SEMA5A

Summary

SEMA5A (semaphorin 5A, HGNC:10736) is a protein-coding gene on chromosome 5p15.31, encoding Semaphorin-5A (Q13591). Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate proteoglycans (CSPGs).

This gene belongs to the semaphorin gene family that encodes membrane proteins containing a semaphorin domain and several thrombospondin type-1 repeats. Members of this family are involved in axonal guidance during neural development. This gene has been implicated as an autism susceptibility gene.

Source: NCBI Gene 9037 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 273 total
• Phenotypes (HPO): 27
• MANE Select transcript: NM_003966

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10736
Approved symbol	SEMA5A
Name	semaphorin 5A
Location	5p15.31
Locus type	gene with protein product
Status	Approved
Aliases	semF
Ensembl gene	ENSG00000112902
Ensembl biotype	protein_coding
OMIM	609297
Entrez	9037

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000382496, ENST00000509486, ENST00000513968, ENST00000514923, ENST00000652226, ENST00000897596, ENST00000897597, ENST00000897598, ENST00000897599, ENST00000897600, ENST00000897601, ENST00000897602, ENST00000897603, ENST00000957025

RefSeq mRNA: 1 — MANE Select: NM_003966 NM_003966

CCDS: CCDS3875

Canonical transcript exons

ENST00000382496 — 23 exons

Exon	Start	End
ENSE00000722090	9122656	9122837
ENSE00000722094	9118998	9119141
ENSE00000722129	9044373	9044584
ENSE00000970740	9108140	9108287
ENSE00000970742	9066421	9066646
ENSE00000970744	9062887	9063105
ENSE00000970745	9054087	9054257
ENSE00000970746	9051873	9052028
ENSE00000970747	9050410	9050457
ENSE00001004453	9136504	9136621
ENSE00001004455	9318372	9318417
ENSE00001004460	9337713	9337812
ENSE00001082668	9190267	9190471
ENSE00001082669	9197168	9197303
ENSE00001082670	9226869	9226967
ENSE00001082672	9237828	9237890
ENSE00001082673	9201955	9202240
ENSE00001082674	9224674	9224887
ENSE00001166144	9154488	9154695
ENSE00001492331	9035033	9043016
ENSE00001492356	9437756	9437852
ENSE00001492358	9545584	9546075
ENSE00003771130	9379823	9380023

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 97.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.9140 / max 177.6391, expressed in 1178 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60877	8.7768	1154
60878	0.6486	397
203486	0.4886	287

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephric glomerulus	UBERON:0004736	97.04	gold quality
renal glomerulus	UBERON:0000074	96.80	gold quality
stromal cell of endometrium	CL:0002255	94.91	gold quality
periodontal ligament	UBERON:0008266	94.91	gold quality
synovial joint	UBERON:0002217	94.24	gold quality
nipple	UBERON:0002030	92.63	gold quality
olfactory bulb	UBERON:0002264	92.13	gold quality
sural nerve	UBERON:0015488	91.46	gold quality
parietal pleura	UBERON:0002400	90.31	gold quality
trigeminal ganglion	UBERON:0001675	90.10	gold quality
decidua	UBERON:0002450	89.70	gold quality
germinal epithelium of ovary	UBERON:0001304	89.31	gold quality
dorsal root ganglion	UBERON:0000044	89.02	gold quality
pleura	UBERON:0000977	88.85	gold quality
kidney epithelium	UBERON:0004819	88.67	gold quality
layer of synovial tissue	UBERON:0007616	88.65	gold quality
hair follicle	UBERON:0002073	88.28	gold quality
endometrium	UBERON:0001295	87.71	gold quality
urethra	UBERON:0000057	87.55	gold quality
inferior vagus X ganglion	UBERON:0005363	87.18	gold quality
mammary duct	UBERON:0001765	87.17	gold quality
heart right ventricle	UBERON:0002080	87.17	gold quality
epithelium of mammary gland	UBERON:0003244	87.16	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.84	gold quality
corpus callosum	UBERON:0002336	86.58	gold quality
visceral pleura	UBERON:0002401	85.89	gold quality
metanephros	UBERON:0000081	85.71	gold quality
mammalian vulva	UBERON:0000997	85.46	gold quality
subthalamic nucleus	UBERON:0001906	85.24	gold quality
cortex of kidney	UBERON:0001225	84.90	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	921.95
E-CURD-7	yes	774.72
E-ENAD-21	yes	742.80
E-HCAD-35	yes	82.03
E-CURD-119	yes	34.70
E-HCAD-25	yes	25.32
E-ANND-3	yes	12.64
E-MTAB-6678	yes	10.88
E-GEOD-93593	yes	5.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FEZF2

miRNA regulators (miRDB)

360 targeting SEMA5A, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Literature-anchored findings (GeneRIF, showing 31)

• Plexin-B3 is a functional receptor for semaphorin 5A (PMID:15218527)
• The results of this study make us suggest SEMA5A as a candidate gene in the etiology of idiopathic autism. (PMID:17028446)
• Data show that the haplotypes of SEMA5A are associated with a risk of Parkinson’s disease in a Chinese Han population. (PMID:18950607)
• A virtual expression database search and RT-PCR analysis showed co-expression of SEMA5A and Plexin B3, and the interaction of SEMA5A with Plexin B3 was confirmed by co-immunoprecipitation studies. (PMID:19329067)
• expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene (PMID:19812673)
• Semaphorin 5a is not implicated in Parkinson’s disease risk in a Chinese Han population. (PMID:19957501)
• data demonstrate that the expression of SEMA5A in pancreatic cancer cells regulates tumorigenesis, growth, invasion and metastasis, and it also suggests a novel target for diagnosis and treatment of pancreatic cancer (PMID:20073063)
• Data represent a novel signaling of semaphorin 5A and plexin B3 in the control of cell motility by indirect inactivation of Rac1 through RhoGDIalpha. (PMID:20696765)
• The downregulation of SEMA5A in tumor tissue, both at the transcriptional and translational levels, was associated with poor survival among nonsmoking women with NSCLC. (PMID:20802022)
• Data show that Semaphorin 5A (Sema5A) and plexin-B3 inhibit glioma cell invasion through Rac1 inactivation. (PMID:21706053)
• Results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases. (PMID:22782341)
• Using human gastric cancer cell lines, found semaphorin 5A significantly promoted invasive & metastatic abilities of gastric cancer cell in vitro. Semaphorin 5A increased expression of MMP9 by activating phosphorylated ErK1/2 in gastric cancer cell. (PMID:22821546)
• SEMA5A gene is associated with hippocampal volume, and their interaction is associated with reasoning ability. (PMID:24291503)
• The Single-Nucleotide Polymorphism (SNP) of rs7702187 within the SEMA5A gene would be a high-penetrant risk factor for PD development. (PMID:24706317)
• De novo translocation t(5;22)(p15.3;q11.21) associated with a partial deletion of SEMA5A identified in a patient with ASD. (PMID:26395558)
• Multigenerational autosomal dominant inheritance of 5p chromosomal deletions resulting in Cri-du-Chat Syndrome with SEMA5A, CTNND2, and ICE1 deficiencies has been described. (PMID:26601658)
• Our data demonstrated that elevated serum Semaphorin5A (Sema5A) in SLE patients correlated with disease activity and are involved in kidney and blood system damage; ADAM17 might be involved in the release of secreted Sema5A. (PMID:28063160)
• data demonstrated that elevated serum Semaphorin5A in systemic lupus erythematosus patients correlated with disease activity and are involved in kidney and blood system damage; ADAM17 might be involved in the release of secreted Sema5A (PMID:28063160)
• Data provide evidences supporting the role of Sema5A in melanoma progression and the involvement of Bcl-2, miR-204 and c-Myb in regulating its expression. (PMID:30454024)
• Collectively, our data suggest that SEMA5A expression maintains epithelial phenotype in the metastatic microenvironment (PMID:30577767)
• Study provide the first evidence that SEMA3C, SEMA5A and SEMA6D can be considered as markers of liver injury in chronic hepatitis C. While serum concentrations of SEMA3C and SEMA6D significantly increased with fibrosis stage in both HCV-g1 and HCV-g3 infections, the concentration of SEMA5A inversely correlated with fibrosis stage in both HCV genotypes. (PMID:30592759)
• Semaphorin-5A downregulation is associated with enhanced migration and invasion of BRAF-positive melanoma cells under vemurafenib treatment in melanomas with heterogeneous BRAF status (PMID:31116162)
• In our study of SEMA5A expression in endometrial cancer, we observed an increased level of this protein compared to the control. The homogeneity of expression changes at the transcriptome and proteome levels suggests that SEMA5A could be a new potential supplementary molecular marker in endometrial cancer. (PMID:31544715)
• High Expression Levels of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 and Semaphorin 5A Indicate Poor Prognosis in Multiple Myeloma. (PMID:31597158)
• Circular RNA circSEMA5A promotes bladder cancer progression by upregulating ENO1 and SEMA5A expression. (PMID:33176280)
• TSP1 is the essential domain of SEMA5A involved in pannus formation in rheumatoid arthritis. (PMID:33616619)
• Relationship between disease and disease severity and semaphorin 5A and hemogram level in obsessive-compulsive disorder. (PMID:33771090)
• The Expression of IL-17, in Chronic Spontaneous Urticaria Is Linked to Semaphorin5A. (PMID:33801296)
• Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis. (PMID:35835748)
• SEMA5A-PLXNB3 Axis Promotes PDAC Liver Metastasis Outgrowth through Enhancing the Warburg Effect. (PMID:36741230)
• Circular RNA circSEMA5A facilitates colorectal cancer development by regulating microRNA-195-5p to target CCNE1 axis. (PMID:37164546)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sema5a	ENSDARG00000058821
mus_musculus	Sema5a	ENSMUSG00000022231
rattus_norvegicus	Sema5a	ENSRNOG00000011977

Paralogs (19): SEMA3F (ENSG00000001617), SEMA3G (ENSG00000010319), SEMA3B (ENSG00000012171), SEMA3A (ENSG00000075213), SEMA3C (ENSG00000075223), SEMA5B (ENSG00000082684), SEMA6A (ENSG00000092421), SEMA4G (ENSG00000095539), SEMA4F (ENSG00000135622), SEMA6D (ENSG00000137872), SEMA7A (ENSG00000138623), SEMA6C (ENSG00000143434), SEMA3D (ENSG00000153993), SEMA6B (ENSG00000167680), SEMA4C (ENSG00000168758), SEMA3E (ENSG00000170381), SEMA4B (ENSG00000185033), SEMA4D (ENSG00000187764), SEMA4A (ENSG00000196189)

Protein

Protein identifiers

Semaphorin-5A — Q13591 (reviewed: Q13591)

Alternative names: Semaphorin-F

All UniProt accessions (3): D6RAF4, Q13591, X5DR95

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate proteoglycans (CSPGs). Ligand for receptor PLXNB3. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1. May promote angiogenesis by increasing endothelial cell proliferation and migration and inhibiting apoptosis.

Subunit / interactions. Binds PLXNB3.

Subcellular location. Membrane.

Similarity. Belongs to the semaphorin family.

RefSeq proteins (1): NP_003957* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001627	Semap_dom	Domain
IPR002165	Plexin_repeat	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016201	PSI	Domain
IPR027231	Semaphorin	Family
IPR036352	Semap_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR042821	Sema5A_sema	Domain
IPR057563	Sema5A/B-like_TSP-1	Domain

Pfam: PF00090, PF01403, PF01437, PF23260

UniProt features (64 total): disulfide bond 18, strand 12, glycosylation site 11, domain 8, sequence conflict 6, sequence variant 3, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, helix 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8CKK	X-RAY DIFFRACTION	1.56
8CKG	X-RAY DIFFRACTION	1.71
8CKL	X-RAY DIFFRACTION	2.56
8CKM	X-RAY DIFFRACTION	2.72

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13591-F1	77.97	0.37

Functional residue map

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

Disulfide bonds (18): 104–114, 131–140, 254–357, 278–320, 487–504, 496–513, 607–644, 611–650, 622–634, 665–696, 669–701, 680–686, 796–833, 800–838, 811–823, 853–890, 857–895, 868–880

Glycosylation sites (11): 142, 168, 227, 277, 323, 367, 437, 536, 591, 717, 933

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-416700	Other semaphorin interactions
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1266738	Developmental Biology
R-HSA-1643685	Disease
R-HSA-373755	Semaphorin interactions
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-5173105	O-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification
R-HSA-9675108	Nervous system development

