KIDINS220

Summary

KIDINS220 (kinase D interacting substrate 220, HGNC:29508) is a protein-coding gene on chromosome 2p25.1, encoding Kinase D-interacting substrate of 220 kDa (Q9ULH0). Promotes a prolonged MAP-kinase signaling by neurotrophins through activation of a Rap1-dependent mechanism.

This gene encodes a transmembrane protein that is preferentially expressed in the nervous system where it controls neuronal cell survival, differentiation into exons and dendrites, and synaptic plasticity. The encoded protein interacts with membrane receptors, cytosolic signaling components, and cytoskeletal proteins, serving as a scaffold that mediates crosstalk between the neurotrophin pathway and several other intracellular signaling pathways. Aberrant expression of this gene is associated with the onset of various neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer’s disease. Naturally occurring mutations in this gene are associated with a syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 57498 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ventriculomegaly and arthrogryposis (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 1,173 total — 26 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 50
• MANE Select transcript: NM_020738

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29508
Approved symbol	KIDINS220
Name	kinase D interacting substrate 220
Location	2p25.1
Locus type	gene with protein product
Status	Approved
Aliases	ARMS
Ensembl gene	ENSG00000134313
Ensembl biotype	protein_coding
OMIM	615759
Entrez	57498

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 24 protein_coding, 17 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000256707, ENST00000319688, ENST00000459813, ENST00000471275, ENST00000471685, ENST00000473731, ENST00000474782, ENST00000488729, ENST00000489024, ENST00000496383, ENST00000496725, ENST00000569008, ENST00000638224, ENST00000685083, ENST00000685097, ENST00000685274, ENST00000686179, ENST00000686383, ENST00000686906, ENST00000687240, ENST00000687526, ENST00000687894, ENST00000687912, ENST00000689114, ENST00000689369, ENST00000689531, ENST00000689852, ENST00000690467, ENST00000690607, ENST00000691030, ENST00000691349, ENST00000692419, ENST00000692889, ENST00000693249, ENST00000693366, ENST00000693394, ENST00000693432, ENST00000693597, ENST00000882909, ENST00000882910, ENST00000933256, ENST00000933257, ENST00000959946, ENST00000959947, ENST00000959948, ENST00000959949

RefSeq mRNA: 14 — MANE Select: NM_020738 NM_001348729, NM_001348731, NM_001348732, NM_001348734, NM_001348735, NM_001348736, NM_001348738, NM_001348739, NM_001348740, NM_001348741, NM_001348742, NM_001348743, NM_001348745, NM_020738

CCDS: CCDS42650, CCDS86818, CCDS86819, CCDS92711, CCDS92712

Canonical transcript exons

ENST00000256707 — 30 exons

Exon	Start	End
ENSE00000962126	8747887	8748000
ENSE00001147800	8728858	8731982
ENSE00001279654	8747145	8747201
ENSE00003472036	8778639	8778727
ENSE00003473798	8802930	8803127
ENSE00003476032	8785741	8786030
ENSE00003479584	8776748	8776892
ENSE00003483485	8812395	8812493
ENSE00003488417	8798202	8798300
ENSE00003496153	8786206	8786357
ENSE00003526290	8817618	8817716
ENSE00003526513	8778896	8779139
ENSE00003530428	8813237	8813335
ENSE00003535339	8779674	8779814
ENSE00003536308	8806271	8806369
ENSE00003542018	8800400	8800498
ENSE00003554854	8751466	8751644
ENSE00003565028	8750112	8750335
ENSE00003565460	8734655	8734753
ENSE00003567986	8826986	8827129
ENSE00003577409	8770670	8770832
ENSE00003589327	8791060	8791224
ENSE00003591269	8789880	8790059
ENSE00003602375	8736868	8736999
ENSE00003630557	8733444	8733680
ENSE00003673751	8796771	8796869
ENSE00003674863	8818695	8818793
ENSE00003676364	8793810	8793987
ENSE00003688155	8788647	8788812
ENSE00003903193	8837480	8837613

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.0780 / max 832.5096, expressed in 1782 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26801	20.8718	1779
26800	0.1501	57
26798	0.0562	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle frontal gyrus	UBERON:0002702	99.48	gold quality
cortical plate	UBERON:0005343	99.37	gold quality
paraflocculus	UBERON:0005351	99.32	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.08	gold quality
frontal pole	UBERON:0002795	98.93	gold quality
endothelial cell	CL:0000115	98.24	gold quality
corpus callosum	UBERON:0002336	98.14	gold quality
ganglionic eminence	UBERON:0004023	97.87	gold quality
calcaneal tendon	UBERON:0003701	97.85	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.92	gold quality
visceral pleura	UBERON:0002401	96.54	gold quality
choroid plexus epithelium	UBERON:0003911	96.51	gold quality
parietal pleura	UBERON:0002400	96.38	gold quality
germinal epithelium of ovary	UBERON:0001304	96.33	gold quality
pleura	UBERON:0000977	96.31	gold quality
tibia	UBERON:0000979	96.20	gold quality
adrenal tissue	UBERON:0018303	96.01	gold quality
orbitofrontal cortex	UBERON:0004167	95.94	gold quality
embryo	UBERON:0000922	95.73	gold quality
middle temporal gyrus	UBERON:0002771	95.73	gold quality
postcentral gyrus	UBERON:0002581	95.71	gold quality
blood vessel layer	UBERON:0004797	95.67	gold quality
superior frontal gyrus	UBERON:0002661	95.65	gold quality
subthalamic nucleus	UBERON:0001906	95.40	gold quality
entorhinal cortex	UBERON:0002728	95.40	gold quality
parietal lobe	UBERON:0001872	95.35	gold quality
inferior vagus X ganglion	UBERON:0005363	95.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.31	gold quality
superior vestibular nucleus	UBERON:0007227	95.31	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.28	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1432.45
E-HCAD-5	yes	45.15
E-CURD-114	yes	7.01
E-GEOD-93593	no	14.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1

miRNA regulators (miRDB)

94 targeting KIDINS220, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-9902	99.89	69.15	2250

Literature-anchored findings (GeneRIF, showing 28)

• endogenous PKD1, PKD2, and Kidins220 co-exist with neurotensin-containing vesicles (PMID:18048355)
• Down-regulation of ARMS results in inhibition of anchorage-independent growth in soft agar and restrictive growth of melanoma in severe combined immunodeficient mice (PMID:18089783)
• Ankyrin-rich membrane spanning protein is a major factor that links neurotrophin signaling to nuclear factor-kappa B. (PMID:18501627)
• sigma-1R overexpression drives sigma agonist-independent dissociation of ANK 220 from IP3R-3, resulting in activation (PMID:18539593)
• Ankyrin repeat-rich membrane spanning expression, conjunctly with tumour thickness or ulceration, may serve as a prognostic factor in patients with cutaneous melanoma. (PMID:21343931)
• induction of morphological polarization in primary T lymphocytes and Jurkat cells enhances Kidins220/ARMS colocalization with ICAM-3 (PMID:21381019)
• Kidins220/ARMS is a functional mediator of multiple receptor signalling pathways. (PMID:22562556)
• a novel partner of Kidins220/ARMS (PMID:22609016)
• Kidins220 levels are increased in human brain necropsies from Alzheimer’s disease patients. Kidins220 localizes within hyperphosphorylated tau aggregates, and is a substrate for GSK3beta. (PMID:23118350)
• Kidins220 depletion is associated with the neural-to Schwann-like transition in neuroblastoma. (PMID:23333500)
• Kidins220 is a novel T-cell receptor (TCR)-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling and is crucial for TCR-mediated T cell activation. (PMID:23359496)
• Kidins220 is expressed in neuroblastoma tumors and stabilizes NGF-induced, but not BDNF-induced, survival signaling in neuroblastoma cell lines. (PMID:23999075)
• Our results establish the role of ARMS in microglial activation by HIV Tat (PMID:25636783)
• the existence of novel Kidins220/ARMS splice isoforms with unique properties (PMID:26083449)
• overexpression of ARMS blocked NGF-mediated secretion, without affecting basal secretion, a decrease in ARMS resulted in potentiation. Similar effects were observed with synembryn-B, a protein that interacts directly with ARMS. Downstream of ARMS and synembryn-B are Galphaq and Trio proteins, which modulate the activity of Rac1 in response to NGF (PMID:26966186)
• This work reveals a crucial physiological role of KIDINS220 in development and provides insight into how perturbation of the complex interplay of KIDINS220 isoforms and their relative expression can affect neuron control and human metabolism. Altogether, we here show that de novo protein-truncating KIDINS220 variants cause a new syndrome, SINO. This is the first report of KIDINS220 variants causing a human disease. (PMID:27005418)
• The Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. (PMID:27858709)
• Kidins220 has a prominent role in tumor development by participating in a complex signaling pathways. (Review) (PMID:28849114)
• Authors hence propose that the identified homozygous loss-of-function variant in KIDINS220 causes the phenotype in the presented fetuses, and that this represents a hitherto undescribed severe autosomal recessive neurodevelopmental disorder. (PMID:28934391)
• data indicate that ARMS/Kidins220 controls the regulated secretion of BDNF and might play a crucial role in the pathogenesis of Huntington’s disease (PMID:29769266)
• Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants. (PMID:31577543)
• Study reveals a non-classical hereditary spastic paraplegia (HSP), intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 nonsense mutation, which broadens both the clinical and genetic spectrum for autosomal dominant HSP. (PMID:31630374)
• Functional analysis of a novel fusion protein PAX5-KIDINS220 identified in a pediatric Ph-like ALL patient. (PMID:32656633)
• Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant. (PMID:32909676)
• TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly. (PMID:33205811)
• Reduced kinase Dinteracting substrate of 220 kDa (Kidins220) in pancreatic cancer promotes EGFR/ERK signalling and disease progression. (PMID:33955519)
• Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer. (PMID:35437317)
• Gain-of-Function KIDINS220 Variants Disrupt Neuronal Development and Cause Cerebral Palsy. (PMID:38148610)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kidins220b	ENSDARG00000017338
danio_rerio	kidins220a	ENSDARG00000031240
mus_musculus	Kidins220	ENSMUSG00000036333
rattus_norvegicus	Kidins220	ENSRNOG00000023176

Protein

Protein identifiers

Kinase D-interacting substrate of 220 kDa — Q9ULH0 (reviewed: Q9ULH0)

Alternative names: Ankyrin repeat-rich membrane-spanning protein

All UniProt accessions (16): A0A1W2PPB7, A0A1W2PPY4, A0A8I5KPM9, Q9ULH0, A0A8I5KQK7, A0A8I5KT58, A0A8I5KTG3, A0A8I5KTL1, A0A8I5KX08, A0A8I5KZ42, A0A8I5QJC0, A0A8I5QL22, E9PH70, F8WAY8, H0Y8E4, H7C584

UniProt curated annotations — full annotation on UniProt →

Function. Promotes a prolonged MAP-kinase signaling by neurotrophins through activation of a Rap1-dependent mechanism. Provides a docking site for the CRKL-C3G complex, resulting in Rap1-dependent sustained ERK activation. May play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EPHA4. In cooperation with SNTA1 can enhance EPHA4-induced JAK/STAT activation. Plays a role in nerve growth factor (NGF)-induced recruitment of RAPGEF2 to late endosomes and neurite outgrowth. May play a role in neurotrophin- and ephrin-mediated neuronal outgrowth and in axon guidance during neural development and in neuronal regeneration. Modulates stress-induced apoptosis of melanoma cells via regulation of the MEK/ERK signaling pathway.

Subunit / interactions. Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a nerve growth factor (NGF)-dependent manner. Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation. Isoform 2 interacts (via C-terminal domain) with MAGI2 isoform 1 (via PDZ domain). Interacts with NTRK1, NTRK2, NTRK3, ERKL and NGFR. Can form a ternary complex with NGFR and NTRK1 and this complex is affected by the expression levels of KIDINS220/ARMS. An increase in KIDINS220/ARMS expression leads to a decreased association of NGFR and NTRK1. Interacts (via PDZ-binding motif) with SNTA1 and SNTB2 (via PDZ domains). Interacts with EPHA4 and PRKD1.

Subcellular location. Membrane. Late endosome.

Tissue specificity. Abundant in developing and adult neural tissues as well as neuroendocrine cells and dendritic cells. Overexpressed in melanoma and melanoma cell lines.

Post-translational modifications. Tyrosine phosphorylated by NTRK1, NTRK2, EPHB2 and EPHA4. Phosphorylation at Ser-918 is induced by phorbol ester treatment. Phosphorylation by NTRK2 is induced by brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5. Phosphorylation by NTRK1 is induced by nerve growth factor (NGF).

Disease relevance. Spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) [MIM:617296] An autosomal dominant syndrome characterized by rapid growth in infancy, obesity, global developmental delay, intellectual disability, spastic paraplegia, ocular defects, and dysmorphic facial features. The disease is caused by variants affecting the gene represented in this entry. Ventriculomegaly and arthrogryposis (VENARG) [MIM:619501] An autosomal recessive disorder with fatal outcome, characterized by prenatal onset of severe features including limb contractures, arthrogryposis, and enlarged brain ventricles that may be associated with hydrocephalus, abnormalities of the corpus callosum, and cerebellar hypoplasia. Some affected fetuses may also have congenital heart disease and hydrops fetalis. Death occurs in utero. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The transmembrane domain mediates interaction with NTRK1.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9ULH0-1	1	yes
Q9ULH0-2	2
Q9ULH0-3	3
Q9ULH0-4	4
Q9ULH0-5	5

RefSeq proteins (14): NP_001335658, NP_001335660, NP_001335661, NP_001335663, NP_001335664, NP_001335665, NP_001335667, NP_001335668, NP_001335669, NP_001335670, NP_001335671, NP_001335672, NP_001335674, NP_065789* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR011646	KAP_P-loop	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR052771	Neurotrophin_sig_adaptor	Family
IPR057092	SAM_KIDINS220	Domain

Pfam: PF00023, PF07693, PF12796, PF23307

UniProt features (75 total): modified residue 20, repeat 12, compositionally biased region 9, region of interest 7, splice variant 7, sequence variant 6, topological domain 5, transmembrane region 4, sequence conflict 2, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9JXQ	ELECTRON MICROSCOPY	3.44

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULH0-F1	61.96	0.16

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 (20): 882, 885, 914, 918, 1163, 1296, 1352, 1359, 1361, 1362, 1365, 1521, 1526, 1555, 1574, 1623, 1633, 1679, 1681, 1684

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-170984	ARMS-mediated activation
R-HSA-9696270	RND2 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-169893	Prolonged ERK activation events
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-187687	Signalling to ERKs
R-HSA-194315	Signaling by Rho GTPases
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 270 (showing top): GCM_MAP4K4, chr2p25, GCM_GSPT1, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GCM_ZNF198, GOBP_NEUROGENESIS, GOBP_RESPONSE_TO_NERVE_GROWTH_FACTOR, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, SASSON_RESPONSE_TO_FORSKOLIN_DN, REACTOME_SIGNALLING_TO_ERKS, GCM_SUFU, SCHLOSSER_SERUM_RESPONSE_DN, GOBP_REGULATION_OF_NEURON_PROJECTION_DEVELOPMENT, GOBP_RESPONSE_TO_GROWTH_FACTOR, GCM_CALM1

GO Biological Process (6): in utero embryonic development (GO:0001701), positive regulation of neuron projection development (GO:0010976), nerve growth factor signaling pathway (GO:0038180), dendrite morphogenesis (GO:0048813), cellular response to nerve growth factor stimulus (GO:1990090), nervous system development (GO:0007399)

GO Molecular Function (3): protein kinase regulator activity (GO:0019887), PDZ domain binding (GO:0030165), protein binding (GO:0005515)

GO Cellular Component (5): late endosome (GO:0005770), cytosol (GO:0005829), membrane (GO:0016020), protein-containing complex (GO:0032991), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
RHO GTPase cycle	2
Signal Transduction	2
Prolonged ERK activation events	1
Signaling by Receptor Tyrosine Kinases	1
Signalling to ERKs	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
chordate embryonic development	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
neurotrophin signaling pathway	1
cellular response to nerve growth factor stimulus	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
cellular response to growth factor stimulus	1
response to nerve growth factor	1
system development	1
protein kinase activity	1
kinase regulator activity	1
protein kinase binding	1
protein domain specific binding	1
binding	1
endosome	1
cytoplasm	1
cellular_component	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

1528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KIDINS220	NTRK1	P04629	817
KIDINS220	PRKD3	O94806	706
KIDINS220	PRKD1	Q15139	678
KIDINS220	NTRK2	Q16620	605
KIDINS220	PRKD2	Q9BZL6	575
KIDINS220	OLFM1	Q99784	538
KIDINS220	PDZRN3	Q9UPQ7	532
KIDINS220	RAPGEF1	Q13905	517
KIDINS220	KLC1	Q07866	456
KIDINS220	BDNF	P23560	452
KIDINS220	SNX27	Q96L92	446
KIDINS220	ECPAS	Q5VYK3	430
KIDINS220	CREB1	P16220	428
KIDINS220	STEAP3	Q658P3	405
KIDINS220	FKBP15	Q5T1M5	404

IntAct

280 interactions, top by confidence:

A	B	Type	Score
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAGEE1	MCC	psi-mi:“MI:0914”(association)	0.670
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
KIDINS220	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.590
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
VSIG4	TCAF2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
EVA1C	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
PBXIP1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
IL27RA	B4GALT5	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
CLMP	UTP20	psi-mi:“MI:0914”(association)	0.530
DLK1	SCAMP3	psi-mi:“MI:0914”(association)	0.530
XPR1	MYORG	psi-mi:“MI:0914”(association)	0.530
DGCR2	HOXD13	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
EVA1C	STK25	psi-mi:“MI:0914”(association)	0.530
KLC1	KIF5C	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480

BioGRID (276): KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Proximity Label-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS), KIDINS220 (Affinity Capture-MS)

ESM2 similar proteins: A0A084AFG7, A0A084B9Z8, A0A0U1LQE1, A0A142C7A1, A0A1B1JE71, A0A1B4XBK1, A0A1B5L8S2, A0A1U8QH20, A0A1U8QHS4, A0A1U9YHZ6, A0A2J6RX17, A0A3G1DJE9, A0A481WNM8, A0A4P8WAD3, A0A5C1RDA3, A0A7T8F1J6, A0A823A1C6, A2QX45, A2R345, A4RKC3, B0Y8Y5, B2ACC7, B9DHT4, G0LET6, I1R9A9, I1R9B3, I1S489, M2XHU6, P0C5H7, P0CI62, P9WEL8, Q03689, Q0CS62, Q0D1P0, Q0UL22, Q2M3Z7, Q2M3Z8, Q2UNX5, Q2VF18, Q4WAZ4

Diamond homologs: Q7T163, Q9EQG6, Q9ULH0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKD1	unknown	KIDINS220	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 251 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
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	17.7×	7e-04
SHC1 events in ERBB2 signaling	5	14.8×	1e-03
Signaling by ERBB2 TMD/JMD mutants	5	14.8×	1e-03
Signaling by ERBB2 KD Mutants	5	13.1×	1e-03
Downstream signal transduction	5	11.8×	2e-03
Formation of the dystrophin-glycoprotein complex (DGC)	6	11.5×	9e-04
NCAM signaling for neurite out-growth	6	10.1×	1e-03
Negative regulation of MAPK pathway	6	9.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
receptor clustering	5	14.1×	7e-03
peptidyl-tyrosine phosphorylation	7	13.3×	7e-04
cell surface receptor protein tyrosine kinase signaling pathway	10	7.8×	7e-04
axonogenesis	9	6.5×	6e-03
transmembrane transport	8	6.1×	9e-03
protein autophosphorylation	9	5.9×	7e-03
positive regulation of neuron projection development	9	5.5×	8e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	12	4.2×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1173 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	26
Uncertain significance	612
Likely benign	371
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1217311	NM_020738.4(KIDINS220):c.4389_4390del (p.Val1465fs)	Pathogenic
1217312	NM_020738.4(KIDINS220):c.3394_3403del (p.Gln1132fs)	Pathogenic
1217313	NM_020738.4(KIDINS220):c.208del	Pathogenic
1217314	NM_020738.4(KIDINS220):c.2137_2145del (p.Gln713_Leu715del)	Pathogenic
1323147	NM_020738.4(KIDINS220):c.4292_4293del (p.Leu1431fs)	Pathogenic
1685907	NM_020738.4(KIDINS220):c.3415-4A>G	Pathogenic
1804954	NM_020738.4(KIDINS220):c.3395dup (p.His1133fs)	Pathogenic
1895452	NM_020738.4(KIDINS220):c.4412delinsAAG (p.Ser1471Ter)	Pathogenic
2106447	NM_020738.4(KIDINS220):c.2374C>T (p.Arg792Ter)	Pathogenic
2161861	NM_020738.4(KIDINS220):c.1960del (p.Thr654fs)	Pathogenic
2444156	NM_020738.4(KIDINS220):c.3504dup (p.Pro1169fs)	Pathogenic
2579573	NM_020738.4(KIDINS220):c.1263_1264del (p.Gln421fs)	Pathogenic
3027103	NM_020738.4(KIDINS220):c.3874dup (p.Ser1292fs)	Pathogenic
3365203	NM_020738.4(KIDINS220):c.3934G>T (p.Glu1312Ter)	Pathogenic
3602731	NM_020738.4(KIDINS220):c.3991delinsAGCCCTACACACTCAAC (p.Glu1331fs)	Pathogenic
3658634	NM_020738.4(KIDINS220):c.3949G>T (p.Glu1317Ter)	Pathogenic
374908	NM_020738.4(KIDINS220):c.4050G>A (p.Trp1350Ter)	Pathogenic
374909	NM_020738.4(KIDINS220):c.4096C>T (p.Gln1366Ter)	Pathogenic
374910	NM_020738.4(KIDINS220):c.4520dup (p.Leu1507fs)	Pathogenic
3769798	NM_020738.4(KIDINS220):c.4388C>G (p.Ser1463Ter)	Pathogenic
3893243	NM_020738.4(KIDINS220):c.4177C>T (p.Gln1393Ter)	Pathogenic
4075008	NM_020738.4(KIDINS220):c.4499C>G (p.Ser1500Ter)	Pathogenic
4685503	NM_020738.4(KIDINS220):c.535C>T (p.Arg179Ter)	Pathogenic
4724605	NM_020738.4(KIDINS220):c.3726_3733del (p.Ile1242fs)	Pathogenic
817924	NM_020738.4(KIDINS220):c.4276del (p.Ser1426fs)	Pathogenic
987490	NM_020738.4(KIDINS220):c.3994G>T (p.Glu1332Ter)	Pathogenic
1172823	NM_020738.4(KIDINS220):c.4497del (p.Arg1499fs)	Likely pathogenic
1324621	NM_020738.4(KIDINS220):c.3436_3443dup (p.Arg1149fs)	Likely pathogenic
1526161	NM_020738.4(KIDINS220):c.4388C>A (p.Ser1463Ter)	Likely pathogenic
1711490	NM_020738.4(KIDINS220):c.4040del (p.Asn1347fs)	Likely pathogenic

SpliceAI

5424 predictions. Top by Δscore:

Variant	Effect	Δscore
2:8731978:TGTGA:T	acceptor_gain	1.0000
2:8731979:GTGA:G	acceptor_gain	1.0000
2:8731983:C:CC	acceptor_gain	1.0000
2:8733445:TGCCA:T	donor_gain	1.0000
2:8733454:A:AC	donor_gain	1.0000
2:8733455:G:C	donor_gain	1.0000
2:8733456:A:AC	donor_gain	1.0000
2:8733459:A:AC	donor_gain	1.0000
2:8733460:C:CC	donor_gain	1.0000
2:8733678:TAC:T	acceptor_gain	1.0000
2:8733680:CC:C	acceptor_loss	1.0000
2:8733680:CCT:C	acceptor_gain	1.0000
2:8733681:C:T	acceptor_gain	1.0000
2:8733682:T:C	acceptor_gain	1.0000
2:8733686:C:CT	acceptor_gain	1.0000
2:8733687:A:T	acceptor_gain	1.0000
2:8734635:CAATG:C	donor_gain	1.0000
2:8734653:A:AC	donor_gain	1.0000
2:8734654:C:CT	donor_gain	1.0000
2:8734654:CTGTG:C	donor_gain	1.0000
2:8736862:CCTCA:C	donor_loss	1.0000
2:8736863:CTCA:C	donor_loss	1.0000
2:8736864:TCA:T	donor_loss	1.0000
2:8736865:CA:C	donor_loss	1.0000
2:8736866:A:AG	donor_loss	1.0000
2:8736995:GACCC:G	acceptor_gain	1.0000
2:8736996:ACCC:A	acceptor_gain	1.0000
2:8736997:CCC:C	acceptor_gain	1.0000
2:8736997:CCCC:C	acceptor_gain	1.0000
2:8736998:CC:C	acceptor_gain	1.0000

AlphaMissense

11645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:8734675:A:G	W1266R	1.000
2:8734675:A:T	W1266R	1.000
2:8734707:A:G	L1255P	1.000
2:8734731:A:G	L1247S	1.000
2:8734740:C:T	G1244D	1.000
2:8751483:A:G	L1058P	1.000
2:8751495:A:G	L1054P	1.000
2:8770740:A:G	W981R	1.000
2:8770740:A:T	W981R	1.000
2:8770758:A:G	W975R	1.000
2:8770758:A:T	W975R	1.000
2:8770779:A:G	W968R	1.000
2:8770779:A:T	W968R	1.000
2:8770787:A:G	L965P	1.000
2:8770797:A:G	W962R	1.000
2:8770797:A:T	W962R	1.000
2:8770823:A:G	L953P	1.000
2:8778997:A:T	V838D	1.000
2:8779021:C:T	G830D	1.000
2:8779022:C:G	G830R	1.000
2:8779090:T:C	D807G	1.000
2:8779092:A:C	S806R	1.000
2:8779092:A:T	S806R	1.000
2:8779094:T:G	S806R	1.000
2:8779681:A:G	L788P	1.000
2:8786355:A:G	F597S	1.000
2:8790043:G:C	F486L	1.000
2:8790043:G:T	F486L	1.000
2:8790045:A:G	F486L	1.000
2:8791065:A:G	L479P	1.000

dbSNP variants (sampled 300 via entrez): RS1000026437 (2:8727469 G>C), RS1000027468 (2:8836239 T>C), RS1000083297 (2:8804282 A>C,G), RS1000127593 (2:8813762 A>C), RS1000142438 (2:8739264 C>G,T), RS1000180071 (2:8721260 G>A), RS1000193818 (2:8767494 A>G), RS1000199135 (2:8797526 A>C,G), RS1000252642 (2:8794451 T>C), RS1000345040 (2:8759897 A>C), RS1000464923 (2:8814678 T>A,C,G), RS1000503786 (2:8819852 A>G), RS1000506126 (2:8725286 A>C,G), RS1000530750 (2:8800851 A>G), RS1000536906 (2:8752913 A>G,T)

Disease associations

OMIM: gene MIM:615759 | disease phenotypes: MIM:617296, MIM:619501, MIM:147920, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
ventriculomegaly and arthrogryposis	Definitive	Autosomal recessive
spastic paraplegia, intellectual disability, nystagmus, and obesity	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
spastic paraplegia, intellectual disability, nystagmus, and obesity	Moderate	AD
ventriculomegaly and arthrogryposis	Definitive	AR

Mondo (7): spastic paraplegia, intellectual disability, nystagmus, and obesity (MONDO:0015007), ventriculomegaly and arthrogryposis (MONDO:0859184), cerebral palsy (MONDO:0006497), Kabuki syndrome 1 (MONDO:0007843), intellectual disability (MONDO:0001071), hereditary spastic paraplegia (MONDO:0019064), obesity disorder (MONDO:0011122)

Orphanet (6): Spastic paraplegia-intellectual disability-nystagmus-obesity syndrome (Orphanet:521390), Kabuki syndrome (Orphanet:2322), Hereditary spastic paraplegia (Orphanet:685), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0000293	Full cheeks
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000639	Nystagmus
HP:0000678	Dental crowding
HP:0000750	Delayed speech and language development
HP:0001093	Optic nerve dysplasia
HP:0001188	Hand clenching
HP:0001249	Intellectual disability
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001321	Cerebellar hypoplasia
HP:0001338	Partial agenesis of the corpus callosum
HP:0001347	Hyperreflexia
HP:0001357	Plagiocephaly
HP:0001513	Obesity
HP:0001561	Polyhydramnios
HP:0001762	Talipes equinovarus
HP:0002007	Frontal bossing
HP:0002059	Cerebral atrophy
HP:0002064	Spastic gait

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001059_11	Neutrophil count	2.000000e-07
GCST004860_70	Alcoholic chronic pancreatitis	7.000000e-06
GCST008155_4	Waist-hip ratio	6.000000e-06
GCST009251_2	Skin aging measurement	6.000000e-09
GCST009996_1	HDL cholesterol levels	3.000000e-07
GCST012490_369	Femur bone mineral density x serum urate levels interaction	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0004343	waist-hip ratio
EFO:0007805	HDL cholesterol change measurement
EFO:0004531	urate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects methylation	2
trichostatin A	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Valproic Acid	affects expression, increases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
lead acetate	affects cotreatment, increases expression	1
sodium arsenate	increases expression	1
arsenite	affects binding, decreases reaction	1
zinc protoporphyrin	affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
coumarin	affects phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Caffeine	affects phosphorylation	1
Catechin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
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
NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	PHASE3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A
NCT03306212	PHASE3	COMPLETED	Efficacy of Intermittent Serial Casting on Spastic Wrist Flexion Deformity