NCS1

Summary

NCS1 (neuronal calcium sensor 1, HGNC:3953) is a protein-coding gene on chromosome 9q34.11, encoding Neuronal calcium sensor 1 (P62166). Neuronal calcium sensor, regulator of G protein-coupled receptor phosphorylation in a calcium dependent manner.

This gene is a member of the neuronal calcium sensor gene family, which encode calcium-binding proteins expressed predominantly in neurons. The protein encoded by this gene regulates G protein-coupled receptor phosphorylation in a calcium-dependent manner and can substitute for calmodulin. The protein is associated with secretory granules and modulates synaptic transmission and synaptic plasticity. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23413 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 23 total
• Druggable target: yes
• MANE Select transcript: NM_014286

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3953
Approved symbol	NCS1
Name	neuronal calcium sensor 1
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	NCS-1
Ensembl gene	ENSG00000107130
Ensembl biotype	protein_coding
OMIM	603315
Entrez	23413

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000372398, ENST00000493042, ENST00000630865, ENST00000937011, ENST00000937012, ENST00000946320, ENST00000946321, ENST00000946322

RefSeq mRNA: 2 — MANE Select: NM_014286 NM_001128826, NM_014286

CCDS: CCDS6932, CCDS78448

Canonical transcript exons

ENST00000372398 — 8 exons

Exon	Start	End
ENSE00000927338	130217832	130217970
ENSE00000927339	130219725	130219803
ENSE00000927340	130222650	130222738
ENSE00000927341	130223082	130223159
ENSE00001052772	130226389	130226504
ENSE00001457687	130232990	130237303
ENSE00001457688	130172404	130172727
ENSE00003506681	130200958	130200982

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.1790 / max 506.9513, expressed in 1704 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98992	31.6266	1700
98993	3.7004	1311
98995	1.0262	639
98994	0.6209	336
98996	0.6159	387
98997	0.5240	293
99005	0.3693	150
99003	0.2801	122
99006	0.1702	70
98998	0.1234	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	98.84	gold quality
anterior cingulate cortex	UBERON:0009835	98.38	gold quality
amygdala	UBERON:0001876	98.28	gold quality
nucleus accumbens	UBERON:0001882	98.28	gold quality
cingulate cortex	UBERON:0003027	98.26	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.79	gold quality
postcentral gyrus	UBERON:0002581	97.69	gold quality
prefrontal cortex	UBERON:0000451	97.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.13	gold quality
caudate nucleus	UBERON:0001873	97.12	gold quality
Ammon’s horn	UBERON:0001954	97.05	gold quality
parietal lobe	UBERON:0001872	97.02	gold quality
frontal cortex	UBERON:0001870	96.81	gold quality
neocortex	UBERON:0001950	96.72	gold quality
temporal lobe	UBERON:0001871	96.54	gold quality
cortical plate	UBERON:0005343	96.44	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.36	gold quality
cerebral cortex	UBERON:0000956	96.20	gold quality
telencephalon	UBERON:0001893	96.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.91	gold quality
superior frontal gyrus	UBERON:0002661	95.54	gold quality
putamen	UBERON:0001874	95.53	gold quality
mucosa of stomach	UBERON:0001199	95.50	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.48	gold quality
cerebellar hemisphere	UBERON:0002245	95.33	gold quality
cerebellar cortex	UBERON:0002129	95.28	gold quality
popliteal artery	UBERON:0002250	95.26	gold quality
tibial artery	UBERON:0007610	95.25	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.09	gold quality
lower esophagus	UBERON:0013473	95.05	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	962.15
E-GEOD-109979	no	66.76
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting NCS1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-497-5P	99.92	71.83	2674

Literature-anchored findings (GeneRIF, showing 35)

• up-regulated in the prefrontal cortex of schizophrenic and bipolar patients (PMID:12496348)
• Analysis with chimeric proteins between KChIP2 and NCS-1 reveals that the three regions of KChIP2 are necessary and sufficient for its effective binding to Kv4.3 protein (PMID:12928444)
• may serve as regulator of certain isoforms of phosphatidylinositol 4-kinase (PMID:14512421)
• key role for residues within the motif EELTRK in NCS-1 in keeping the myristoyl group exposed and allowing the protein to be constitutively membrane-associated. (PMID:14726528)
• NCS-1 is shown to be mainly associated with azurophilic granules in human neutrophils and promyelocitic cells and, therefore could play an instrumental role in the calcium-dependent secretion of azurophilic granules (PMID:14760944)
• These results demonstrate a novel role for NCS-1 and PI4Kbeta in regulating ERK1/2 signaling and inflammatory reactions in mast cells. (PMID:16837555)
• occurrence of an unusual TG 3’ splice site in intron 2 (PMID:17672918)
• NCS-1 expression was diminished in CD4+T lymphocytes, CD19+ B lymphocytes and CD14+ monocytes of bipolar disorder patients and also decreased in CD4+ T lymphocytes and CD56+ natural killer cells of schizophrenia patients (PMID:19091302)
• Impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain. (PMID:20479890)
• NCS-1 is a novel regulator of cardiac calcium signaling, specifically in immature and hypertrophic hearts. (PMID:21737792)
• [review] Receptor interaction properties in schizophrenia are dependent upon NCS-1, a protein found to regulate the phosphorylation, trafficking, and signaling profile of the D2 dopamine receptor (D2R) in neurons. (PMID:21777187)
• it is possible to protect cells from paclitaxel-induced degradation of NCS-1 by inhibiting calpain activity (PMID:21808066)
• analysis of the interaction between the D2 dopamine receptor and neuronal calcium sensor-1 (PMID:21875085)
• the C-terminal tail is important for regulating the conformational stability of NCS1 in Ca(2+)-activated state (PMID:22227393)
• data suggest that genetic variants in the NCS-1 gene contribute to susceptibility of Cocaine Abuse in individuals of African descent. (PMID:22999924)
• NCS1 has evolved a remarkable complex interdomain cooperativity and a fundamentally different folding mechanism compared to structurally related proteins. (PMID:24012477)
• The functional link in substantia nigra dopamine neurons between Cav1.3- L-type-Ca2+ channels and D2-autoreceptor activity is an adaptive signalling network controlled by NCS-1. (PMID:24934288)
• single-molecule optical tweezers were used to monitor misfolding reactions of the human neuronal calcium sensor-1. (PMID:25157171)
• results reveal the important role of salt bridges on the structural properties of NCS-1 protein and that R102Q mutation disables the dynamic relocation of C-terminus, which may block the binding of NCS-1 protein to its receptors (PMID:25343687)
• A strong liason was characterized between myristoylation and cryptic EF-1 in NCS-1. (PMID:25565019)
• Study determined the salient features of the folding free-energy landscapes of the Mg2+-bound and apo states of NCS-1 (PMID:26153708)
• structural and dynamical response of NCS-1 protein to elevated temperature may be one of its intrinsic functional properties (PMID:27007011)
• Lithium normalizes gamma band oscillations mediated by P/Q-type calcium channels modulated by NCS-1. (PMID:27033453)
• Results show that although NCS-1 Var2mRNA can be detected, protein expression was not detectable. When overexpressed in cell lines NCS-1 Var2 appears to be folded properly, yet it has a lower calcium affinity. Because most NCS-1 binding to its protein partners requires calcium binding, it is unlikely that NCS-1 Var2 would play a major regulatory role in cells. (PMID:27575489)
• NCS-1, a calcium-binding protein, is associated with clinicopathologic features of aggressiveness in breast cancer cells and worse outcome in two breast cancer patient cohorts (PMID:28275088)
• High NCS1 expression is associated with Hepatocellular Carcinoma. (PMID:29789326)
• NCS1 regulates endoplasmic reticulum-mitochondria cross-talk, which is impaired in Wolfram syndrome (PMID:30352948)
• NCS-1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin. (PMID:31647602)
• NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. (PMID:31704946)
• Membrane Binding of Neuronal Calcium Sensor-1: Highly Specific Interaction with Phosphatidylinositol-3-Phosphate. (PMID:31973069)
• Neuronal Calcium Sensor 1 is up-regulated in response to stress to promote cell survival and motility in cancer cells. (PMID:32239615)
• Disorder in a two-domain neuronal Ca(2+)-binding protein regulates domain stability and dynamics using ligand mimicry. (PMID:32936312)
• Disulfide Dimerization of Neuronal Calcium Sensor-1: Implications for Zinc and Redox Signaling. (PMID:34830487)
• [Neuronal Calcium Sensor-1: A Zinc/Redox-Dependent Protein of Nervous System Signaling Pathways]. (PMID:38062964)
• NCS-1 protein regulates TRPA1 channel through the PI3K pathway in breast cancer and neuronal cells. (PMID:38564162)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncs1b	ENSDARG00000054186
danio_rerio	ncs1a	ENSDARG00000055229
mus_musculus	Ncs1	ENSMUSG00000062661
drosophila_melanogaster	CG7646	FBGN0036926
drosophila_melanogaster	CG5890	FBGN0039380
caenorhabditis_elegans	ncs-2	WBGENE00003564
caenorhabditis_elegans		WBGENE00015867

Paralogs (14): CLXN (ENSG00000034239), GUCA1A (ENSG00000048545), NCALD (ENSG00000104490), RCVRN (ENSG00000109047), GUCA1B (ENSG00000112599), KCNIP3 (ENSG00000115041), HPCAL1 (ENSG00000115756), HPCAL4 (ENSG00000116983), KCNIP2 (ENSG00000120049), HPCA (ENSG00000121905), GUCA1C (ENSG00000138472), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Neuronal calcium sensor 1 — P62166 (reviewed: P62166)

Alternative names: Frequenin homolog, Frequenin-like protein, Frequenin-like ubiquitous protein

All UniProt accessions (1): P62166

UniProt curated annotations — full annotation on UniProt →

Function. Neuronal calcium sensor, regulator of G protein-coupled receptor phosphorylation in a calcium dependent manner. Directly regulates GRK1 (RHOK), but not GRK2 to GRK5. Can substitute for calmodulin. Stimulates PI4KB kinase activity. Involved in long-term synaptic plasticity through its interaction with PICK1. May also play a role in neuron differentiation through inhibition of the activity of N-type voltage-gated calcium channel.

Subunit / interactions. Monomer. Interacts with KCND2. Interacts in a calcium-independent manner with PI4KB. This binding competes with CALN2/CABP7 binding to PI4KB. Interacts in a calcium-dependent manner with PICK1 (via AH domain). Interacts with ARF1, ARF3, ARF5 and ARF6. Interacts with IL1RAPL1. Interacts with RIC8A; interaction is favored in the absence of Ca(2+) and myristoylation of NCS1 is not required.

Subcellular location. Golgi apparatus. Postsynaptic density. Cytoplasm. Perinuclear region. Cell membrane. Membrane.

Miscellaneous. Binds 3 calcium ions via the second, third and fourth EF-hand.

Similarity. Belongs to the recoverin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P62166-1	1	yes
P62166-2	2

RefSeq proteins (2): NP_001122298, NP_055101* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028846	Recoverin	Family

Pfam: PF00036, PF13499

UniProt features (52 total): binding site 16, helix 14, strand 7, domain 4, mutagenesis site 4, sequence conflict 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9GUA	X-RAY DIFFRACTION	1.65
9GU8	X-RAY DIFFRACTION	1.67
8AHY	X-RAY DIFFRACTION	1.7
4GUK	X-RAY DIFFRACTION	1.75
6QI4	X-RAY DIFFRACTION	1.78
8ALM	X-RAY DIFFRACTION	1.85
8ALH	X-RAY DIFFRACTION	1.86
1G8I	X-RAY DIFFRACTION	1.9
9T0H	X-RAY DIFFRACTION	1.91
9GU6	X-RAY DIFFRACTION	1.93
9GUZ	X-RAY DIFFRACTION	2.28
9GTO	X-RAY DIFFRACTION	2.3
5O9S	X-RAY DIFFRACTION	2.7
2LCP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62166-F1	88.26	0.65

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 (16): 79; 81; 84; 109; 111; 113; 115; 120; 157; 159; 161; 163 …

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (4):

Position	Phenotype
2	no effect on interaction with ric8a.
81	reduces calcium binding; when associated with a-117 or a-165. abolishes calcium binding; when associated with a-117 and
117	reduces calcium binding; when associated with t-81. abolishes calcium binding; when associated with t-81 and a-165.
165	reduces calcium binding; when associated with a-117. abolishes calcium binding; when associated with t-81 and a-117.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 181 (showing top): TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEUROGENESIS, GOBP_MONOATOMIC_CATION_TRANSPORT, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_2_DN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, BACH2_01, TGANTCA_AP1_C, TTGGAGA_MIR5155P_MIR519E, GOBP_REGULATION_OF_NEURON_PROJECTION_DEVELOPMENT, GOCC_NEURON_PROJECTION, GOBP_CELL_PROJECTION_ORGANIZATION, GCM_MAPK10, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT

GO Biological Process (3): regulation of signal transduction (GO:0009966), regulation of neuron projection development (GO:0010975), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (5): voltage-gated calcium channel activity (GO:0005245), calcium ion binding (GO:0005509), calcium sensitive guanylate cyclase activator activity (GO:0008048), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), axon (GO:0030424), dendrite (GO:0030425), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
neuron projection	2
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
metal ion binding	1
guanylate cyclase activator activity	1
binding	1
cation binding	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
asymmetric synapse	1
postsynaptic specialization	1
dendritic tree	1
cell junction	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

127 interactions, top by confidence:

A	B	Type	Score
DTX2	NCS1	psi-mi:“MI:0915”(physical association)	0.830
NCS1	DTX2	psi-mi:“MI:0915”(physical association)	0.830
MGLL	HPCAL1	psi-mi:“MI:0914”(association)	0.640
HSD17B3	NCS1	psi-mi:“MI:0915”(physical association)	0.620
NCS1	CEP89	psi-mi:“MI:0915”(physical association)	0.600
NBL1	NCS1	psi-mi:“MI:0915”(physical association)	0.560
NCS1	NBL1	psi-mi:“MI:0915”(physical association)	0.560
NCS1	SFTPA2	psi-mi:“MI:0915”(physical association)	0.560
NCS1	LY6G6D	psi-mi:“MI:0915”(physical association)	0.560
NCS1	CREM	psi-mi:“MI:0915”(physical association)	0.560
NCS1		psi-mi:“MI:0915”(physical association)	0.560
NCS1	PRDM4	psi-mi:“MI:0915”(physical association)	0.560
NCS1	CTAG1A	psi-mi:“MI:0915”(physical association)	0.560
NCS1	SIGLEC9	psi-mi:“MI:0915”(physical association)	0.560
NCS1	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
NCS1	ZC3H10	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (115): NCS1 (Two-hybrid), DTX2 (Two-hybrid), NCS1 (Affinity Capture-MS), NCS1 (Affinity Capture-MS), NCS1 (Affinity Capture-MS), NCS1 (Affinity Capture-MS), NCS1 (Affinity Capture-MS), DTX2 (Two-hybrid), NCS1 (Proximity Label-MS), NCS1 (Two-hybrid), NCS1 (Affinity Capture-MS), IL1RAPL1 (Two-hybrid), BSPRY (Affinity Capture-MS), ABHD6 (Affinity Capture-MS), NMT2 (Affinity Capture-MS)

ESM2 similar proteins: A9JTH1, B3DLU1, B3VSB7, B5FZ84, P29104, P29105, P35332, P36608, P37235, P37236, P42324, P42325, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762, P62763, P62764, P84074, P84075, P84076, Q06AT0, Q06AT1, Q09711, Q16982, Q28IM6, Q4PL64, Q4R4N4, Q4R5F7, Q5PQN0, Q5R632, Q5R6S5

Diamond homologs: A9JTH1, B3DLU1, B3VSB7, B5FZ84, O73761, O73762, O73763, O95843, P21457, P22728, P25296, P29104, P29105, P31227, P34057, P35243, P35332, P36608, P36609, P37235, P37236, P42322, P42324, P42325, P43080, P43081, P46065, P51177, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NCS1	“down-regulates activity”	DRD2	binding
NCS1	“down-regulates activity”	GRK2	binding
IL1RAPL1	“up-regulates activity”	NCS1	binding
NCS1	“up-regulates activity”	PI4KB
IL1RAPL2	“up-regulates activity”	NCS1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
TNFR1-induced NF-kappa-B signaling pathway	5	28.0×	6e-04
MAPK family signaling cascades	5	8.6×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	5	22.3×	2e-03
negative regulation of canonical NF-kappaB signal transduction	6	12.6×	3e-03
positive regulation of canonical NF-kappaB signal transduction	8	7.1×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1933 predictions. Top by Δscore:

Variant	Effect	Δscore
9:130172717:G:GT	donor_gain	1.0000
9:130172723:CTACT:C	donor_gain	1.0000
9:130172724:TACT:T	donor_gain	1.0000
9:130172725:ACT:A	donor_gain	1.0000
9:130172725:ACTGT:A	donor_loss	1.0000
9:130172726:CT:C	donor_gain	1.0000
9:130172726:CTG:C	donor_loss	1.0000
9:130172727:TG:T	donor_loss	1.0000
9:130172728:G:C	donor_loss	1.0000
9:130172728:G:GG	donor_gain	1.0000
9:130172729:T:G	donor_loss	1.0000
9:130200980:GTG:G	donor_gain	1.0000
9:130217820:T:TA	acceptor_gain	1.0000
9:130217823:T:A	acceptor_gain	1.0000
9:130217830:A:C	acceptor_loss	1.0000
9:130217971:G:GC	donor_loss	1.0000
9:130219719:TGTCA:T	acceptor_loss	1.0000
9:130219720:GTCA:G	acceptor_loss	1.0000
9:130219721:TCA:T	acceptor_loss	1.0000
9:130219722:CAGG:C	acceptor_loss	1.0000
9:130219723:A:AG	acceptor_gain	1.0000
9:130219723:A:AT	acceptor_loss	1.0000
9:130219723:AG:A	acceptor_gain	1.0000
9:130219723:AGGAC:A	acceptor_gain	1.0000
9:130219724:G:GA	acceptor_gain	1.0000
9:130219724:GG:G	acceptor_gain	1.0000
9:130219724:GGAC:G	acceptor_gain	1.0000
9:130219724:GGACG:G	acceptor_gain	1.0000
9:130219797:C:G	donor_gain	1.0000
9:130219799:ACGGT:A	donor_gain	1.0000

AlphaMissense

1267 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:130217842:T:C	F34L	1.000
9:130217843:T:C	F34S	1.000
9:130217844:C:A	F34L	1.000
9:130217844:C:G	F34L	1.000
9:130219740:T:C	F82L	1.000
9:130219742:C:A	F82L	1.000
9:130219742:C:G	F82L	1.000
9:130219780:G:A	G95E	1.000
9:130219798:T:C	L101P	1.000
9:130222655:T:C	F105L	1.000
9:130222657:C:A	F105L	1.000
9:130222657:C:G	F105L	1.000
9:130222689:T:A	I116N	1.000
9:130222721:G:C	A127P	1.000
9:130226419:T:C	F169L	1.000
9:130226420:T:C	F169S	1.000
9:130226421:C:A	F169L	1.000
9:130226421:C:G	F169L	1.000
9:130172710:T:C	L16P	0.999
9:130200973:T:A	V27D	0.999
9:130217843:T:G	F34C	0.999
9:130217870:T:C	L43P	0.999
9:130217884:T:C	F48L	0.999
9:130217885:T:C	F48S	0.999
9:130217886:C:A	F48L	0.999
9:130217886:C:G	F48L	0.999
9:130217905:T:C	F55L	0.999
9:130217907:C:A	F55L	0.999
9:130217907:C:G	F55L	0.999
9:130217908:T:C	F56L	0.999

dbSNP variants (sampled 300 via entrez): RS1000091266 (9:130223771 A>C,G,T), RS1000192258 (9:130228164 A>G), RS1000327841 (9:130233938 G>A,C), RS1000352424 (9:130195791 G>A,T), RS1000497876 (9:130174287 G>A), RS1000510663 (9:130212185 G>A), RS1000557203 (9:130180386 C>A), RS1000563205 (9:130210757 A>G,T), RS1000634181 (9:130222240 C>A,T), RS1000715554 (9:130185046 A>G), RS1000741134 (9:130215863 T>C), RS1000942749 (9:130199957 G>C), RS1001017349 (9:130205332 T>A,G), RS1001116912 (9:130211256 C>G), RS1001298246 (9:130205972 T>C)

Disease associations

OMIM: gene MIM:603315 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001915_24	Alzheimer’s disease (cognitive decline)	7.000000e-07
GCST007231_10	Tuberculosis	2.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4295788 (SINGLE PROTEIN), CHEMBL4296100 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.90	Kd	1250	nM	CHEMBL3235533

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(1,3-benzothiazol-2-yl)-3,3-diphenylpropanamide	1350731: Binding affinity to human NCS1 expressed in Escherichia coli BL21 Star (DE3) by fluorescence emission assay	kd	1.2500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Valproic Acid	increases methylation, affects expression, decreases expression	2
Cadmium Chloride	increases expression	2
propylparaben	increases expression	1
bisphenol A	increases expression	1
glycidyl methacrylate	increases expression	1
lead acetate	increases expression	1
methylparaben	increases expression	1
benzo(e)pyrene	decreases methylation	1
cupric chloride	increases expression	1
abrine	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Decitabine	increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases expression, increases abundance	1
Benzoates	decreases expression	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Methapyrilene	decreases methylation	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4145365	Binding	Binding affinity to human NCS1 expressed in Escherichia coli BL21 Star (DE3) by fluorescence emission assay	Deciphering the Inhibition of the Neuronal Calcium Sensor 1 and the Guanine Exchange Factor Ric8a with a Small Phenothiazine Molecule for the Rational Generation of Therapeutic Synapse Function Regulators. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D6KM	HMGUi001-A-22	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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