KCNIP3

Summary

KCNIP3 (potassium voltage-gated channel interacting protein 3, HGNC:15523) is a protein-coding gene on chromosome 2q11.1, encoding Calsenilin (Q9Y2W7). Calcium-dependent transcriptional repressor that binds to the DRE element of genes including PDYN and FOS.

This gene encodes a member of the family of voltage-gated potassium (Kv) channel-interacting proteins, which belong to the recoverin branch of the EF-hand superfamily. Members of this family are small calcium binding proteins containing EF-hand-like domains. They are integral subunit components of native Kv4 channel complexes that may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium. The encoded protein also functions as a calcium-regulated transcriptional repressor, and interacts with presenilins. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 30818 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 56 total
• Phenotypes (HPO): 1
• Transcription factor: yes — 16 downstream targets (CollecTRI)
• MANE Select transcript: NM_013434

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15523
Approved symbol	KCNIP3
Name	potassium voltage-gated channel interacting protein 3
Location	2q11.1
Locus type	gene with protein product
Status	Approved
Aliases	DREAM, KCHIP3
Ensembl gene	ENSG00000115041
Ensembl biotype	protein_coding
OMIM	604662
Entrez	30818

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000295225, ENST00000360990, ENST00000377181, ENST00000461336, ENST00000468529, ENST00000475491, ENST00000486055, ENST00000698060, ENST00000873166, ENST00000873167, ENST00000873168

RefSeq mRNA: 2 — MANE Select: NM_013434 NM_001034914, NM_013434

CCDS: CCDS2013, CCDS33245

Canonical transcript exons

ENST00000295225 — 9 exons

Exon	Start	End
ENSE00001383497	95310355	95310520
ENSE00001931064	95297347	95297453
ENSE00003482345	95384002	95386077
ENSE00003482823	95374296	95374420
ENSE00003485425	95383232	95383294
ENSE00003519704	95381596	95381703
ENSE00003564363	95375138	95375208
ENSE00003615905	95374848	95374917
ENSE00003660203	95382377	95382481

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 94.17.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3352 / max 157.8898, expressed in 648 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21424	2.3663	288
21425	1.0355	118
21433	0.3574	168
21432	0.2532	126
21430	0.1409	72
21431	0.1100	46
21434	0.0719	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	94.17	gold quality
anterior cingulate cortex	UBERON:0009835	93.36	gold quality
prefrontal cortex	UBERON:0000451	92.96	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.31	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.26	gold quality
left lobe of thyroid gland	UBERON:0001120	91.20	gold quality
amygdala	UBERON:0001876	91.12	gold quality
right lobe of thyroid gland	UBERON:0001119	91.06	gold quality
thyroid gland	UBERON:0002046	90.31	gold quality
frontal cortex	UBERON:0001870	90.30	gold quality
neocortex	UBERON:0001950	90.10	gold quality
cerebral cortex	UBERON:0000956	88.23	gold quality
parotid gland	UBERON:0001831	87.66	gold quality
nucleus accumbens	UBERON:0001882	87.55	gold quality
caudate nucleus	UBERON:0001873	87.41	gold quality
hypothalamus	UBERON:0001898	86.68	gold quality
putamen	UBERON:0001874	86.67	gold quality
forebrain	UBERON:0001890	86.50	gold quality
temporal lobe	UBERON:0001871	85.43	gold quality
Ammon’s horn	UBERON:0001954	85.18	gold quality
brain	UBERON:0000955	84.80	gold quality
left uterine tube	UBERON:0001303	83.50	gold quality
metanephros cortex	UBERON:0010533	83.47	gold quality
substantia nigra	UBERON:0002038	83.43	gold quality
apex of heart	UBERON:0002098	83.12	gold quality
endocervix	UBERON:0000458	82.83	gold quality
ganglionic eminence	UBERON:0004023	82.68	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.65	gold quality
lower esophagus	UBERON:0013473	82.59	gold quality
primary visual cortex	UBERON:0002436	81.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.44

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

16 targets.

Target	Regulation
CACNA1C
CALCA
CAMK2A
CDK1
CDKN1A
FMR1
GCM1	Repression
GFAP	Repression
HRK
IL3
KIF23
NPFF
PDYN	Repression
PLK4
SLC8A3	Repression
TG	Unknown

miRNA regulators (miRDB)

104 targeting KCNIP3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-6764-5P	99.75	67.89	2304

Literature-anchored findings (GeneRIF, showing 40)

• apoptosis inducers as diverse as oncoprotein inhibitors and cell death receptor activators trigger Hrk expression via blockade of DREAM in leukemia cells (PMID:12217801)
• Immunoreactivity of calsenilin in the hippocampus derived from an epilepsy patient is significantly decreased compared with normal brain. (PMID:12648752)
• calsenilin can be phosphorylated by casein kinase I and that its phosphorylation can be regulated by intracellular calcium. (PMID:12837631)
• The level of intracellular calcium can modulate the nuclear translocation of calsenilin and this process does not involve the direct binding of calcium to calsenilin (PMID:15086516)
• Calsenilin overexpression in both neurons and reactive astrocytes may play an important role in apoptosis and in Alzheimer’s disease pathology. (PMID:15770150)
• DREAM is a Ca2+-dependent repressor of the immune response. (PMID:16177826)
• The downregulation of the regulator of Ca2+ homeostasis NCX3 by Ca2+-regulated DREAM is a striking example of the autoregulatory property of the Ca2+ signal in neurons. (PMID:16306395)
• DREAM plays an important role in human calcitonin gene expression in a Ca(2+)- and cAMP-dependent manner (PMID:16840549)
• interaction of DREAM with GRK6 and GRK2, members of the G protein-coupled receptor kinase family of proteins, and their phosphorylation of DREAM (PMID:17102134)
• analysis of calcium-binding properties of EF-hands 3 and 4 of calsenilin (PMID:17962406)
• CALP and calsenilin are involved in the trafficking of Golgi glycosyltransferases. (PMID:18269347)
• These results reveal a new role for KChIP3 in the regulation of calcium regulated secretion and also suggest that the functions of each of the KChIPs may be more specialized than previously appreciated. (PMID:18393943)
• DREAM transcripts are present in synovial fibroblast-like cells as well as peripheral blood mononuclear cells from osteoarthritis patients and healthy controls. (PMID:18507845)
• Data show that calsenilin/DREAM/KChIP3 is distributed throughout the cytoplasm of SK-N-BE2(C), Jurkat, and HeLa cells and the expression of calsenilin suppresses the ATP-induced increase in intracellular Ca2+ concentrations. (PMID:18628663)
• Interplay of the Ca2+-binding protein DREAM with presenilin in neuronal Ca2+ signaling (PMID:18664571)
• KChIP4a, KChIP2x, and KChIP3x comprise a novel class of KChIP isoforms characterized by an unusual transmembrane domain at their N termini that modulates Kv4 channel gating and trafficking. (PMID:18957440)
• DREAM (downstream regulatory element antagonist modulator) modulates TSHR activity through a direct protein-protein interaction that promotes coupling between the receptor and Galphas. (PMID:19299442)
• These findings suggest that calsenilin degradation is primarily mediated by the UPP and that impairment in the UPP may contribute to the involvement of calsenilin in disease-associated neurodegeneration. (PMID:21216226)
• The results show that continued human papillomavirus 16 E6/E7 expression is necessary in cervical cancer cells to prevent cell-cycle arrest by a repressive p130-DREAM complex. (PMID:21813705)
• expression of calsenilin leads to a disruption of presenilin 1/gamma-secretase-mediated epsilon-cleavage of N-cadherin, which results in the significant accumulation of N-cadherin C-terminal fragment 1 (PMID:21852538)
• Genetic variation in the DREAM pathway genes was associated with the extent of pain reporting in a population-based cohort. (PMID:22730276)
• The potassium channel interacting protein 3 (DREAM/KChIP3) heterodimerizes with and regulates calmodulin function. (PMID:23019329)
• p53 can repress transcription of cell cycle genes through a p21(WAF1/CIP1)-dependent switch from MMB to DREAM protein complex binding at CHR promoter elements. (PMID:23187802)
• GCM1-directed villous trophoblast differentiation is repressed by DREAM (PMID:23300953)
• Our results support the hypothesis that KChIPs enhances Kv4.2 functional expression by a 1 : 1 suppression of the N-terminal FERN domain and by producing additional positive regulatory effects on functional channel expression. (PMID:23692269)
• Imatinib induces GIST cell quiescence in vivo and that this process also involves the DREAM complex. (PMID:23786773)
• The aim of this study was to investigate somatic mutations and DREAM gene expression in human multinodular goiter (PMID:26319784)
• downregulation of these genes through the p53-p21-DREAM-CDE/CHR pathway appears to be a principal mechanism for G2/M cell cycle arrest by p53. (PMID:26384566)
• Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest. (PMID:27280975)
• this study shows that human papilloma virus E7 oncoprotein abrogates the p53-p21-DREAM pathway (PMID:28572607)
• This study shows the application of hydrogen-deuterium exchange mass spectrometry and site-directed mutagenesis to investigate the Ca(2+) binding properties and the subsequent conformational changes of full-length DREAM. EF-hands undergo large conformation changes upon calcium binding even though the EF-1 hand is not capable of binding to Ca(2+). (PMID:28627884)
• Disruption of DREAM and RB-E2F complexes by oncoproteins from DNA tumor viruses leads to upregulation of cell cycle genes and impairs growth-inhibiting pathways, including the p53-mediated downregulation of cell cycle genes. [review] (PMID:28799433)
• targeting SmgGDS induces nucleolar stress, resulting in profound loss of DREAM target gene expression required for G1, S and G2 progression, and ultimately resulting in cell cycle arrest. (PMID:28806394)
• Data show that Ca(2+)-binding protein (KChIP3) levels regulate baseline Mucin 5AC (MUC5AC) secretion. (PMID:30272559)
• TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. (PMID:30451831)
• DREAM cooperates with RB in repressing E2F-dependent gene expression and cell cycle entry and supports a role for DREAM as a therapeutic target in cancer. (PMID:30833638)
• Modulation of Kv4.2/KChIP3 interaction by the ceroid lipofuscinosis neuronal 3 protein CLN3. (PMID:32641494)
• PAF remodels the DREAM complex to bypass cell quiescence and promote lung tumorigenesis. (PMID:33626321)
• Neutrophil DREAM promotes neutrophil recruitment in vascular inflammation. (PMID:34751735)
• KCNIP3 silence promotes proliferation and epithelial-mesenchymal transition of papillary thyroid carcinoma through activating Wnt/beta-catenin pathway. (PMID:35066335)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnip3b	ENSDARG00000017880
mus_musculus	Kcnip3	ENSMUSG00000079056
rattus_norvegicus	Kcnip3	ENSRNOG00000014152
drosophila_melanogaster	CG7646	FBGN0036926
drosophila_melanogaster	CG5890	FBGN0039380
caenorhabditis_elegans	ncs-2	WBGENE00003564
caenorhabditis_elegans		WBGENE00015867

Paralogs (14): CLXN (ENSG00000034239), GUCA1A (ENSG00000048545), NCALD (ENSG00000104490), NCS1 (ENSG00000107130), RCVRN (ENSG00000109047), GUCA1B (ENSG00000112599), HPCAL1 (ENSG00000115756), HPCAL4 (ENSG00000116983), KCNIP2 (ENSG00000120049), HPCA (ENSG00000121905), GUCA1C (ENSG00000138472), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Calsenilin — Q9Y2W7 (reviewed: Q9Y2W7)

Alternative names: A-type potassium channel modulatory protein 3, DRE-antagonist modulator, Kv channel-interacting protein 3

All UniProt accessions (2): Q9Y2W7, A0A8V8TMV8

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-dependent transcriptional repressor that binds to the DRE element of genes including PDYN and FOS. Affinity for DNA is reduced upon binding to calcium and enhanced by binding to magnesium. Seems to be involved in nociception. Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels, such as KCND2/Kv4.2 and KCND3/Kv4.3. Modulates channel expression at the cell membrane, gating characteristics, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. May play a role in the regulation of PSEN2 proteolytic processing and apoptosis. Together with PSEN2 involved in modulation of amyloid-beta formation.

Subunit / interactions. Binds to DNA as a homomultimer. Dimerization is induced by binding to calcium. Interacts with the C-terminus of PSEN1 and PSEN2 and with PSEN2 CTF subunit. Associates with KCN1. Component of heteromultimeric potassium channels. Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10. Interacts with KCND2 and KCND3.

Subcellular location. Cytoplasm. Cell membrane. Endoplasmic reticulum. Golgi apparatus. Nucleus.

Tissue specificity. Highly expressed in brain. Widely expressed at lower levels. Expression levels are elevated in brain cortex regions affected by Alzheimer disease.

Post-translational modifications. Palmitoylated. Palmitoylation enhances association with the plasma membrane. Proteolytically cleaved by caspase-3. Phosphorylation at Ser-63 inhibits cleavage by CASP3.

Similarity. Belongs to the recoverin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y2W7-1	1, KChIP3.1	yes
Q9Y2W7-2	2, KChIP3.2, KChIP4.2
Q9Y2W7-3	3, KChip3.x

RefSeq proteins (2): NP_001030086, NP_038462* (*=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: PF13499, PF13833

UniProt features (41 total): binding site 9, helix 5, domain 4, modified residue 3, splice variant 3, sequence variant 3, strand 3, lipid moiety-binding region 2, cross-link 2, mutagenesis site 2, sequence conflict 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2E6W	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2W7-F1	69.45	0.14

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 (9): 181; 186; 223; 225; 227; 234; 175; 177; 179

Post-translational modifications (7): 14, 60, 63, 45, 46, 26, 90

Mutagenesis-validated functional residues (2):

Position	Phenotype
61	abolishes cleavage by caspase-3.
64	abolishes cleavage by caspase-3.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5576894	Phase 1 - inactivation of fast Na+ channels
R-HSA-9768777	Regulation of NPAS4 gene transcription

MSigDB gene sets: 145 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, RNGTGGGC_UNKNOWN, MYOGENIN_Q6, GCANCTGNY_MYOD_Q6, CAGCTG_AP4_Q5, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_MONOATOMIC_CATION_TRANSPORT, ACATTCC_MIR1_MIR206, IRF_Q6, DBP_Q6, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOBP_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, ISRE_01, GOBP_TRANSMEMBRANE_TRANSPORT

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), apoptotic process (GO:0006915), signal transduction (GO:0007165), regulation of signal transduction (GO:0009966), protein localization to plasma membrane (GO:0072659), regulation of potassium ion transmembrane transport (GO:1901379), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), monoatomic ion transmembrane transport (GO:0034220), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), potassium channel activity (GO:0005267), calcium ion binding (GO:0005509), potassium channel regulator activity (GO:0015459), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), cytoplasm (GO:0005737), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cardiac conduction	1
Regulation of NPAS4 gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cytoplasm	3
cellular anatomical structure	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
endomembrane system	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
protein localization to membrane	1
protein localization to cell periphery	1
regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of monoatomic cation transmembrane transport	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
cis-regulatory region sequence-specific DNA binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
metal ion binding	1
potassium channel activity	1
ion channel regulator activity	1

Protein interactions and networks

STRING

2677 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNIP3	KCNC1	P48547	987
KCNIP3	PSEN2	P49810	953
KCNIP3	KCND2	Q9NZV8	941
KCNIP3	KCND3	Q9UK17	927
KCNIP3	PSEN1	P49768	885
KCNIP3	CLN3	Q13286	850
KCNIP3	TEAD3	Q99594	773
KCNIP3	DPP10	Q8N608	718
KCNIP3	KCND1	Q9NSA2	677
KCNIP3	PDYN	P01213	658
KCNIP3	CAV3	P56539	655
KCNIP3	UHMK1	Q8TAS1	655
KCNIP3	HOOK1	Q9UJC3	597
KCNIP3	CSH1	P01243	589
KCNIP3	CACNA1C	Q13936	587

IntAct

93 interactions, top by confidence:

A	B	Type	Score
KCNIP3	CD177	psi-mi:“MI:0915”(physical association)	0.780
CD177	KCNIP3	psi-mi:“MI:0915”(physical association)	0.780
KCNIP3	IGF1R	psi-mi:“MI:0915”(physical association)	0.720
IGF1R	KCNIP3	psi-mi:“MI:0915”(physical association)	0.720
IL6ST	KCNIP3	psi-mi:“MI:0915”(physical association)	0.600
IL6ST	KCNIP3	psi-mi:“MI:0915”(physical association)	0.560
MAVS	KCNIP3	psi-mi:“MI:0915”(physical association)	0.560
	KCNIP3	psi-mi:“MI:0915”(physical association)	0.560
KCNIP3	IL6ST	psi-mi:“MI:0915”(physical association)	0.560
KCNIP3	MAVS	psi-mi:“MI:0915”(physical association)	0.560
KCNIP3		psi-mi:“MI:0915”(physical association)	0.560
CPR2	KCNIP3	psi-mi:“MI:0915”(physical association)	0.560
CPR5	KCNIP3	psi-mi:“MI:0915”(physical association)	0.560
KCNIP3	CPR2	psi-mi:“MI:0915”(physical association)	0.560
KCNIP3	CPR5	psi-mi:“MI:0915”(physical association)	0.560
KCNIP3	GOLGA7	psi-mi:“MI:0915”(physical association)	0.560
KCNIP3	C1QTNF2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (55): KCNIP3 (Two-hybrid), KCNIP3 (Two-hybrid), KCNIP3 (Two-hybrid), CD177 (Two-hybrid), MAVS (Two-hybrid), CD177 (Two-hybrid), CTBP1 (Affinity Capture-Western), CTBP2 (Affinity Capture-Western), CTBP2 (Two-hybrid), KCNIP3 (Two-hybrid), KCNIP3 (Two-hybrid), KCNIP3 (Two-hybrid), KCNIP3 (Affinity Capture-RNA), KCNIP3 (Two-hybrid), KIAA0907 (Two-hybrid)

ESM2 similar proteins: A0A8I6A2H6, A2A2Y4, F1LQY6, O43379, O94806, O95267, P0C0T1, Q13572, Q17QD9, Q2KI69, Q32L26, Q3LAC4, Q3U3T8, Q3UGM2, Q496Y0, Q5R803, Q5RHX6, Q69ZK0, Q6PHZ8, Q6PIL6, Q70Z35, Q86XE3, Q8BWW9, Q8BYN3, Q8CCA0, Q8HXL3, Q8HYN7, Q8K1Y2, Q8R426, Q8TCU6, Q8WN03, Q91ZP9, Q92564, Q96GE6, Q99MG9, Q9BUY7, Q9CTY5, Q9D3N2, Q9HAE3, Q9HBU6

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

1 interactions.

A	Effect	B	Mechanism
KCNIP3	“down-regulates quantity by repression”	PDYN	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2368 predictions. Top by Δscore:

Variant	Effect	Δscore
2:95297452:AG:A	donor_gain	1.0000
2:95297453:GG:G	donor_gain	1.0000
2:95297454:G:GG	donor_gain	1.0000
2:95366391:C:G	donor_gain	1.0000
2:95374292:CCA:C	acceptor_loss	1.0000
2:95374294:A:AG	acceptor_gain	1.0000
2:95374295:G:GA	acceptor_gain	1.0000
2:95374295:GA:G	acceptor_gain	1.0000
2:95374295:GAT:G	acceptor_gain	1.0000
2:95374295:GATA:G	acceptor_gain	1.0000
2:95374416:AGAAT:A	donor_gain	1.0000
2:95374417:GAAT:G	donor_gain	1.0000
2:95374417:GAATG:G	donor_gain	1.0000
2:95374418:AAT:A	donor_gain	1.0000
2:95374419:AT:A	donor_gain	1.0000
2:95374419:ATGTG:A	donor_loss	1.0000
2:95374420:TGTGA:T	donor_loss	1.0000
2:95374421:G:C	donor_loss	1.0000
2:95374421:G:GG	donor_gain	1.0000
2:95374422:T:TG	donor_loss	1.0000
2:95374423:G:GG	donor_loss	1.0000
2:95374424:AGTGT:A	donor_loss	1.0000
2:95375133:CCCAG:C	acceptor_loss	1.0000
2:95375134:CCAG:C	acceptor_loss	1.0000
2:95375135:CAGA:C	acceptor_loss	1.0000
2:95375136:A:T	acceptor_loss	1.0000
2:95375205:TGAGG:T	donor_loss	1.0000
2:95375209:G:GA	donor_loss	1.0000
2:95375210:T:A	donor_loss	1.0000
2:95381683:G:GT	donor_gain	1.0000

AlphaMissense

1721 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:95374377:T:C	F88S	0.999
2:95374392:T:C	L93P	0.999
2:95374403:T:G	Y97D	0.999
2:95374412:T:C	F100L	0.999
2:95374413:T:C	F100S	0.999
2:95374414:T:A	F100L	0.999
2:95374414:T:G	F100L	0.999
2:95374417:G:C	K101N	0.999
2:95374417:G:T	K101N	0.999
2:95375164:T:C	F135L	0.999
2:95375166:C:A	F135L	0.999
2:95375166:C:G	F135L	0.999
2:95381648:T:C	L167P	0.999
2:95381659:T:C	F171L	0.999
2:95381661:T:A	F171L	0.999
2:95381661:T:G	F171L	0.999
2:95381666:T:C	L173P	0.999
2:95381693:T:A	I182N	0.999
2:95383275:T:C	F235S	0.999
2:95374376:T:C	F88L	0.998
2:95374378:C:A	F88L	0.998
2:95374378:C:G	F88L	0.998
2:95374401:T:C	L96P	0.998
2:95375203:T:C	F148L	0.998
2:95375205:T:A	F148L	0.998
2:95375205:T:G	F148L	0.998
2:95381612:T:C	L155P	0.998
2:95381614:T:C	S156P	0.998
2:95381653:T:A	W169R	0.998
2:95381653:T:C	W169R	0.998

dbSNP variants (sampled 300 via entrez): RS1000030898 (2:95331961 T>G), RS1000043347 (2:95346492 G>A), RS1000188822 (2:95382782 G>A,C), RS1000194621 (2:95305384 G>T), RS1000200346 (2:95340957 T>C), RS1000243513 (2:95351855 G>T), RS1000256290 (2:95299129 A>G), RS1000309551 (2:95334256 G>A,T), RS1000337935 (2:95376532 G>A), RS1000417532 (2:95370218 C>T), RS1000471731 (2:95370641 T>C), RS1000561715 (2:95324705 G>A), RS1000613934 (2:95324780 G>A), RS1000667654 (2:95319636 A>G), RS1000670288 (2:95376187 G>A)

Disease associations

OMIM: gene MIM:604662 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Mondo (2): primary ovarian failure (MONDO:0005387), autism (MONDO:0005260)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

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

HPO	Term
HP:0000717	Autism

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009325_35	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Arsenic	increases expression, increases abundance	3
Resveratrol	increases ubiquitination, affects reaction, affects cotreatment, decreases expression, decreases reaction (+2 more)	2
Benzo(a)pyrene	affects methylation	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	increases expression	1
sodium arsenate	increases expression, increases abundance	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
pentanal	increases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases response to substance, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
N-butyrylglucosamine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Lead	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism