CADPS2

Summary

CADPS2 (calcium dependent secretion activator 2, HGNC:16018) is a protein-coding gene on chromosome 7q31.32, encoding Calcium-dependent secretion activator 2 (Q86UW7). Calcium-binding protein involved in exocytosis of vesicles filled with neurotransmitters and neuropeptides.

This gene encodes a member of the calcium-dependent activator of secretion (CAPS) protein family, which are calcium binding proteins that regulate the exocytosis of synaptic and dense-core vesicles in neurons and neuroendocrine cells. Mutations in this gene may contribute to autism susceptibility. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 93664 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Limited, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 489 total — 1 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_017954

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16018
Approved symbol	CADPS2
Name	calcium dependent secretion activator 2
Location	7q31.32
Locus type	gene with protein product
Status	Approved
Aliases	CAPS2
Ensembl gene	ENSG00000081803
Ensembl biotype	protein_coding
OMIM	609978
Entrez	93664

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 25 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000313070, ENST00000397721, ENST00000412584, ENST00000449022, ENST00000462699, ENST00000476131, ENST00000870411, ENST00000870412, ENST00000870413, ENST00000925367, ENST00000951078, ENST00000951079, ENST00000951080, ENST00000951081, ENST00000951082, ENST00000951083, ENST00000951084, ENST00000951085, ENST00000951086, ENST00000951087, ENST00000951088, ENST00000951089, ENST00000951090, ENST00000951091, ENST00000951092, ENST00000951093

RefSeq mRNA: 15 — MANE Select: NM_017954 NM_001009571, NM_001167940, NM_001363389, NM_001363390, NM_001363391, NM_001363392, NM_001363393, NM_001363394, NM_001363395, NM_001363396, NM_001363397, NM_001363398, NM_001363399, NM_001363400, NM_017954

CCDS: CCDS47691, CCDS55158

Canonical transcript exons

ENST00000449022 — 30 exons

Exon	Start	End
ENSE00001592686	122325477	122325581
ENSE00001602910	122393196	122393315
ENSE00001627797	122360930	122361013
ENSE00001640336	122388583	122388738
ENSE00001678504	122387026	122387173
ENSE00001692722	122393441	122393582
ENSE00001707832	122885999	122886460
ENSE00001719945	122318411	122320338
ENSE00001740949	122345574	122345681
ENSE00001751259	122360788	122360820
ENSE00001757718	122407540	122407696
ENSE00002341754	122379368	122379442
ENSE00002438619	122474381	122474517
ENSE00002447835	122471375	122471562
ENSE00002465727	122451374	122451475
ENSE00002476512	122663237	122663569
ENSE00002483005	122736955	122737068
ENSE00002491426	122491312	122491420
ENSE00002495046	122414068	122414076
ENSE00002499849	122629248	122629328
ENSE00002499922	122490081	122490281
ENSE00002508073	122480852	122480860
ENSE00002521218	122621481	122621717
ENSE00002521532	122416061	122416164
ENSE00002526930	122438341	122438464
ENSE00002531456	122615181	122615299
ENSE00002531790	122441512	122441575
ENSE00003601921	122581179	122581290
ENSE00003676812	122513249	122513315
ENSE00003683465	122554550	122554689

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1556 / max 704.1578, expressed in 1222 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85957	3.2846	1042
85958	2.5483	566
85959	0.6323	188
85960	0.3461	115
85956	0.2459	122
204675	0.0984	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	98.95	gold quality
cerebellar cortex	UBERON:0002129	98.28	gold quality
cerebellar hemisphere	UBERON:0002245	98.25	gold quality
cerebellum	UBERON:0002037	98.16	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.62	gold quality
parotid gland	UBERON:0001831	95.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.21	gold quality
primary visual cortex	UBERON:0002436	95.09	gold quality
endothelial cell	CL:0000115	95.08	gold quality
middle temporal gyrus	UBERON:0002771	93.94	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.66	gold quality
lower esophagus	UBERON:0013473	93.53	gold quality
adrenal tissue	UBERON:0018303	93.37	gold quality
mucosa of stomach	UBERON:0001199	92.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.17	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.50	gold quality
occipital lobe	UBERON:0002021	91.31	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.84	gold quality
body of pancreas	UBERON:0001150	90.66	gold quality
calcaneal tendon	UBERON:0003701	90.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.28	gold quality
germinal epithelium of ovary	UBERON:0001304	90.21	gold quality
prefrontal cortex	UBERON:0000451	90.04	gold quality
superior frontal gyrus	UBERON:0002661	89.77	gold quality
right frontal lobe	UBERON:0002810	89.54	gold quality
pancreatic ductal cell	CL:0002079	89.53	gold quality
frontal cortex	UBERON:0001870	89.41	gold quality
right lung	UBERON:0002167	89.34	gold quality
right adrenal gland cortex	UBERON:0035827	89.28	gold quality
postcentral gyrus	UBERON:0002581	89.21	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	4216.63
E-CURD-119	yes	4176.17
E-HCAD-25	yes	898.64
E-HCAD-35	yes	63.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): LRRK2, SNCA

miRNA regulators (miRDB)

94 targeting CADPS2, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6766-5P	99.68	67.70	2325

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 11)

• identification, cloning, and comparative characterization of a second mammalian CAPS isoform, CAPS2; concluded that at the functional level, CAPS2 is largely redundant with CAPS1 (PMID:14530279)
• CADPS2-KO mice show autistic-like phenotypes. Moreover, the results show that some autistic patients have an aberrant splicing variant of CADPS2 mRNA, suggesting that a disturbance in CADPS2-mediated neurotrophin release contributes to autism. (PMID:17380209)
• Genetic disturbance in CADPS2-mediated neurotrophin release contributes to autism susceptibility. (PMID:17380209)
• Results from Cadps2-deficient mice and human data suggest that a disturbance in CADPS2-mediated neurotrophin release contributes to autistic-like cellular and behavioral phenotypes. (PMID:17380209)
• CAPS proteins are involved in optimizing vesicular monoamine uptake and storage mediated by VMAT1 and VMAT2 (PMID:19008227)
• We speculate that haploinsufficiency of CADPS2 contributes to ASDs. (PMID:21626674)
• This study suggested that CADPS2DeltaExon3 affects intelligence and memory in the non-clinical population. (PMID:22001167)
• Mutation screening of 187 patients with autism spectrum disorders and 36 with intellectual disability identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. (PMID:24737869)
• These results indicate that LRRK2 and alpha-synuclein participate in the dysregulation of CADPS2 by altering transcription and support the hypothesis that synaptic dysfunctions, through different mechanisms, might contribute to the neuronal defects of diseases such as Parkinson’s disease. (PMID:28647363)
• The top SNP rs2049161 involved gene DLGAP1 and the top gene CADPS2 in the gene-based analysis resulted in much literature evidence of associations with psychiatric disorders. Gene expression and network analysis showed their contribution to cognition function. (PMID:28971736)
• Down-regulation of habenular calcium-dependent secretion activator 2 induces despair-like behavior. (PMID:33580180)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cadps2	ENSDARG00000013312
mus_musculus	Cadps2	ENSMUSG00000017978
rattus_norvegicus	Cadps2	ENSRNOG00000007636
drosophila_melanogaster	Cadps	FBGN0053653
caenorhabditis_elegans		WBGENE00006767

Protein

Protein identifiers

Calcium-dependent secretion activator 2 — Q86UW7 (reviewed: Q86UW7)

Alternative names: Calcium-dependent activator protein for secretion 2

All UniProt accessions (5): Q86UW7, F8W8P5, H0Y8B5, H7BYR4, X5DNG0

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-binding protein involved in exocytosis of vesicles filled with neurotransmitters and neuropeptides. Probably acts upstream of fusion in the biogenesis or maintenance of mature secretory vesicles. Regulates neurotrophin release from granule cells leading to regulate cell differentiation and survival during cerebellar development. May specifically mediate the Ca(2+)-dependent exocytosis of large dense-core vesicles (DCVs) and other dense-core vesicles.

Subunit / interactions. Homodimer. Interacts with the dopamine receptor DRD2.

Subcellular location. Cytoplasmic vesicle membrane. Synapse. Cell projection. Cilium. Cytoplasm. Cytoskeleton. Cilium basal body. Microtubule organizing center. Centrosome.

Tissue specificity. Widely expressed. Expressed in all adult and fetal tissues examined, with the strongest expression in kidney and pancreas. In brain, it is expressed at high levels in cerebellum, to a lesser degree in cerebral cortex, occipital pole, and frontal and temporal lobes. Only weakly expressed in medulla, spinal cord and putamen.

Domain organisation. The PH domain is essential for regulated exocytosis and binds phospholipids.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86UW7-1	1	yes
Q86UW7-2	2
Q86UW7-3	3

RefSeq proteins (15): NP_001009571, NP_001161412, NP_001350318, NP_001350319, NP_001350320, NP_001350321, NP_001350322, NP_001350323, NP_001350324, NP_001350325, NP_001350326, NP_001350327, NP_001350328, NP_001350329, NP_060424* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001849	PH_domain	Domain
IPR010439	MUN_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014770	Munc13_1	Domain
IPR033227	CAPS	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR057457	CAPS_C2	Domain

Pfam: PF00169, PF06292, PF25341

UniProt features (25 total): sequence conflict 7, domain 4, splice variant 4, modified residue 3, region of interest 3, compositionally biased region 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UW7-F1	79.91	0.44

Functional residue map

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

Post-translational modifications (3): 56, 58, 1290

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 296 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_VESICLE_LOCALIZATION, MODULE_45, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_FOREBRAIN_GENERATION_OF_NEURONS

GO Biological Process (8): exocytosis (GO:0006887), cellular response to starvation (GO:0009267), protein transport (GO:0015031), synaptic vesicle priming (GO:0016082), positive regulation of exocytosis (GO:0045921), hematopoietic stem cell homeostasis (GO:0061484), dense core granule exocytosis (GO:1990504), synaptic vesicle exocytosis (GO:0016079)

GO Molecular Function (2): lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (17): nucleoplasm (GO:0005654), centrosome (GO:0005813), cilium (GO:0005929), cytoplasmic vesicle membrane (GO:0030659), ciliary basal body (GO:0036064), presynaptic membrane (GO:0042734), postsynaptic membrane (GO:0045211), parallel fiber to Purkinje cell synapse (GO:0098688), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202), presynapse (GO:0098793)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
presynapse	2
microtubule organizing center	2
synaptic membrane	2
synapse	2
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
synaptic vesicle exocytosis	1
protein-containing complex assembly	1
exocytic process	1
exocytosis	1
regulation of exocytosis	1
positive regulation of secretion by cell	1
homeostasis of number of cells	1
calcium-ion regulated exocytosis	1
dense core granule localization	1
establishment of vesicle localization	1
neurotransmitter secretion	1
regulated exocytosis	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1
binding	1
cation binding	1
nuclear lumen	1
centriole	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
vesicle membrane	1
cytoplasmic vesicle	1
cilium	1

Protein interactions and networks

STRING

1416 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CADPS2	AUTS2	Q8WXX7	871
CADPS2	NRG3	P56975	858
CADPS2	DYRK1A	Q13627	811
CADPS2	BDNF	P23560	638
CADPS2	DCTN1	Q14203	532
CADPS2	ECPAS	Q5VYK3	527
CADPS2	CNTNAP2	Q9UHC6	467
CADPS2	CACNA1H	O95180	451
CADPS2	BACE2	Q9Y5Z0	435
CADPS2	PCLO	Q9Y6V0	427
CADPS2	RIMS2	Q9UQ26	426
CADPS2	CLDN23	Q96B33	422
CADPS2	ANO10	Q9NW15	409
CADPS2	NLGN2	Q8NFZ4	408
CADPS2	CDKN2A	P42771	396

IntAct

21 interactions, top by confidence:

A	B	Type	Score
CADPS2	UBE2D1	psi-mi:“MI:0915”(physical association)	0.370
UBE2D2	CADPS2	psi-mi:“MI:0915”(physical association)	0.370
UBE2D3	CADPS2	psi-mi:“MI:0915”(physical association)	0.370
UBE2D4	CADPS2	psi-mi:“MI:0915”(physical association)	0.370
CADPS2	UBE2E1	psi-mi:“MI:0915”(physical association)	0.370
CADPS2	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
CADPS2	UBE2N	psi-mi:“MI:0915”(physical association)	0.370
UBE2U	CADPS2	psi-mi:“MI:0915”(physical association)	0.370
UBE2W	CADPS2	psi-mi:“MI:0915”(physical association)	0.370
MEGF10	CADPS2	psi-mi:“MI:0915”(physical association)	0.370
	CADPS2	psi-mi:“MI:0915”(physical association)	0.370
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SAXO5	WDR47	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350
HRAS	IGHV1-45	psi-mi:“MI:0914”(association)	0.350
CADPS2		psi-mi:“MI:0915”(physical association)	0.000
CADPS2	rstB	psi-mi:“MI:0915”(physical association)	0.000
WDR4	CADPS2	psi-mi:“MI:0915”(physical association)	0.000
TTC3	CADPS2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): CADPS2 (Biochemical Activity), CADPS2 (Affinity Capture-MS), CADPS2 (Affinity Capture-MS), CADPS2 (Affinity Capture-MS), CADPS2 (Affinity Capture-MS), CADPS2 (Co-fractionation), CADPS2 (Affinity Capture-MS), CADPS2 (Two-hybrid), CADPS2 (Two-hybrid), CADPS2 (Affinity Capture-MS), CTTN (Cross-Linking-MS (XL-MS)), CADPS2 (Two-hybrid), CADPS2 (Cross-Linking-MS (XL-MS)), CADPS2 (Cross-Linking-MS (XL-MS)), CADPS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A5F9C6I2, A1L3F5, A2BDA5, A3KGS3, A8E4X8, D3ZXK7, F1R7R1, O75129, P21359, P51593, P97526, Q04690, Q1JPG0, Q2PPJ7, Q3SZD5, Q4QQM5, Q4R5A4, Q5RC14, Q5XPI3, Q5XPI4, Q62717, Q66K64, Q6GLR7, Q6NXD8, Q6P4S8, Q6PFH3, Q6VNB8, Q7L4E1, Q7TMY8, Q7Z6Z7, Q80TJ1, Q86UW7, Q8BHR8, Q8BK03, Q8BYR5, Q8CDG3, Q8CF97, Q8CID0, Q8IY22, Q8IZQ1

Diamond homologs: Q23658, Q60PC0, Q62717, Q6GLR7, Q80TJ1, Q86UW7, Q8BYR5, Q9NHE5, Q9ULU8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
“phosphatidylinositol bisphosphate”	“up-regulates activity”	CADPS2	“chemical activation”
CADPS2	“up-regulates activity”	STX1A	binding
CADPS2	“up-regulates activity”	SNAP25	binding
CADPS2	“up-regulates activity”	VAMP2	binding
LRRK2	“up-regulates quantity”	CADPS2	“transcriptional regulation”
SNCA	“down-regulates quantity”	CADPS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	122.8×	2e-08
E3 ubiquitin ligases ubiquitinate target proteins	5	64.5×	3e-07
Antigen processing: Ubiquitination & Proteasome degradation	9	22.3×	4e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	5	95.5×	7e-08
protein K48-linked ubiquitination	7	65.5×	9e-10
protein polyubiquitination	7	44.9×	7e-09
ubiquitin-dependent protein catabolic process	6	24.8×	3e-06
proteasome-mediated ubiquitin-dependent protein catabolic process	5	14.5×	4e-04
protein ubiquitination	5	11.5×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	388
Likely benign	35
Benign	13

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
815028	GRCh37/hg19 7q31.32(chr7:122244359-122274997)x1	Likely pathogenic

SpliceAI

11236 predictions. Top by Δscore:

Variant	Effect	Δscore
12:75284950:A:AC	donor_gain	1.0000
12:75284951:A:C	donor_gain	1.0000
12:75284958:TACCT:T	donor_loss	1.0000
12:75284959:A:C	donor_loss	1.0000
12:75284960:C:CA	donor_loss	1.0000
12:75284978:T:TA	donor_gain	1.0000
12:75285078:ATCC:A	acceptor_loss	1.0000
12:75285079:TC:T	acceptor_gain	1.0000
12:75285079:TCC:T	acceptor_loss	1.0000
12:75285080:CC:C	acceptor_gain	1.0000
12:75285081:C:CC	acceptor_gain	1.0000
12:75285082:T:G	acceptor_loss	1.0000
12:75289616:CATA:C	donor_loss	1.0000
12:75289617:ATACC:A	donor_loss	1.0000
12:75289618:TA:T	donor_loss	1.0000
12:75289619:A:C	donor_loss	1.0000
12:75289620:CCTTT:C	donor_loss	1.0000
12:75289676:T:C	donor_gain	1.0000
12:75289694:T:TA	donor_gain	1.0000
12:75289771:CACAT:C	acceptor_gain	1.0000
12:75289773:CAT:C	acceptor_gain	1.0000
12:75289776:C:CC	acceptor_gain	1.0000
12:75291739:CATA:C	donor_loss	1.0000
12:75291740:ATAC:A	donor_loss	1.0000
12:75291741:TAC:T	donor_loss	1.0000
12:75291837:C:CT	acceptor_gain	1.0000
12:75293242:AACT:A	donor_loss	1.0000
12:75293244:CTTA:C	donor_loss	1.0000
12:75293245:TTA:T	donor_loss	1.0000
12:75293246:TAC:T	donor_loss	1.0000

AlphaMissense

8546 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:122471401:G:C	F720L	1.000
7:122471401:G:T	F720L	1.000
7:122471403:A:G	F720L	1.000
7:122471410:G:C	S717R	1.000
7:122471410:G:T	S717R	1.000
7:122471412:T:G	S717R	1.000
7:122471465:A:G	L699P	1.000
7:122471551:G:C	S670R	1.000
7:122471551:G:T	S670R	1.000
7:122471553:T:G	S670R	1.000
7:122471559:A:G	W668R	1.000
7:122471559:A:T	W668R	1.000
7:122471561:C:T	G667E	1.000
7:122490192:A:G	W581R	1.000
7:122490192:A:T	W581R	1.000
7:122491415:G:C	S516R	1.000
7:122491415:G:T	S516R	1.000
7:122491417:T:G	S516R	1.000
7:122581231:A:G	L428P	1.000
7:122581287:C:A	W409C	1.000
7:122581287:C:G	W409C	1.000
7:122581289:A:G	W409R	1.000
7:122581289:A:T	W409R	1.000
7:122615247:A:T	V386D	1.000
7:122629285:A:G	L277P	1.000
7:122663307:A:G	L239P	1.000
7:122663416:A:G	W203R	1.000
7:122663416:A:T	W203R	1.000
7:122325578:A:G	W1206R	0.999
7:122325578:A:T	W1206R	0.999

dbSNP variants (sampled 300 via entrez): RS1000009348 (7:122521509 A>C), RS1000013623 (7:122501114 G>T), RS1000017089 (7:122783568 C>T), RS1000020190 (7:122875576 T>C), RS1000033100 (7:122578136 G>C,T), RS1000041259 (7:122408007 T>C), RS1000045231 (7:122417285 T>C), RS1000057487 (7:122584448 T>C), RS1000064226 (7:122825099 T>C), RS1000069029 (7:122541833 A>G), RS1000076490 (7:122475273 C>T), RS1000085956 (7:122365132 G>A), RS1000087056 (7:122700985 G>A), RS1000090436 (7:122863783 A>T), RS1000093748 (7:122319508 G>C)

Disease associations

OMIM: gene MIM:609978 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability	Limited	Autosomal recessive

Mondo (1): intellectual disability (MONDO:0001071)

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000597_17	Brain structure	6.000000e-07
GCST002097_9	Coronary artery calcification	8.000000e-06
GCST002541_61	Menarche (age at onset)	4.000000e-11
GCST003518_77	Daytime sleep phenotypes	8.000000e-06
GCST003723_1	Serum sulfate level	9.000000e-10
GCST007325_125	General risk tolerance (MTAG)	4.000000e-11
GCST007326_18	Number of sexual partners	3.000000e-08
GCST007327_57	Smoking status (ever vs never smokers)	3.000000e-08
GCST007543_10	Attention deficit hyperactivity disorder	3.000000e-06
GCST008151_23	Waist circumference	7.000000e-06
GCST008160_7	Waist circumference	7.000000e-06
GCST010291_2	Attention deficit hyperactivity disorder	2.000000e-08
GCST010988_170	Adult body size	4.000000e-08
GCST012490_430	Femur bone mineral density x serum urate levels interaction	2.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004703	age at menarche
EFO:0007828	daytime rest measurement
EFO:0007864	sulfate measurement
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	5
Cyclosporine	affects expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects methylation, decreases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
bisphenol A	increases methylation	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Quercetin	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
sulforaphane	decreases expression	1
cobaltous chloride	decreases expression	1
gossypol acetic acid	increases 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	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Copper	affects binding, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Drugs, Chinese Herbal	decreases expression	1
Etoposide	affects response to substance	1
Formaldehyde	decreases expression	1
Progesterone	increases expression	1

Clinical trials (associated diseases)

197 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
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)
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)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders