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with severe motor impairment and absent language	Definitive	AD

Mondo (8): neurodevelopmental disorder with severe motor impairment and absent language (MONDO:0060622), autism, susceptiblity to (MONDO:0020836), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), strabismus (MONDO:0003432), autism (MONDO:0005260), hearing loss disorder (MONDO:0005365), hereditary ataxia (MONDO:0100309)

Orphanet (3): Neurodevelopmental delay-intellectual disability-ataxia-feeding difficulty syndrome (Orphanet:647788), Hereditary ataxia (Orphanet:183518), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000274	Small face
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000319	Smooth philtrum
HP:0000348	High forehead
HP:0000349	Widow’s peak
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000664	Synophrys
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0000957	Cafe-au-lait spot
HP:0000963	Thin skin
HP:0001169	Broad palm
HP:0001182	Tapered finger
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D013285	Strabismus	C10.292.562.887; C11.590.810
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105814 (SINGLE PROTEIN)

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
8.22	Kd	6	nM	CHEMBL3688339

PubChem BioAssay actives

1 with measured affinity, of 169 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
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1424979: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0060	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression	4
Valproic Acid	decreases expression, increases methylation, affects cotreatment	4
bisphenol A	affects binding, affects folding, increases reaction, decreases reaction, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, decreases expression, increases abundance	2
bisphenol AF	affects folding, affects reaction, decreases reaction, affects binding	2
Acetaminophen	decreases expression	2
Acrolein	affects cotreatment, increases oxidation, decreases expression, increases abundance	2
Ozone	affects cotreatment, increases oxidation, decreases expression, increases abundance	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
beta-methylcholine	affects expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects binding, decreases reaction	1
Sunitinib	decreases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Clozapine	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Endosulfan	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	decreases reaction, affects binding	1
Ivermectin	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
CHEMBL3991692	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B5J6	HAP1 DHX30 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00461656	PHASE4	COMPLETED	Povidone-iodine Antisepsis for Strabismus Surgery
NCT01901588	PHASE4	COMPLETED	Efficacy of Single-Shot Dexmedetomidine Versus Placebo in Preventing Pediatric Emergence Delirium in Strabismus Surgery
NCT02379546	PHASE4	COMPLETED	The Effect of Anaesthesia Depth on Oculo-cardiac Reflex
NCT03349515	PHASE4	COMPLETED	The Effect of Povidone-iodine Ophthalmic Surgical Prep Solution on Respiration in Children Undergoing Strabismus Surgery With General Anesthesia.
NCT04549844	PHASE4	UNKNOWN	Peribulbar Block for Prevention of Oculocardiac Reflex
NCT06035757	PHASE4	RECRUITING	The Occurrence of Emergence Agitation in Pediatric Strabismus Surgery
NCT06560268	PHASE4	NOT_YET_RECRUITING	Low Flow Anesthesia in Children Undergoing Strabismus Surgery
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00000128	PHASE3	UNKNOWN	A Trial of Bifocals in Myopic Children With Esophoria
NCT00001864	PHASE3	COMPLETED	Amblyopia (Lazy Eye) Treatment Study
NCT00038753	PHASE3	UNKNOWN	Vision In Preschoolers Study (VIP Study)
NCT01584843	PHASE3	COMPLETED	Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Strabismus
NCT04060771	PHASE3	UNKNOWN	Post-Operative Nausea and Vomiting in Children Submitted to Strabismus Surgery
NCT06863675	PHASE3	NOT_YET_RECRUITING	Highly Aspherical Lenslet (HAL) and Binocular Vision (BV) Disorders [HALT X(T) Study]
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00478907	PHASE2	COMPLETED	Prevention of Complications of Eye Surgery
NCT06689943	PHASE2	NOT_YET_RECRUITING	Pain After Strabismus Surgery
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00917982	PHASE1	UNKNOWN	The Effect of Vision Therapy/Orthoptic on Motor & Sensory Status of the 3 to 7 Years Old Strabismic Patients
NCT02246556	PHASE1	TERMINATED	Dichoptic Virtual Reality Therapy for Amblyopia in Adults
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities