CRMP1

Summary

CRMP1 (collapsin response mediator protein 1, HGNC:2365) is a protein-coding gene on chromosome 4p16.2, encoding Dihydropyrimidinase-related protein 1 (Q14194). Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton.

This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1400 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 132 total — 1 likely-pathogenic
• MANE Select transcript: NM_001014809

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2365
Approved symbol	CRMP1
Name	collapsin response mediator protein 1
Location	4p16.2
Locus type	gene with protein product
Status	Approved
Aliases	DRP-1, DPYSL1
Ensembl gene	ENSG00000072832
Ensembl biotype	protein_coding
OMIM	602462
Entrez	1400

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000324989, ENST00000397890, ENST00000506216, ENST00000511535, ENST00000512574, ENST00000513911

RefSeq mRNA: 4 — MANE Select: NM_001014809 NM_001014809, NM_001288661, NM_001288662, NM_001313

CCDS: CCDS33950, CCDS43207, CCDS75102

Canonical transcript exons

ENST00000324989 — 14 exons

Exon	Start	End
ENSE00001390904	5892589	5893086
ENSE00001897677	5820764	5821851
ENSE00003488608	5856143	5856307
ENSE00003524215	5839522	5839678
ENSE00003530357	5861026	5861210
ENSE00003550354	5866668	5866756
ENSE00003551397	5843093	5843161
ENSE00003560810	5835915	5836085
ENSE00003583009	5825494	5825659
ENSE00003604649	5849392	5849472
ENSE00003620230	5851408	5851469
ENSE00003641978	5836765	5836906
ENSE00003652920	5841308	5841428
ENSE00003680854	5828489	5828668

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 99.68.

FANTOM5 (CAGE): breadth broad, TPM avg 17.0058 / max 1596.1913, expressed in 512 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51222	12.4902	495
51227	1.9372	231
51226	1.2440	214
51223	0.3648	167
51225	0.2437	127
51220	0.2151	111
51221	0.1576	69
51224	0.1559	89
51228	0.0970	41
51229	0.0513	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.68	gold quality
ganglionic eminence	UBERON:0004023	99.50	gold quality
ventricular zone	UBERON:0003053	98.50	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.21	gold quality
embryo	UBERON:0000922	96.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.61	gold quality
middle temporal gyrus	UBERON:0002771	96.53	gold quality
cerebellar hemisphere	UBERON:0002245	96.47	gold quality
cerebellar cortex	UBERON:0002129	96.46	gold quality
prefrontal cortex	UBERON:0000451	96.36	gold quality
cerebellum	UBERON:0002037	96.26	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.26	gold quality
right frontal lobe	UBERON:0002810	96.25	gold quality
paraflocculus	UBERON:0005351	96.18	gold quality
adenohypophysis	UBERON:0002196	96.03	gold quality
frontal pole	UBERON:0002795	96.01	gold quality
frontal cortex	UBERON:0001870	95.93	gold quality
neocortex	UBERON:0001950	95.92	gold quality
pituitary gland	UBERON:0000007	95.87	gold quality
cingulate cortex	UBERON:0003027	95.76	gold quality
anterior cingulate cortex	UBERON:0009835	95.71	gold quality
cerebral cortex	UBERON:0000956	95.70	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.64	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.57	gold quality
amygdala	UBERON:0001876	95.54	gold quality
cerebellar vermis	UBERON:0004720	95.45	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.32	gold quality
orbitofrontal cortex	UBERON:0004167	95.30	gold quality
temporal lobe	UBERON:0001871	95.17	gold quality
nucleus accumbens	UBERON:0001882	95.03	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	53.69
E-CURD-114	yes	11.60
E-ANND-3	yes	5.72
E-HCAD-10	yes	5.28
E-GEOD-137537	yes	5.24
E-GEOD-93593	no	1772.83
E-MTAB-7303	no	1530.81
E-CURD-11	no	22.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, NFKB1, SP1

miRNA regulators (miRDB)

59 targeting CRMP1, 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-8485	100.00	77.57	4731
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-3202	99.66	67.70	2737

Literature-anchored findings (GeneRIF, showing 30)

• CRMP-1 and CRMP-2 have a role in RhoA-dependent signaling, through interaction with and regulation of ROKalpha (PMID:12482610)
• Collapsin response mediator protein-1: a novel invasion-suppressor gene. (PMID:12650609)
• CTGF inhibits metastasis and invasion of human lung adenocarcinoma by a CRMP-1-dependent mechanism. (PMID:14996858)
• CRMP1 and EVC genes are located near WFS1, the Wolfram syndrome type 1 gene. (PMID:15492864)
• The CRMP1 protein is characterizing as modulators of Wnt protein signaling of Axin-1. (PMID:16169070)
• GSK3 alters phosphorylation of CRMP-1, -2, and -4 isoforms (PMID:16611631)
• The collapsin response mediator protein 1 and the promyelocytic leukemia zinc finger protein interact with UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). (PMID:17118363)
• Transcription of the invasion suppressor, CRMP-1, is reciprocally regulated at the promoter region by C/EBPalpha and Sp1. (PMID:18524846)
• ChIP and EMSA demonstrated that p50 binds to a kappaB site residing between -1753 and -1743 of the CRMP-1 promoter region. (PMID:18782567)
• LCRMP-1 was a cancer invasion enhancer that could be a novel prognostic biomarker in non-small cell lung cancer. (PMID:19362386)
• loss of CRMP1 contribute to the increased invasive phenotype of human Glioblastoma multiforme brain tumors expressing mutant EGFRvIII. (PMID:19903856)
• Data demonstrate that CRMP1 tyrosine 504 is a primary target of the Src family of tyrosine kinases (SFKs), specifically Fyn. (PMID:20506281)
• LCRMP-1 and CRMP-1 have opposing functions in regulating cancer cell invasion and metastasis (PMID:21747164)
• in pilocarpine-induced animal model of epilepsy, CRMP-1 dynamically decreased in a range of 2 months. Thus, our results indicate that CRMP-1 may be involved in the development of TLE (PMID:22359051)
• GSK3beta-dependent phosphorylation of LCRMP-1 provides an important mechanism for regulation of LCRMP-1 on cancer cell invasiveness and clinical outcome. (PMID:22363707)
• CRMP1 is a novel candidate protein for schizophrenia traits (PMID:22798627)
• Aberrant upregulation of CRMP-1 expression may link to the mechanism of developing early-onset preeclampsia. (PMID:25194153)
• CRMP1 interacted with Spy1 which would disturb the association of CRMP1 with actin and was involved in the collapse of growth cones induced by Sema3A and regeneration after sciatic nerve crush. (PMID:25526860)
• CRMP1 targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly. (PMID:25908449)
• Results show that expression of CRMP1 is downregulated in medulloblastoma (MB) tumors. its overexpression inhibits proliferation, migration and invasion of cells suggesting that CRMP1 is implicated in MB pathogenesis. (PMID:26009886)
• The mitochondrial fragmentation protein DRP1 play a role in the development of malignant melanoma. (PMID:26032958)
• Human CRMP-1 comprises a tetrameric assembly. (PMID:26249678)
• These results demonstrate an important role for CRMP-1 in Listeria actin comet tail formation and open the possibility that CRMP-1 controls cell motility by modulating Arp2/3 activation. (PMID:26598519)
• Study shows that CRMP1 acts an EMT and metastasis suppressor in prostate cancer cells via its regulation of actin polymerization. (PMID:27321179)
• The present study reports that miR-187 was significantly overexpressed in gastric cancer tissues compared to that in non-tumor tissues and was associated with malignant clinical factors such as depth of invasion (P = 0.005), tumor size (P = 0.024), lymph node metastasis . It was found that collapsin response mediator protein 1 (CRMP1), a tumor suppressor, was a direct downstream target of miR-187. (PMID:27864146)
• miR200a-3p promotes the proliferation of human esophageal cancer cells by post-transcriptionally regulating CRMP1. (PMID:28025999)
• Identify CRMP-1 as a novel regulator of actin filament elongation and reveal a surprisingly important role for CRMP-1, EVL, and actin polymerization in maintaining the structural integrity of epithelial sheets. (PMID:28630144)
• Study provides a novel insight into the relevance of collapsin response mediator protein 1, a key molecule in semaphorin-3A signaling during neurodevelopment, in the molecular mechanism of action of lithium, and in the pathophysiology of bipolar disorder. (PMID:29666369)
• CRMP-1 might have implications for the pathogenesis of preeclampsia by regulating the biological behavior of trophoblast cells. (PMID:30466368)
• Monoallelic CRMP1 gene variants cause neurodevelopmental disorder. (PMID:36511780)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	crmp1	ENSDARG00000056742
mus_musculus	Crmp1	ENSMUSG00000029121
rattus_norvegicus	Crmp1	ENSRNOG00000004781

Paralogs (5): DPYSL2 (ENSG00000092964), DPYSL3 (ENSG00000113657), DPYS (ENSG00000147647), DPYSL4 (ENSG00000151640), DPYSL5 (ENSG00000157851)

Protein

Protein identifiers

Dihydropyrimidinase-related protein 1 — Q14194 (reviewed: Q14194)

Alternative names: Collapsin response mediator protein 1, Inactive dihydropyrimidinase, Unc-33-like phosphoprotein 3

All UniProt accessions (3): Q14194, E9PD68, X5DNI1

UniProt curated annotations — full annotation on UniProt →

Function. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance. During the axon guidance process, acts downstream of SEMA3A to promote FLNA dissociation from F-actin which results in the rearrangement of the actin cytoskeleton and the collapse of the growth cone. Involved in invasive growth and cell migration. May participate in cytokinesis.

Subunit / interactions. Homotetramer, and heterotetramer with DPYSL2, DPYSL3, DPYSL4 or DPYSL5. Interacts with PLXNA1. Interacts with FLNA (via calponin-homology (CH) domain 1 and filamin repeat 24); the interaction alters FLNA ternary structure and thus promotes FLNA dissociation from F-actin.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle. Cell projection. Growth cone. Perikaryon.

Tissue specificity. Brain.

Post-translational modifications. Phosphorylation at Ser-522 enhances CRMP1-mediated alteration of FLNA ternary structure and FLNA dissociation from F-actin.

Similarity. Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14194-1	1	yes
Q14194-2	LCRMP-1

RefSeq proteins (4): NP_001014809, NP_001275590, NP_001275591, NP_001304 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006680	Amidohydro-rel	Domain
IPR011059	Metal-dep_hydrolase_composite	Homologous_superfamily
IPR011778	Hydantoinase/dihydroPyrase	Family
IPR032466	Metal_Hydrolase	Homologous_superfamily
IPR050378	Metallo-dep_Hydrolases_sf	Family

Pfam: PF01979

UniProt features (62 total): helix 19, strand 16, modified residue 11, turn 6, sequence conflict 2, compositionally biased region 2, chain 1, region of interest 1, splice variant 1, sequence variant 1, mutagenesis site 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4B3Z	X-RAY DIFFRACTION	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14194-F1	90.46	0.83

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 (11): 509, 521, 522, 537, 540, 542, 8, 101, 102, 316, 504

Mutagenesis-validated functional residues (1):

Position	Phenotype
101–102	2.5-fold increase in cells with a defect of cytokinesis.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-399956	CRMPs in Sema3A signaling

MSigDB gene sets: 239 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, BENPORATH_ES_WITH_H3K27ME3, GGTGTGT_MIR329, GOBP_SYNAPSE_ASSEMBLY, LFA1_Q6, AREB6_03, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, USF_C, GOBP_PYRIMIDINE_NUCLEOBASE_METABOLIC_PROCESS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOLDRATH_ANTIGEN_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (5): nucleobase-containing compound metabolic process (GO:0006139), nervous system development (GO:0007399), negative regulation of neuron projection development (GO:0010977), semaphorin-plexin signaling pathway (GO:0071526), regulation of postsynapse assembly (GO:0150052)

GO Molecular Function (7): hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides (GO:0016812), filamin binding (GO:0031005), identical protein binding (GO:0042802), phosphoprotein binding (GO:0051219), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds (GO:0016810)

GO Cellular Component (14): centrosome (GO:0005813), spindle (GO:0005819), cytosol (GO:0005829), actin cytoskeleton (GO:0015629), dendrite (GO:0030425), growth cone (GO:0030426), midbody (GO:0030496), perikaryon (GO:0043204), presynapse (GO:0098793), postsynapse (GO:0098794), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Semaphorin interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
protein binding	2
intracellular membraneless organelle	2
synapse	2
primary metabolic process	1
system development	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
cell surface receptor signaling pathway	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
cytoskeletal protein binding	1
binding	1
catalytic activity	1
hydrolase activity	1
centriole	1
microtubule organizing center	1
microtubule cytoskeleton	1
cytoplasm	1
cytoskeleton	1
neuron projection	1
dendritic tree	1
site of polarized growth	1
distal axon	1
neuronal cell body	1
intracellular anatomical structure	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

1908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRMP1	GNE	Q9Y223	898
CRMP1	EVC2	Q86UK5	736
CRMP1	STIP1	P31948	724
CRMP1	NSG1	P42857	717
CRMP1	GDA	Q9Y2T3	714
CRMP1	SCN9A	Q15858	706
CRMP1	STX18	Q9P2W9	689
CRMP1	SEMA3A	Q14563	683
CRMP1	STK32B	Q9NY57	616
CRMP1	PLXNA1	Q9UIW2	597
CRMP1	NRP1	O14786	518
CRMP1	CDK5	Q00535	518
CRMP1	WASF1	Q92558	517
CRMP1	YBX1	P16990	509
CRMP1	GABRB3	P28472	506

IntAct

175 interactions, top by confidence:

A	B	Type	Score
RACGAP1	KIF23	psi-mi:“MI:0914”(association)	0.920
CRMP1	DPYSL2	psi-mi:“MI:0915”(physical association)	0.740
CRMP1	DPYSL3	psi-mi:“MI:0915”(physical association)	0.720
AP3M1	CRMP1	psi-mi:“MI:0915”(physical association)	0.720
CRMP1	AP3M1	psi-mi:“MI:0915”(physical association)	0.720
HTT	CRMP1	psi-mi:“MI:0915”(physical association)	0.700
CRMP1	HTT	psi-mi:“MI:0915”(physical association)	0.700
DPYSL3	DPYSL4	psi-mi:“MI:0914”(association)	0.640

BioGRID (175): CRMP1 (Two-hybrid), DPYSL3 (Two-hybrid), AP3M1 (Two-hybrid), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0F7GG06, A0A1I9LN01, B9FDB8, D4B2N2, D4DEJ7, F4JXC5, M1VV65, O08553, O13022, O14057, O14124, O14531, O35098, O50039, O81220, P14671, P32375, P34480, P47942, P97427, Q07729, Q0JJD1, Q10LR9, Q14117, Q14194, Q14195, Q2QMN7, Q2UPB0, Q52PJ5, Q5RAV9, Q62188, Q62950, Q62951, Q62952, Q63150, Q640K6, Q6GL72, Q6Q886, Q94AP0, Q9BPU6

Diamond homologs: A1AF64, A7ZQY1, A7ZXG5, A8A415, B1ITC8, B1IZ89, B1XEG2, B6I0G2, B6I707, B7L7D8, B7LF59, B7LYD8, B7M4L5, B7MM60, B7MZ27, B7N7B8, B7N966, B7NW14, B7UHS3, C5A0E6, O02675, O08553, O13022, O14531, O35098, O69809, P47942, P81006, P97427, Q02C42, Q0TDX8, Q14117, Q14194, Q14195, Q16555, Q18677, Q1AS71, Q1J391, Q1R7F8, Q21773

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CDK5	up-regulates	CRMP1	phosphorylation
GSK3B	up-regulates	CRMP1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	108
Likely benign	6
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3338039	NM_001014809.3(CRMP1):c.1755del (p.Lys586fs)	Likely pathogenic

SpliceAI

5490 predictions. Top by Δscore:

Variant	Effect	Δscore
4:5748145:C:G	acceptor_gain	1.0000
4:5748145:CAGA:C	acceptor_loss	1.0000
4:5748146:A:AG	acceptor_gain	1.0000
4:5748146:AG:A	acceptor_loss	1.0000
4:5748147:G:GG	acceptor_gain	1.0000
4:5748251:A:T	donor_gain	1.0000
4:5752832:GCA:G	acceptor_loss	1.0000
4:5752834:A:AG	acceptor_gain	1.0000
4:5752834:AG:A	acceptor_gain	1.0000
4:5752834:AGGAC:A	acceptor_gain	1.0000
4:5752835:G:GA	acceptor_gain	1.0000
4:5752835:GG:G	acceptor_gain	1.0000
4:5752835:GGA:G	acceptor_gain	1.0000
4:5752835:GGAC:G	acceptor_gain	1.0000
4:5752835:GGACG:G	acceptor_gain	1.0000
4:5753031:G:GT	donor_gain	1.0000
4:5753050:GGG:G	donor_gain	1.0000
4:5753051:GG:G	donor_gain	1.0000
4:5753051:GGG:G	donor_gain	1.0000
4:5753052:GG:G	donor_gain	1.0000
4:5753052:GGTG:G	donor_loss	1.0000
4:5753053:G:GG	donor_gain	1.0000
4:5753053:GTGA:G	donor_loss	1.0000
4:5753777:A:AG	acceptor_gain	1.0000
4:5753784:GA:G	acceptor_gain	1.0000
4:5756259:CACA:C	acceptor_loss	1.0000
4:5756261:CAGG:C	acceptor_loss	1.0000
4:5774999:GAGCC:G	donor_gain	1.0000
4:5783760:AGCAG:A	donor_loss	1.0000
4:5783761:GCAG:G	donor_gain	1.0000

AlphaMissense

4492 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:5825504:G:C	F539L	0.999
4:5825504:G:T	F539L	0.999
4:5825506:A:G	F539L	0.999
4:5835962:A:G	W412R	0.999
4:5835962:A:T	W412R	0.999
4:5836001:C:G	G399R	0.999
4:5836001:C:T	G399R	0.999
4:5836002:T:A	K398N	0.999
4:5836002:T:G	K398N	0.999
4:5836041:G:C	S385R	0.999
4:5836041:G:T	S385R	0.999
4:5836043:T:G	S385R	0.999
4:5836054:A:T	V381D	0.999
4:5836882:G:C	S331R	0.999
4:5836882:G:T	S331R	0.999
4:5836884:T:G	S331R	0.999
4:5841406:C:G	R238P	0.999
4:5821791:C:T	G563D	0.998
4:5825505:A:C	F539C	0.998
4:5825505:A:G	F539S	0.998
4:5836000:C:T	G399E	0.998
4:5836001:C:A	G399W	0.998
4:5836030:G:T	A389D	0.998
4:5861041:C:A	G100W	0.998
4:5861052:G:T	A96E	0.998
4:5861145:A:T	V65D	0.998
4:5825511:G:A	S537F	0.997
4:5825525:T:A	R532S	0.997
4:5825525:T:G	R532S	0.997
4:5828613:A:T	V446D	0.997

dbSNP variants (sampled 300 via entrez): RS1000009226 (4:5882290 T>C), RS10000356 (4:5885083 G>A), RS1000110327 (4:5828221 G>T), RS1000148603 (4:5825136 G>T), RS1000158533 (4:5887060 C>A,T), RS10001745 (4:5893806 T>A,C), RS1000176136 (4:5837607 G>A), RS1000192743 (4:5829551 G>A), RS1000204643 (4:5842162 C>A,T), RS1000276312 (4:5820701 C>T), RS1000288564 (4:5833160 T>A,C), RS1000302954 (4:5847589 A>G), RS1000356616 (4:5838163 A>G), RS1000384102 (4:5887410 C>A,T), RS1000404858 (4:5865955 C>T)

Disease associations

OMIM: gene MIM:602462 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002040_6	Blood trace element (Zn levels)	3.000000e-06
GCST009391_390	Metabolite levels	6.000000e-06
GCST009391_871	Metabolite levels	4.000000e-06
GCST010699_16	Brain morphology (min-P)	3.000000e-10
GCST010701_68	Cortical surface area (MOSTest)	2.000000e-09
GCST010702_71	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_28	Brain morphology (MOSTest)	6.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010437	triacylglycerol 58:10 measurement
EFO:0010535	sucrose measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
bisphenol A	decreases expression, decreases methylation, affects cotreatment, increases methylation	2
sodium arsenite	affects methylation, decreases expression	2
aristolochic acid I	increases expression	1
terbufos	increases methylation	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	decreases phosphorylation	1
LDN 193189	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Fonofos	increases methylation	1
Estradiol	decreases phosphorylation	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Parathion	increases methylation	1
Selenomethionine	affects expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice