DHX16

Summary

DHX16 (DEAH-box helicase 16, HGNC:2739) is a protein-coding gene on chromosome 6p21.33, encoding Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 (O60231). Required for pre-mRNA splicing as a component of the spliceosome. It is a common-essential gene (DepMap: required in 98.8% of cancer 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 family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is a functional homolog of fission yeast Prp8 protein involved in cell cycle progression. This gene is mapped to the MHC region on chromosome 6p21.3, a region where many malignant, genetic and autoimmune disease genes are linked. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8449 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuromuscular disease and ocular or auditory anomalies with or without seizures (Strong, GenCC)
• GWAS associations: 20
• Clinical variants (ClinVar): 239 total — 1 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 33
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_003587

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2739
Approved symbol	DHX16
Name	DEAH-box helicase 16
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	DBP2, Prp2, PRPF2
Ensembl gene	ENSG00000204560
Ensembl biotype	protein_coding
OMIM	603405
Entrez	8449

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000376437, ENST00000376442, ENST00000415603, ENST00000480966, ENST00000871055, ENST00000871056, ENST00000934641, ENST00000934642, ENST00000968599, ENST00000968600, ENST00000968601

RefSeq mRNA: 3 — MANE Select: NM_003587 NM_001164239, NM_001363515, NM_003587

CCDS: CCDS4685, CCDS87382

Canonical transcript exons

ENST00000376442 — 20 exons

Exon	Start	End
ENSE00001593288	30656597	30656759
ENSE00001596833	30671036	30671274
ENSE00001686462	30670410	30670466
ENSE00001686754	30662627	30662742
ENSE00001690560	30670790	30670952
ENSE00001701307	30654706	30654879
ENSE00001703368	30659472	30659624
ENSE00001710595	30656198	30656265
ENSE00001712464	30662911	30663021
ENSE00001712635	30656952	30657092
ENSE00001723007	30655435	30655597
ENSE00001731105	30656391	30656509
ENSE00001751546	30655175	30655336
ENSE00001755303	30665071	30665274
ENSE00001763864	30665479	30665733
ENSE00001767492	30660032	30660242
ENSE00001777074	30664801	30664992
ENSE00001920246	30672635	30673006
ENSE00003641258	30659736	30659834
ENSE00003846447	30653127	30653370

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.8002 / max 123.6232, expressed in 1820 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72552	23.5979	1820
72554	0.1194	28
72553	0.0828	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.59	gold quality
granulocyte	CL:0000094	93.97	gold quality
left testis	UBERON:0004533	93.95	gold quality
right testis	UBERON:0004534	93.87	gold quality
right uterine tube	UBERON:0001302	93.73	gold quality
right lobe of thyroid gland	UBERON:0001119	93.46	gold quality
left lobe of thyroid gland	UBERON:0001120	93.36	gold quality
testis	UBERON:0000473	93.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.06	gold quality
thyroid gland	UBERON:0002046	93.05	gold quality
spleen	UBERON:0002106	92.79	gold quality
metanephros cortex	UBERON:0010533	92.67	gold quality
minor salivary gland	UBERON:0001830	92.60	gold quality
duodenum	UBERON:0002114	92.49	gold quality
small intestine	UBERON:0002108	92.43	gold quality
saliva-secreting gland	UBERON:0001044	92.34	gold quality
blood	UBERON:0000178	92.00	gold quality
mucosa of transverse colon	UBERON:0004991	91.95	gold quality
gastrocnemius	UBERON:0001388	91.85	gold quality
transverse colon	UBERON:0001157	91.73	gold quality
vermiform appendix	UBERON:0001154	91.64	gold quality
muscle of leg	UBERON:0001383	91.58	gold quality
body of pancreas	UBERON:0001150	91.44	gold quality
lymph node	UBERON:0000029	91.34	gold quality
body of stomach	UBERON:0001161	91.25	gold quality
pituitary gland	UBERON:0000007	91.19	gold quality
endocervix	UBERON:0000458	91.12	gold quality
right lobe of liver	UBERON:0001114	90.88	gold quality
prostate gland	UBERON:0002367	90.76	gold quality
fundus of stomach	UBERON:0001160	90.72	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.69

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting DHX16, 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-5692A	100.00	74.40	6850
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-4733-5P	97.75	67.44	866
HSA-MIR-4678	97.59	68.31	902
HSA-MIR-331-5P	96.59	67.94	705

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 6)

• DHX16 is required for human pre-mRNA splicing after the formation of a pre-catalytic spliceosome. (PMID:20423332)
• Results suggest that mutant DHX16/hPRP2 causes a defective spliceosome to retain unspliced gene transcripts in the nuclei. (PMID:20841358)
• Data show that G patch domain and KOW motifs protein (GPKOW )interacted directly with the DEAH-box protein 16 (DHX16/hPRP2) and with RNA. (PMID:25296192)
• Missense mutation in DHX16 gene is associated with neurodevelopmental disorder. (PMID:31256877)
• The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity. (PMID:35263596)
• Infantile onset encephalomyopathy, retinopathy, optic atrophy, and mitochondrial DNA depletion associated with a novel pathogenic DHX16 variant. (PMID:37574199)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhx16	ENSDARG00000013150
mus_musculus	Dhx16	ENSMUSG00000024422
rattus_norvegicus	Dhx16	ENSRNOG00000030157
drosophila_melanogaster	l(2)37Cb	FBGN0086444
caenorhabditis_elegans		WBGENE00003392

Paralogs (18): DHX33 (ENSG00000005100), YTHDC2 (ENSG00000047188), DHX29 (ENSG00000067248), DHX8 (ENSG00000067596), 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)

Protein

Protein identifiers

Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 — O60231 (reviewed: O60231)

Alternative names: ATP-dependent RNA helicase #3, DEAH-box protein 16

All UniProt accessions (4): A2AB15, O60231, Q5SQH4, Q5SQH5

UniProt curated annotations — full annotation on UniProt →

Function. Required for pre-mRNA splicing as a component of the spliceosome. Contributes to pre-mRNA splicing after spliceosome formation and prior to the first transesterification reaction. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs. Also plays a role in innate antiviral response by acting as a pattern recognition receptor sensing splicing signals in viral RNA. Mechanistically, TRIM6 promotes the interaction between unanchored ‘Lys-48’-polyubiquitin chains and DHX16, leading to DHX16 interaction with RIGI and ssRNA to amplify RIGI-dependent innate antiviral immune responses.

Subunit / interactions. Component of pre-catalytic spliceosome complexes. Component of the minor spliceosome, which splices U12-type introns. Interacts with GPKOW. Interacts with TRIM6. Interacts with RIGI.

Subcellular location. Nucleus. Nucleoplasm. Cytoplasm.

Tissue specificity. Expressed in the spleen, thyroid and testis. Also expressed in the brain and cerebellum.

Disease relevance. Neuromuscular oculoauditory syndrome (NMOAS) [MIM:618733] An autosomal dominant neuromuscular disorder characterized by variable features including myopathy, neuropathy, hypotonia, joint contractures, growth delay, chorioretinal lacunae, sensorineuronal deafness, agenesis of the corpus callosum, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DEAD box helicase family. DEAH subfamily. DDX16/PRP8 sub-subfamily.

RefSeq proteins (3): NP_001157711, NP_001350444, NP_003578* (*=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
IPR048333	HA2_WH	Domain

Pfam: PF00270, PF00271, 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 (104 total): helix 33, strand 27, turn 11, sequence variant 7, sequence conflict 6, modified residue 5, mutagenesis site 5, compositionally biased region 3, domain 2, region of interest 2, chain 1, short sequence motif 1, binding site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7DVQ	ELECTRON MICROSCOPY	2.89
8I0R	ELECTRON MICROSCOPY	3
8I0T	ELECTRON MICROSCOPY	3
8I0V	ELECTRON MICROSCOPY	3
7QTT	ELECTRON MICROSCOPY	3.1
8I0U	ELECTRON MICROSCOPY	3.3
8I0S	ELECTRON MICROSCOPY	4.2
6FF7	ELECTRON MICROSCOPY	4.5
5Z58	ELECTRON MICROSCOPY	4.9
5Z56	ELECTRON MICROSCOPY	5.1
8CH6	ELECTRON MICROSCOPY	5.9
5Z57	ELECTRON MICROSCOPY	6.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60231-F1	77.82	0.29

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): 422–429

Post-translational modifications (5): 103, 106, 107, 160, 712

Mutagenesis-validated functional residues (5):

Position	Phenotype
428	impairs pre-mrna splicing activity.
520	impairs pre-mrna splicing activity.
523	no loss of pre-mrna splicing activity.
552	dominant-negative mutant. impairs pre-mrna splicing activity. fails to interact with any of viral rna forms.
724	dominant-negative mutant. impairs pre-mrna splicing activity. fails to interact with any of viral rna forms.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 254 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, GOBP_DEFENSE_RESPONSE_TO_VIRUS, ACEVEDO_LIVER_CANCER_UP, LIU_BREAST_CANCER, GOBP_RESPONSE_TO_VIRUS, REACTOME_METABOLISM_OF_RNA, GOCC_U2_TYPE_SPLICEOSOMAL_COMPLEX, YAGI_AML_WITH_11Q23_REARRANGED, GOCC_PRECATALYTIC_SPLICEOSOME, GOCC_CATALYTIC_STEP_2_SPLICEOSOME, GOCC_SPLICEOSOMAL_COMPLEX

GO Biological Process (6): mRNA splicing, via spliceosome (GO:0000398), RNA splicing (GO:0008380), antiviral innate immune response (GO:0140374), immune system process (GO:0002376), mRNA processing (GO:0006397), innate immune response (GO:0045087)

GO Molecular Function (13): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), helicase activity (GO:0004386), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), pattern recognition receptor activity (GO:0038187), ubiquitin binding (GO:0043130), molecular adaptor activity (GO:0060090), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), protein binding (GO:0005515), ATP-dependent activity, acting on RNA (GO:0008186), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), cytoplasm (GO:0005737), U2-type precatalytic spliceosome (GO:0071005), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
mRNA Splicing	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ATP-dependent activity	3
binding	3
RNA processing	2
cellular anatomical structure	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
innate immune response	1
defense response to virus	1
biological_process	1
mRNA metabolic process	1
immune response	1
defense response to symbiont	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
signaling receptor activity	1
ubiquitin-like protein binding	1
molecular_function	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
intracellular anatomical structure	1
U2-type spliceosomal complex	1
U1 snRNP	1
U2 snRNP	1
U4/U6 x U5 tri-snRNP complex	1
precatalytic spliceosome	1
protein-containing complex	1

Protein interactions and networks

STRING

2934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHX16	YJU2	Q9BW85	821
DHX16	CWC25	Q9NXE8	762
DHX16	EFTUD2	Q15029	752
DHX16	DDX23	Q9BUQ8	744
DHX16	SLU7	O95391	718
DHX16	GPKOW	Q92917	709
DHX16	SNRNP200	O75643	708
DHX16	CRNKL1	Q9BZJ0	697
DHX16	DDX46	Q7L014	668
DHX16	BUD13	Q9BRD0	645
DHX16	RNF113A	O15541	641
DHX16	PRPF18	Q99633	641
DHX16	CDC5L	Q99459	618
DHX16	SF3B1	O75533	604
DHX16	CWC22	Q9HCG8	597

IntAct

114 interactions, top by confidence:

A	B	Type	Score
GPKOW	DHX16	psi-mi:“MI:0914”(association)	0.820
DHX16	GPKOW	psi-mi:“MI:0915”(physical association)	0.820
GPKOW	DHX16	psi-mi:“MI:0915”(physical association)	0.820
AP3M1	AP3B1	psi-mi:“MI:0914”(association)	0.640
DHX38	DHX16	psi-mi:“MI:0914”(association)	0.630
DHX38	DHX16	psi-mi:“MI:0915”(physical association)	0.630
SUMO1	CBX4	psi-mi:“MI:0914”(association)	0.600
NCBP3	SAP18	psi-mi:“MI:0914”(association)	0.530
SNRPC	SNRPGP15	psi-mi:“MI:0914”(association)	0.530
AKIRIN2	RGPD8	psi-mi:“MI:0914”(association)	0.530
CPLX2	CPLX1	psi-mi:“MI:0914”(association)	0.530
OIP5	CYTH3	psi-mi:“MI:0914”(association)	0.530
EZH1	EPOP	psi-mi:“MI:0914”(association)	0.530
DHX16	XAB2	psi-mi:“MI:0915”(physical association)	0.510
DHX16	SF3B2	psi-mi:“MI:0915”(physical association)	0.510
XAB2	DHX16	psi-mi:“MI:0915”(physical association)	0.510
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
DHX16	CSNK2A1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
DHX16	PLOD3	psi-mi:“MI:0915”(physical association)	0.400
DHX16	TOP2A	psi-mi:“MI:0915”(physical association)	0.400
DHX16	HSD17B4	psi-mi:“MI:0915”(physical association)	0.400
DHX16	DEK	psi-mi:“MI:0915”(physical association)	0.400
Bud13	DDX39A	psi-mi:“MI:0915”(physical association)	0.400
MEGF10	DHX16	psi-mi:“MI:0915”(physical association)	0.370
ESS2	DHX16	psi-mi:“MI:0915”(physical association)	0.370
Smad3		psi-mi:“MI:0914”(association)	0.350

BioGRID (231): DHX16 (Affinity Capture-MS), DHX16 (Affinity Capture-MS), DHX16 (Affinity Capture-Western), DHX16 (Reconstituted Complex), GPKOW (Affinity Capture-Western), DHX16 (Affinity Capture-MS), DHX16 (Affinity Capture-MS), DHX16 (Affinity Capture-MS), CSNK1E (Co-fractionation), DHX16 (Co-fractionation), DHX16 (Co-fractionation), DHX16 (Co-fractionation), DHX16 (Affinity Capture-MS), DHX16 (Affinity Capture-MS), DHX16 (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

2 interactions.

A	Effect	B	Mechanism
GPKOW	“up-regulates quantity”	DHX16	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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	5	22.9×	9e-05
mRNA 3’-end processing	9	21.4×	3e-08
mRNA Splicing - Minor Pathway	6	16.2×	8e-05
mRNA Splicing	12	15.9×	1e-09
RNA Polymerase II Transcription Termination	6	15.9×	8e-05
Transport of Mature mRNA derived from an Intron-Containing Transcript	8	14.7×	3e-06
Processing of Capped Intron-Containing Pre-mRNA	14	13.9×	2e-10
mRNA Splicing - Major Pathway	19	12.5×	2e-13

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	6	39.0×	3e-06
mRNA splicing, via spliceosome	16	12.4×	2e-10
RNA splicing	10	7.5×	3e-04
mRNA processing	9	6.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	182
Likely benign	11
Benign	10

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
691934	NM_003587.5(DHX16):c.2021C>T (p.Thr674Met)	Pathogenic
1700085	NM_003587.5(DHX16):c.1558G>A (p.Asp520Asn)	Likely pathogenic
2445996	NM_003587.5(DHX16):c.2033A>G (p.Glu678Gly)	Likely pathogenic
4277517	NM_003587.5(DHX16):c.50C>A (p.Ser17Ter)	Likely pathogenic

SpliceAI

3499 predictions. Top by Δscore:

Variant	Effect	Δscore
6:30653369:ACC:A	acceptor_loss	1.0000
6:30655171:TGA:T	donor_loss	1.0000
6:30655172:GACCT:G	donor_loss	1.0000
6:30655173:A:AT	donor_loss	1.0000
6:30655174:C:G	donor_loss	1.0000
6:30655221:T:TA	donor_gain	1.0000
6:30655332:GCCCA:G	acceptor_gain	1.0000
6:30655333:CCCA:C	acceptor_gain	1.0000
6:30655333:CCCAC:C	acceptor_gain	1.0000
6:30655334:CCA:C	acceptor_gain	1.0000
6:30655334:CCAC:C	acceptor_gain	1.0000
6:30655335:CA:C	acceptor_gain	1.0000
6:30655335:CAC:C	acceptor_gain	1.0000
6:30655337:C:CC	acceptor_gain	1.0000
6:30655346:CAGT:C	acceptor_gain	1.0000
6:30655347:A:T	acceptor_gain	1.0000
6:30655348:G:C	acceptor_gain	1.0000
6:30655348:G:GC	acceptor_gain	1.0000
6:30655349:T:C	acceptor_gain	1.0000
6:30655349:T:TC	acceptor_gain	1.0000
6:30655452:G:C	donor_gain	1.0000
6:30655593:TGTAC:T	acceptor_gain	1.0000
6:30655595:TAC:T	acceptor_gain	1.0000
6:30655598:C:CC	acceptor_gain	1.0000
6:30655604:C:CT	acceptor_gain	1.0000
6:30655605:A:T	acceptor_gain	1.0000
6:30656196:A:AC	donor_gain	1.0000
6:30656197:C:CC	donor_gain	1.0000
6:30656197:CTT:C	donor_gain	1.0000
6:30656197:CTTCT:C	donor_gain	1.0000

AlphaMissense

6725 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:30655254:C:G	R915P	1.000
6:30655304:G:C	C898W	1.000
6:30655505:G:T	A864D	1.000
6:30656261:C:T	G812D	1.000
6:30656706:G:C	C734W	1.000
6:30656714:C:A	G732W	1.000
6:30656745:C:A	Q721H	1.000
6:30656745:C:G	Q721H	1.000
6:30657012:C:A	K696N	1.000
6:30657012:C:G	K696N	1.000
6:30657023:C:A	G693W	1.000
6:30657070:G:T	A677D	1.000
6:30657075:G:C	N675K	1.000
6:30657075:G:T	N675K	1.000
6:30657082:G:T	A673E	1.000
6:30657083:C:G	A673P	1.000
6:30657088:A:T	V671D	1.000
6:30659527:A:G	L651P	1.000
6:30659740:C:T	G617E	1.000
6:30659748:G:C	F614L	1.000
6:30659748:G:T	F614L	1.000
6:30659750:A:G	F614L	1.000
6:30659755:A:G	L612P	1.000
6:30662722:A:C	F483L	1.000
6:30662722:A:T	F483L	1.000
6:30662724:A:G	F483L	1.000
6:30654715:G:C	F996L	0.999
6:30654715:G:T	F996L	0.999
6:30654717:A:G	F996L	0.999
6:30654866:C:T	G946D	0.999

dbSNP variants (sampled 300 via entrez): RS1000218515 (6:30673554 C>A), RS1000255443 (6:30655501 G>A), RS1000266637 (6:30666601 A>G), RS1000340780 (6:30666916 T>A), RS1000462425 (6:30659085 C>G,T), RS1000594369 (6:30653965 T>A,C), RS1000646853 (6:30653778 A>C), RS1000719094 (6:30655110 C>A,G,T), RS1000788274 (6:30661075 T>A), RS1000920473 (6:30668458 C>T), RS1001490840 (6:30661374 C>T), RS1001667776 (6:30657461 C>A), RS1001966141 (6:30670000 G>A), RS1001985959 (6:30674398 G>C), RS1002085193 (6:30663452 T>C)

Disease associations

OMIM: gene MIM:603405 | disease phenotypes: MIM:618733, MIM:217990

GenCC curated gene-disease

Disease	Classification	Inheritance
neuromuscular disease and ocular or auditory anomalies with or without seizures	Strong	Autosomal dominant

Mondo (3): neuromuscular disease and ocular or auditory anomalies with or without seizures (MONDO:0032890), intellectual disability (MONDO:0001071), corpus callosum, agenesis of (MONDO:0009022)

Orphanet (2): Isolated corpus callosum agenesis (Orphanet:200), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000286	Epicanthus
HP:0000358	Posteriorly rotated ears
HP:0000407	Sensorineural hearing impairment
HP:0000514	Slow saccadic eye movements
HP:0000762	Decreased nerve conduction velocity
HP:0001239	Wrist flexion contracture
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001762	Talipes equinovarus
HP:0002069	Bilateral tonic-clonic seizure
HP:0002098	Respiratory distress
HP:0002317	Unsteady gait
HP:0002421	Poor head control
HP:0002835	Aspiration
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003390	Sensory axonal neuropathy
HP:0003458	EMG: myopathic abnormalities
HP:0003713	Muscle fiber necrosis
HP:0005562	Multiple renal cysts
HP:0005565	Reduced renal corticomedullary differentiation
HP:0006380	Knee flexion contracture
HP:0007078	Decreased amplitude of sensory action potentials
HP:0007165	Periventricular heterotopia
HP:0007182	Peripheral hypomyelination
HP:0007814	Retinal pigment epithelial mottling
HP:0007858	Chorioretinal lacunae

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_121	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_132	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_2	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_210	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_263	Autism spectrum disorder or schizophrenia	7.000000e-17
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_269	Autism spectrum disorder or schizophrenia	7.000000e-11
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_48	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_56	Autism spectrum disorder or schizophrenia	1.000000e-22
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_79	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST012228_100	Waist-hip index	4.000000e-08
GCST012230_299	Waist-to-hip ratio adjusted for BMI	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, decreases reaction, increases abundance	2
Valproic Acid	increases expression	2
FR900359	affects phosphorylation	1
ginger extract	decreases expression, decreases reaction, increases abundance	1
triphenyl phosphate	affects expression	1
cupric chloride	increases expression	1
beta-methylcholine	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	increases reaction, affects binding	1
Temozolomide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Carmustine	decreases expression	1
Ivermectin	decreases expression	1
Oils, Volatile	decreases expression, decreases reaction, increases abundance	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

207 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
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
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
NCT01678105	PHASE2	COMPLETED	A Phase II Study of Dovitinib in Recurrent and/or Metastatic Adenoid Cystic Carcinoma of the Salivary Glands
NCT06066333	PHASE2	RECRUITING	Study of Radiotherapy and Pembrolizumab in People With Adrenocortical Carcinoma
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)
NCT01898715	PHASE1	COMPLETED	Phase 1 Study of ATR-101 in Subjects With Advanced Adrenocortical Carcinoma
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
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)