MSigDB gene sets: 426 (showing top): E2F_Q4, E2F_Q4_01, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_RECOGNITION, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_CHEMOTAXIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_CELL_CHEMOTAXIS, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_NEURON_PROJECTION_EXTENSION_INVOLVED_IN_NEURON_PROJECTION_GUIDANCE, REACTOME_OTHER_SEMAPHORIN_INTERACTIONS

GO Biological Process (26): neural crest cell migration (GO:0001755), positive regulation of endothelial cell proliferation (GO:0001938), blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:0002043), cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), cell-cell signaling (GO:0007267), nervous system development (GO:0007399), axon guidance (GO:0007411), axonal fasciculation (GO:0007413), diencephalon development (GO:0021536), positive regulation of cell migration (GO:0030335), positive regulation of actin filament depolymerization (GO:0030836), positive regulation of angiogenesis (GO:0045766), axon extension (GO:0048675), positive regulation of axon extension involved in axon guidance (GO:0048842), negative regulation of axon extension involved in axon guidance (GO:0048843), positive chemotaxis (GO:0050918), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cell chemotaxis (GO:0060326), semaphorin-plexin signaling pathway (GO:0071526), positive regulation of canonical Wnt signaling pathway (GO:0090263), signal clustering (GO:1990256), negative regulation of endothelial cell apoptotic process (GO:2000352), positive regulation of endothelial cell chemotaxis (GO:2001028), cell differentiation (GO:0030154), negative chemotaxis (GO:0050919)

GO Molecular Function (6): semaphorin receptor binding (GO:0030215), chondroitin sulfate proteoglycan binding (GO:0035373), heparan sulfate proteoglycan binding (GO:0043395), chemorepellent activity (GO:0045499), syndecan binding (GO:0045545), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Semaphorin interactions	1
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Axon guidance	1
Diseases of metabolism	1
Diseases of glycosylation	1
Nervous system development	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteoglycan binding	3
endothelial cell proliferation	2
axonogenesis	2
cell migration	2
regulation of axon extension involved in axon guidance	2
axon extension involved in axon guidance	2
chemotaxis	2
neural crest cell development	1
mesenchymal cell migration	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
sprouting angiogenesis	1
cellular process	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
cell communication	1
signaling	1
system development	1
neuron projection guidance	1
neuron recognition	1
axon development	1
neuron projection fasciculation	1
forebrain development	1
anatomical structure development	1
regulation of cell migration	1
positive regulation of cell motility	1
actin filament depolymerization	1
regulation of actin filament depolymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of protein depolymerization	1
positive regulation of supramolecular fiber organization	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
neuron projection extension	1
positive regulation of axon extension	1
positive regulation of chemotaxis	1
negative regulation of axon extension	1
negative regulation of chemotaxis	1

Protein interactions and networks

STRING

1184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA5A	PLXNB3	Q9ULL4	989
SEMA5A	TAS2R1	Q9NYW7	852
SEMA5A	PLXNA1	Q9UIW2	828
SEMA5A	PLXNA3	P51805	809
SEMA5A	CDH9	Q9ULB4	787
SEMA5A	CDH10	Q9Y6N8	741
SEMA5A	PLXNB1	O43157	739
SEMA5A	CTNND2	Q9UQB3	669
SEMA5A	CNTN4	Q8IWV2	655
SEMA5A	NLGN4X	Q8N0W4	645
SEMA5A	NLGN3	Q9NZ94	637
SEMA5A	ASTN2	O75129	609
SEMA5A	PLXNA2	O75051	602
SEMA5A	NRP2	O60462	591
SEMA5A	PLXNB2	O15031	574

IntAct

3 interactions, top by confidence:

A	B	Type	Score
P		psi-mi:“MI:0914”(association)	0.350
SEMA5A		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): SEMA5A (Affinity Capture-MS), SEMA5A (Affinity Capture-RNA)

ESM2 similar proteins: A0JNA2, A2RRU4, A6QM06, C0HL12, D3ZTD8, O14514, O54693, O60241, O60242, O75077, O75462, P08138, P97260, Q0GA42, Q13591, Q29RN8, Q3TMX7, Q3UHD1, Q4V7F2, Q4V9Z5, Q53EL9, Q5R7Y0, Q5VXM1, Q62217, Q6GQT6, Q6UXD5, Q6ZRP7, Q7TSK2, Q7TSQ1, Q7TT36, Q80ZF8, Q8BQC3, Q8BQH6, Q8CGM1, Q8IVU1, Q8IWK6, Q91XD7, Q924S4, Q92838, Q96MU8

Diamond homologs: A7MB70, D3ZTD8, O08665, O09126, O15041, O35464, O42236, O42237, O88632, O95025, O95754, P70275, Q13214, Q13275, Q13591, Q14563, Q17330, Q24322, Q24323, Q26473, Q26972, Q4LFA9, Q5EA85, Q5R7F5, Q5RE75, Q60519, Q62177, Q62178, Q62179, Q62181, Q62217, Q63548, Q64151, Q76KF0, Q8BH34, Q8NFY4, Q90607, Q90663, Q90665, Q92854

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SEMA5A	“up-regulates activity”	PLXNB3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	171
Likely benign	45
Benign	26

Top pathogenic / likely-pathogenic (0)

SpliceAI

6342 predictions. Top by Δscore:

Variant	Effect	Δscore
5:9042951:C:A	donor_gain	1.0000
5:9044370:TACCT:T	donor_loss	1.0000
5:9044371:A:AC	donor_gain	1.0000
5:9044371:AC:A	donor_gain	1.0000
5:9044372:C:CC	donor_gain	1.0000
5:9044372:CC:C	donor_gain	1.0000
5:9044372:CCT:C	donor_gain	1.0000
5:9044372:CCTTG:C	donor_gain	1.0000
5:9044583:CT:C	acceptor_gain	1.0000
5:9044583:CTCTA:C	acceptor_loss	1.0000
5:9044584:TC:T	acceptor_loss	1.0000
5:9044585:C:CC	acceptor_gain	1.0000
5:9044585:C:CG	acceptor_loss	1.0000
5:9050453:TACTT:T	acceptor_gain	1.0000
5:9050455:CTT:C	acceptor_gain	1.0000
5:9051868:CTTA:C	donor_loss	1.0000
5:9051869:TTA:T	donor_loss	1.0000
5:9051870:TA:T	donor_loss	1.0000
5:9051871:ACCT:A	donor_loss	1.0000
5:9051872:C:CA	donor_loss	1.0000
5:9052039:C:CT	acceptor_gain	1.0000
5:9052040:A:T	acceptor_gain	1.0000
5:9054081:GCTTA:G	donor_loss	1.0000
5:9054082:CTTAC:C	donor_loss	1.0000
5:9054083:TTA:T	donor_loss	1.0000
5:9054084:TA:T	donor_loss	1.0000
5:9054085:A:AG	donor_loss	1.0000
5:9054086:C:CG	donor_loss	1.0000
5:9054253:ATCCA:A	acceptor_gain	1.0000
5:9054254:TCCA:T	acceptor_gain	1.0000

AlphaMissense

7067 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:9054226:C:A	W850C	1.000
5:9054226:C:G	W850C	1.000
5:9054235:C:A	W847C	1.000
5:9054235:C:G	W847C	1.000
5:9054244:C:A	W844C	1.000
5:9054244:C:G	W844C	1.000
5:9063026:C:A	W793C	1.000
5:9063026:C:G	W793C	1.000
5:9066537:C:G	R728P	1.000
5:9066581:C:A	W713C	1.000
5:9066581:C:G	W713C	1.000
5:9066583:A:G	W713R	1.000
5:9066583:A:T	W713R	1.000
5:9066590:C:A	W710C	1.000
5:9066590:C:G	W710C	1.000
5:9108236:C:A	W659C	1.000
5:9108236:C:G	W659C	1.000
5:9119111:C:A	W604C	1.000
5:9119111:C:G	W604C	1.000
5:9119120:C:A	W601C	1.000
5:9119120:C:G	W601C	1.000
5:9119129:C:A	W598C	1.000
5:9119129:C:G	W598C	1.000
5:9197201:C:A	W345C	1.000
5:9197201:C:G	W345C	1.000
5:9197203:A:G	W345R	1.000
5:9197203:A:T	W345R	1.000
5:9202055:A:G	C278R	1.000
5:9202083:C:A	W268C	1.000
5:9202083:C:G	W268C	1.000

dbSNP variants (sampled 300 via entrez): RS1000007003 (5:9201129 G>A), RS1000007818 (5:9285946 T>C), RS1000009247 (5:9316282 G>A), RS1000011675 (5:9236129 C>T), RS1000012812 (5:9407616 A>G), RS1000019490 (5:9200274 G>A,T), RS1000023823 (5:9082021 C>T), RS1000024282 (5:9281776 T>A), RS1000032724 (5:9121664 T>A,C), RS1000034804 (5:9514514 A>T), RS1000036693 (5:9419824 G>A), RS1000040191 (5:9127656 T>C), RS1000041361 (5:9329305 T>C), RS1000052631 (5:9537010 A>G), RS1000055236 (5:9041285 C>A,G,T)

Disease associations

OMIM: gene MIM:609297 | disease phenotypes: MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (5): Charcot-Marie-Tooth disease (MONDO:0015626), primary ovarian failure (MONDO:0005387), infantile epilepsy syndrome (MONDO:0020071), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092)

Orphanet (4): Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619), OBSOLETE: Infantile epilepsy syndrome (Orphanet:98258), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000308	Microretrognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0001252	Hypotonia
HP:0001382	Joint hypermobility
HP:0001511	Intrauterine growth retardation
HP:0001608	Abnormality of the voice
HP:0001620	Abnormally high-pitched voice
HP:0002650	Scoliosis
HP:0002757	Recurrent fractures
HP:0004322	Short stature
HP:0004348	Abnormality of bone mineral density
HP:0006101	Finger syndactyly
HP:0010864	Severe intellectual disability
HP:0011344	Severe global developmental delay
HP:0030680	Abnormal cardiovascular system morphology
HP:0200046	Cat cry
HP:0200055	Small hand

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000002_1	Parkinson’s disease	8.000000e-06
GCST000496_1	Autism	2.000000e-07
GCST001374_2	Uric acid levels	7.000000e-08
GCST001762_572	Obesity-related traits	8.000000e-06
GCST001762_675	Obesity-related traits	5.000000e-07
GCST002701_4	Verbal declarative memory	3.000000e-06
GCST002701_40	Verbal declarative memory	3.000000e-06
GCST003251_14	Late-onset myasthenia gravis	5.000000e-07
GCST003854_27	Gut microbiota (functional units)	5.000000e-08
GCST005194_106	Coronary artery disease	2.000000e-12
GCST005195_57	Coronary artery disease	4.000000e-13
GCST005412_6	Thrombin-activatable fibrinolysis inhibitor levels	1.000000e-06
GCST005790_96	Rosacea symptom severity	7.000000e-06
GCST006585_407	Blood protein levels	0.000000e+00
GCST008471_5	Non-alcoholic fatty liver disease activity score in non-alcoholic fatty liver disease	7.000000e-06
GCST008947_2	High chromosomal aberration frequency (chromatid type) in genotoxic compound exposure	6.000000e-07
GCST009207_6	Lateral ventricle volume	3.000000e-06
GCST011362_1	Mental health related quality of life	5.000000e-07

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0005134	amino acid measurement
EFO:0004874	memory performance
EFO:0006806	paragraph delayed recall measurement
EFO:0007874	gut microbiome measurement
EFO:0009180	rosacea severity measurement
EFO:0008421	non-alcoholic fatty liver disease severity measurement
EFO:0009862	chromatid-type aberration frequency
EFO:0008487	lateral ventricle volume measurement
EFO:0011014	health-related quality of life measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
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)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs35719165	SEMA5A		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	5
bisphenol A	affects cotreatment, decreases methylation, decreases expression	3
methylmercuric chloride	decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, affects methylation	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	decreases expression	1
Esketamine	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
methylselenic acid	increases expression	1
trichostatin A	decreases expression	1
arsenite	decreases methylation	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
nickel sulfate	increases expression	1
perfluorooctane sulfonic acid	decreases 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, decreases expression, increases expression	1
tricetin	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
licochalcone B	decreases expression	1
bisphenol S	decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_JY36	MFD-1	Cancer cell line	Male

Clinical trials (associated diseases)

493 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,
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
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
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
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
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis