SEMA3A

Summary

SEMA3A (semaphorin 3A, HGNC:10723) is a protein-coding gene on chromosome 7q21.11, encoding Semaphorin-3A (Q14563). Involved in the development of the olfactory system and in neuronal control of puberty.

This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. Increased expression of this protein is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer’s disease.

Source: NCBI Gene 10371 — RefSeq curated summary.

At a glance

• Gene–disease (curated): skeletal dysplasia (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 407 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 72
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006080

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10723
Approved symbol	SEMA3A
Name	semaphorin 3A
Location	7q21.11
Locus type	gene with protein product
Status	Approved
Aliases	SEMA1, SemD, coll-1, Hsema-I
Ensembl gene	ENSG00000075213
Ensembl biotype	protein_coding
OMIM	603961
Entrez	10371

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000265362, ENST00000420047, ENST00000424555, ENST00000436949, ENST00000448879, ENST00000471474, ENST00000490883, ENST00000864988, ENST00000864989, ENST00000864990, ENST00000864991, ENST00000864992, ENST00000864993, ENST00000864994, ENST00000922179

RefSeq mRNA: 1 — MANE Select: NM_006080 NM_006080

CCDS: CCDS5599

Canonical transcript exons

ENST00000265362 — 17 exons

Exon	Start	End
ENSE00000700118	83963205	83963347
ENSE00000700119	83977132	83977196
ENSE00000700206	84005339	84005558
ENSE00000700313	84007353	84007497
ENSE00000700360	84011022	84011091
ENSE00000700450	84014209	84014351
ENSE00000700464	84046324	84046443
ENSE00000700495	84060465	84060558
ENSE00000700497	84110470	84110589
ENSE00000700499	84129123	84129185
ENSE00000700501	84134794	84134951
ENSE00000877110	83981321	83981478
ENSE00000877111	84001955	84002046
ENSE00000977008	84011183	84011297
ENSE00001013359	83985436	83985477
ENSE00001163665	83955777	83961826
ENSE00001163673	84194475	84194789

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 93.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.0151 / max 465.2137, expressed in 1246 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84647	3.0020	868
84650	1.7436	679
84651	1.1936	525
84646	1.1097	305
84652	1.0391	447
84648	0.5581	288
84649	0.2748	146
84644	0.2178	105
84653	0.2120	93
84659	0.2087	72

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	93.06	gold quality
cortical plate	UBERON:0005343	90.23	gold quality
colonic epithelium	UBERON:0000397	87.42	gold quality
cartilage tissue	UBERON:0002418	87.05	gold quality
ventricular zone	UBERON:0003053	83.10	gold quality
ganglionic eminence	UBERON:0004023	82.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	81.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	80.99	gold quality
lower esophagus	UBERON:0013473	80.94	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	80.25	gold quality
sural nerve	UBERON:0015488	78.49	gold quality
mucosa of stomach	UBERON:0001199	78.17	gold quality
embryo	UBERON:0000922	78.14	gold quality
sigmoid colon	UBERON:0001159	77.21	gold quality
gall bladder	UBERON:0002110	75.43	gold quality
decidua	UBERON:0002450	75.29	gold quality
rectum	UBERON:0001052	74.88	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.77	gold quality
urinary bladder	UBERON:0001255	74.37	gold quality
mucosa of paranasal sinus	UBERON:0005030	74.14	gold quality
bronchial epithelial cell	CL:0002328	73.87	gold quality
epithelium of bronchus	UBERON:0002031	73.70	gold quality
bronchus	UBERON:0002185	73.15	gold quality
colon	UBERON:0001155	72.02	gold quality
large intestine	UBERON:0000059	71.81	gold quality
smooth muscle tissue	UBERON:0001135	70.77	gold quality
right lung	UBERON:0002167	70.64	gold quality
subcutaneous adipose tissue	UBERON:0002190	70.58	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	2549.05
E-MTAB-11268	yes	1075.11
E-ANND-3	yes	6.91
E-GEOD-36552	no	184.91
E-MTAB-10290	no	97.08
E-MTAB-6678	no	3.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

265 targeting SEMA3A, 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-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-33A-5P	99.99	68.62	1055

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• sema3A is elevated in schizophrenia, and is associated with downregulation of genes involved in synaptic formation and maintenance. (PMID:12610647)
• human glioma cells express class 3 semaphorins and receptors for soluble and membrane-bound semaphorins, suggesting a possible role of the semaphorin/neuropilin system in the interactions of human malignant glioma with the nervous and immune systems. (PMID:12730958)
• during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells (PMID:12879061)
• Breast carcinoma cells support an autocrine pathway involving SEMA3A, plexin-A1, and NP1 that impedes their ability to chemotax. (PMID:14500350)
• new role of Sema-3A in VEGF function mediated by p38 MAPK and suggest that the abrogation of regulated Sema-3A expression is responsible for VEGF-driven growth of tumor cells (PMID:14656993)
• the chemorepulsive signals mediated by Sema 3A play an important role in preventing nerve fibers growth in the umbilical cord and in gestational uterine tissues. (PMID:15517571)
• extensive inhibition of platelet function by Sema3A appears to be mediated, at least in part, through impairment of agonist-induced Rac1-dependent actin rearrangement (PMID:15831706)
• Down-regulation of NRP1 by NRSF overexpression reduced Sema3A activity. It was concluded that NRSF is a transcription factor that silences NRP1 expression and thereby diminishes the Sema3A mediated inhibition of HaCaT keratinocyte migration (PMID:16330548)
• Vascular endothelial growth factor165 (VEGF165) and semaphorin3A (SEMA3A) elicit pro- and antiangiogenic signals respectively in endothelial cells (ECs) by binding to their receptors VEGFR-2, neuropilin-1 and plexin-a. (PMID:16684957)
• In the regulation of the immune response Sema-3A plays a novel role as a modulator of cross-talk between activated dendritic cells and T cells. (PMID:16791896)
• NP-1/Sema-3A-mediated interactions participate in the control of human thymocyte development (PMID:17369353)
• sema3A and sema3C have opposite roles in neoplasm invasiveness and adhesion (PMID:17390026)
• combinations of sema3A and sema3F may be able to inhibit tumor angiogenesis more effectively than single semaphorins. (PMID:17569671)
• This review highlights the effect of Sema3A on axonal growth cones, the intracellular signaling pathways that lead to the cellular effects, and the evidence for collapsin-response-mediator proteins (CRMPs) as a component of the Sema3A signaling cascade. (PMID:17607942)
• Overexpression of SEMA3A may favor malignant activities of tumor cells. Negative clinicopathol correlations suggest that SEMA3A might represent a novel intervention target for pancreatic cancer patients. (PMID:17631638)
• structural analysis of semaphorin and VEGF binding (PMID:17989695)
• Semaphorin3A (Sema3A) triggers a proapoptotic program that sensitizes leukemic T cells to Fas (CD95)-mediated apoptosis. (PMID:18056484)
• Human neuroma contains increased levels of semaphorin 3A, which surrounds nerve fibers and reduces neurite extension in vitro. (PMID:18160633)
• The sulfated polysaccharides dextran sulfate and fucoidan, but not others, reduce endothelial cell-surface levels of NRP1, NRP2, and to a lesser extent VEGFR-1 and VEGFR-2, and block the binding and in vitro function of semaphorin3A and VEGF(165). (PMID:18272814)
• The role of semaphorins and their receptors in the progression of lung cancer was studied. (PMID:18625544)
• SEMA3A suppression of tumor cell migration is dependent on alpha2beta1, the expression of which is stimulated in breast tumor cells by an autocrine SEMA3A pathway. (PMID:18787945)
• Sema3A inhibits tumor development from MDA-MB-231 and MCF-7 cancer cells, but not from MDA-MB-435 or MDA-MB-468. It inhibits tumor angiogenesis in all of the formed tumors. The inhibition is correlated with the expression of NRP-1 of the tumors cells. (PMID:18818766)
• These findings indicate that EGF released from corneal epithelial cells up-regulates the expression of Sema3A in corneal fibroblasts. (PMID:18831963)
• Our findings suggest a role for SEMA3A as an antiangiogenic factor in meningiomas with its decrease being associated with the development of recurrences. (PMID:19296128)
• Data show that consistent with increased NRP-1 expression, cell surface binding of Sema3A increased during M2 differentiation. (PMID:19480842)
• Sema3A as an autocrine signal for neuropilin-1 to promote glioblastoma (GBM) dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration. (PMID:19684614)
• Dysregulation of the Sema3A pathway plays a key role in prostatic cancer progression. (PMID:19817889)
• NRP2 is necessary to trigger Sema3A-induced glioma cell repulsion and attraction. (PMID:19855168)
• Results demonstrate the critical role of Galectin-1 and Sema-3A in mesenchymal stem cell functions and may open new perspectives in the understanding and treatment of various immune and neoplastic disorders. (PMID:19886821)
• neither Sema3A nor Sema4D likely influence the susceptibility to Alzheimer’s disease (PMID:19957197)
• In degenerate intervertebral disc samples, sema3A expression decreased significantly (PMID:20051117)
• these findings indicate that semaphorin 3A released from corneal fibroblasts may play an important role in the regulation of intercellular communication between corneal epithelial cells as well as in the maintenance of corneal structure and function. (PMID:20382125)
• incubation of breast tumor cells with recombinant Sema3A rapidly increased eIF4E activity, RhoA protein levels, and RhoA activity; Sema3A impedes breast tumor cell migration in part by stimulating RhoA (PMID:20655307)
• Both systemic and tumor-targeted delivery of SEMA3A inhibits tumor angiogenesis and tumor growth in multiple mouse models; moreover, SEMA3A inhibits the metastatic spreading from primary tumors. (PMID:21205984)
• SEMA3A expression was upregulated in the aganglionic smooth muscle layer of the colon in some patients with HSCR and our data suggest that increased SEMA3A expression may be a risk factor for HSCR pathology (PMID:21656899)
• We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p < 5E-05: SEMA3A, TMEM132D, LRRC7, ALK, and STIP1. (PMID:21784300)
• the downregulated expression of SEMA3A and several SEMA3s results in a loss of inhibitory activities in tumor angiogenesis and tumor growth of VEGFA. (PMID:21842119)
• SEMA-3A is involved in the regulation of CXCL12-driven human thymocyte migration, where it acts as a physiological antagonist. (PMID:21878545)
• A decrease in class 3 semaphorin and their plexin receptors may have some relationship with disease progression in ductal breast carcinoma. (PMID:21884206)
• Sema3A is overexpressed, with a direct correlation with cloning, in osteoarthritic cartilage and that it suppresses the VEGF165-promoted migration of chondrocytes. (PMID:21953086)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sema3ab	ENSDARG00000042210
mus_musculus	Sema3a	ENSMUSG00000028883
rattus_norvegicus	Sema3a	ENSRNOG00000023337

Paralogs (19): SEMA3F (ENSG00000001617), SEMA3G (ENSG00000010319), SEMA3B (ENSG00000012171), SEMA3C (ENSG00000075223), SEMA5B (ENSG00000082684), SEMA6A (ENSG00000092421), SEMA4G (ENSG00000095539), SEMA5A (ENSG00000112902), 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-3A — Q14563 (reviewed: Q14563)

Alternative names: Semaphorin III

All UniProt accessions (4): Q14563, A0A0C4DG50, C9J9C4, C9JD25

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the development of the olfactory system and in neuronal control of puberty. Induces the collapse and paralysis of neuronal growth cones. Could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism. Binds to the complex neuropilin-1/plexin-1.

Subunit / interactions. Interacts with PLXND1.

Subcellular location. Secreted.

Tissue specificity. Expressed in the dorsal root ganglia.

Disease relevance. Hypogonadotropic hypogonadism 16 with or without anosmia (HH16) [MIM:614897] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Domain organisation. Strong binding to neuropilin is mediated by the carboxy third of the protein.

Similarity. Belongs to the semaphorin family.

RefSeq proteins (1): NP_006071* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016201	PSI	Domain
IPR027231	Semaphorin	Family
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036352	Semap_dom_sf	Homologous_superfamily
IPR041416	IL-1RAcP-like_ig	Domain
IPR042820	Sema3A_sema	Domain

Pfam: PF01403, PF18452

UniProt features (30 total): sequence variant 14, disulfide bond 6, glycosylation site 3, domain 2, compositionally biased region 2, signal peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14563-F1	84.50	0.66

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 (6): 103–114, 132–141, 269–381, 293–341, 517–535, 649–722

Glycosylation sites (3): 53, 125, 590

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-399954	Sema3A PAK dependent Axon repulsion
R-HSA-399955	SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion
R-HSA-399956	CRMPs in Sema3A signaling
R-HSA-1266738	Developmental Biology
R-HSA-373755	Semaphorin interactions
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 485 (showing top): GOBP_DENDRITE_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEURON_PROJECTION_EXTENSION_INVOLVED_IN_NEURON_PROJECTION_GUIDANCE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS, GOBP_CRANIAL_NERVE_MORPHOGENESIS, HNF1_Q6, GOBP_CRANIAL_NERVE_DEVELOPMENT, GOBP_ANATOMICAL_STRUCTURE_ARRANGEMENT, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION

GO Biological Process (27): neural crest cell migration (GO:0001755), neuron migration (GO:0001764), axon guidance (GO:0007411), motor neuron axon guidance (GO:0008045), negative regulation of neuron projection development (GO:0010977), facial nerve structural organization (GO:0021612), trigeminal nerve structural organization (GO:0021637), nerve development (GO:0021675), olfactory bulb development (GO:0021772), branchiomotor neuron axon guidance (GO:0021785), positive regulation of cell migration (GO:0030335), positive regulation of JNK cascade (GO:0046330), sympathetic nervous system development (GO:0048485), regulation of axon extension involved in axon guidance (GO:0048841), axon extension involved in axon guidance (GO:0048846), sensory system development (GO:0048880), negative chemotaxis (GO:0050919), axonogenesis involved in innervation (GO:0060385), sympathetic ganglion development (GO:0061549), semaphorin-plexin signaling pathway (GO:0071526), sympathetic neuron projection extension (GO:0097490), sympathetic neuron projection guidance (GO:0097491), basal dendrite arborization (GO:0150020), neural crest cell migration involved in autonomic nervous system development (GO:1901166), nervous system development (GO:0007399), cell differentiation (GO:0030154), forebrain development (GO:0030900)

GO Molecular Function (4): semaphorin receptor binding (GO:0030215), neuropilin binding (GO:0038191), chemorepellent activity (GO:0045499), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), axon (GO:0030424), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Semaphorin interactions	3
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell migration	2
axonogenesis	2
axon guidance	2
cranial nerve structural organization	2
anatomical structure development	2
system development	2
signaling receptor binding	2
neural crest cell development	1
mesenchymal cell migration	1
generation of neurons	1
neuron projection guidance	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
facial nerve morphogenesis	1
trigeminal nerve morphogenesis	1
nervous system development	1
olfactory lobe development	1
motor neuron axon guidance	1
regulation of cell migration	1
positive regulation of cell motility	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
autonomic nervous system development	1
regulation of axon extension	1
axon extension involved in axon guidance	1
axon extension	1
chemotaxis	1
innervation	1
sympathetic nervous system development	1
ganglion development	1
cell surface receptor signaling pathway	1
receptor ligand activity	1
negative chemotaxis	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1
neuron projection	1

Protein interactions and networks

STRING

2048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA3A	NRP1	O14786	999
SEMA3A	PLXNA3	P51805	999
SEMA3A	PLXNA4	Q9HCM2	999
SEMA3A	PLXNA1	Q9UIW2	999
SEMA3A	PLXNA2	O75051	998
SEMA3A	NRP2	O60462	996
SEMA3A	PLXND1	Q9Y4D7	936
SEMA3A	PLXNB1	O43157	813
SEMA3A	NPR1	P16066	811
SEMA3A	L1CAM	P32004	780
SEMA3A	SLIT3	O75094	768
SEMA3A	NTN1	O95631	737
SEMA3A	SLIT2	O94813	712
SEMA3A	DPYSL3	Q14195	690
SEMA3A	EFNA5	P52803	689

IntAct

10 interactions, top by confidence:

A	B	Type	Score
NRP1	CSNK2A2	psi-mi:“MI:0914”(association)	0.790
FAM241A	NRP1	psi-mi:“MI:0914”(association)	0.530
	SEMA3A	psi-mi:“MI:0407”(direct interaction)	0.440
DISC1	AGRN	psi-mi:“MI:0914”(association)	0.350
SEMA3C	ZZEF1	psi-mi:“MI:0914”(association)	0.350
EMID1	POTEF	psi-mi:“MI:0914”(association)	0.350
IL12RB1	PLAU	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (11): SEMA3A (Affinity Capture-Western), SEMA3A (Reconstituted Complex), SEMA3A (Affinity Capture-MS), SEMA3A (Proximity Label-MS), SEMA3A (Affinity Capture-RNA), SEMA3A (Affinity Capture-MS), SEMA3A (Affinity Capture-MS), SEMA3A (Affinity Capture-MS), SEMA3A (Proximity Label-MS), SEMA3A (Proximity Label-MS), SEMA3A (Affinity Capture-RNA)

ESM2 similar proteins: A0M8R7, A0M8S8, A7MB70, O08665, O09126, O42236, O88632, O95025, P08581, P16056, P97523, Q07DV8, Q07DY1, Q07DZ1, Q07E24, Q07E37, Q07E48, Q09YH7, Q09YK0, Q09YL1, Q108U6, Q13275, Q14563, Q24323, Q26473, Q2IBA6, Q2IBD8, Q2IBF2, Q2IBG7, Q2QL89, Q2QLA9, Q2QLC0, Q2QLE0, Q2QLF1, Q2QLG5, Q2QLH6, Q5RE75, Q62181, Q63548, Q75ZY9

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

5 interactions.

A	Effect	B	Mechanism
SEMA3A	“up-regulates activity”	PLXNA4	binding
SEMA3A	“up-regulates activity”	PLXNA1	binding
SEMA3A	“up-regulates activity”	NRP1	binding
SEMA3A	down-regulates	NRP1	binding
SEMA3A	up-regulates	PLXNA2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	206
Likely benign	104
Benign	60

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3245896	NC_000007.13:g.(?83689761)(83823902_?)del	Pathogenic
3245897	NC_000007.13:g.(?83606428)(83614813_?)del	Pathogenic
625633	GRCh37/hg19 7q21.11(chr7:83664877-83740076)	Pathogenic
3255611	NM_006080.3(SEMA3A):c.333+2T>C	Likely pathogenic
3347278	NM_006080.3(SEMA3A):c.607dup (p.Arg203fs)	Likely pathogenic
3352697	NM_006080.3(SEMA3A):c.1591C>T (p.Arg531Ter)	Likely pathogenic
418484	NM_006080.3(SEMA3A):c.1531C>T (p.Gln511Ter)	Likely pathogenic

SpliceAI

3608 predictions. Top by Δscore:

Variant	Effect	Δscore
7:83977259:A:C	acceptor_gain	1.0000
7:84002049:T:C	acceptor_gain	1.0000
7:84002049:T:TC	acceptor_gain	1.0000
7:84005334:TTTA:T	donor_loss	1.0000
7:84005336:TACC:T	donor_loss	1.0000
7:84005337:A:C	donor_loss	1.0000
7:84005338:C:CT	donor_loss	1.0000
7:84005554:GGACA:G	acceptor_gain	1.0000
7:84005555:GACA:G	acceptor_gain	1.0000
7:84005555:GACAC:G	acceptor_gain	1.0000
7:84005556:ACA:A	acceptor_gain	1.0000
7:84005556:ACAC:A	acceptor_gain	1.0000
7:84005557:CA:C	acceptor_gain	1.0000
7:84005557:CAC:C	acceptor_gain	1.0000
7:84005558:AC:A	acceptor_gain	1.0000
7:84005559:C:A	acceptor_loss	1.0000
7:84005559:C:CC	acceptor_gain	1.0000
7:84005559:CT:C	acceptor_gain	1.0000
7:84005560:T:A	acceptor_gain	1.0000
7:84005560:T:G	acceptor_loss	1.0000
7:84005562:T:C	acceptor_gain	1.0000
7:84005562:T:TC	acceptor_gain	1.0000
7:84011020:A:AC	donor_gain	1.0000
7:84011021:C:CC	donor_gain	1.0000
7:84011090:CT:C	acceptor_gain	1.0000
7:84011092:C:CC	acceptor_gain	1.0000
7:84011181:A:AC	donor_gain	1.0000
7:84011182:C:CC	donor_gain	1.0000
7:84011182:CG:C	donor_gain	1.0000
7:84011182:CGCA:C	donor_gain	1.0000

AlphaMissense

5155 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:83961740:G:C	C649W	1.000
7:83961741:C:G	C649S	1.000
7:83961742:A:G	C649R	1.000
7:83961742:A:T	C649S	1.000
7:83961748:A:C	Y647D	1.000
7:83963241:C:A	W608C	1.000
7:83963241:C:G	W608C	1.000
7:83981362:C:A	W537C	1.000
7:83981362:C:G	W537C	1.000
7:83981364:A:G	W537R	1.000
7:83981364:A:T	W537R	1.000
7:83981368:A:C	C535W	1.000
7:84007470:A:C	C341W	1.000
7:84011229:G:C	C293W	1.000
7:84011230:C:T	C293Y	1.000
7:84011231:A:G	C293R	1.000
7:84011261:A:G	W283R	1.000
7:84011261:A:T	W283R	1.000
7:84011287:C:T	G274E	1.000
7:84046383:C:G	R203P	1.000
7:84110500:G:C	C141W	1.000
7:84110501:C:T	C141Y	1.000
7:84110527:A:C	C132W	1.000
7:84129148:C:G	C103S	1.000
7:84129149:A:T	C103S	1.000
7:83961522:C:G	C722S	0.999
7:83961522:C:T	C722Y	0.999
7:83961523:A:G	C722R	0.999
7:83961523:A:T	C722S	0.999
7:83961693:A:G	L665P	0.999

dbSNP variants (sampled 300 via entrez): RS1000000172 (7:83994537 C>A,G), RS1000001349 (7:84357715 T>A), RS1000010660 (7:83996712 G>C), RS1000014170 (7:84034329 G>A), RS1000018654 (7:84392006 G>A), RS1000033853 (7:84094246 A>C,G), RS1000042587 (7:84424362 AAAT>A), RS1000046697 (7:84244112 C>T), RS1000055466 (7:83974739 G>T), RS1000071540 (7:84369621 A>G), RS1000077221 (7:84067463 A>T), RS1000081179 (7:83986477 C>T), RS1000082600 (7:84244433 T>C), RS1000084540 (7:84175212 A>G), RS1000086048 (7:84310795 G>A,T)

Disease associations

OMIM: gene MIM:603961 | disease phenotypes: MIM:614897, MIM:212720

GenCC curated gene-disease

Disease	Classification	Inheritance
skeletal dysplasia	Definitive	Autosomal recessive
hypogonadotropic hypogonadism 16 with or without anosmia	Strong	Autosomal dominant
multiple congenital anomalies/dysmorphic syndrome	Moderate	Autosomal recessive
Brugada syndrome	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant

Mondo (8): hypogonadotropic hypogonadism 16 with or without anosmia (MONDO:0013961), CHARGE syndrome (MONDO:0008965), Martsolf syndrome 1 (MONDO:8000008), amenorrhea (MONDO:0001836), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), Brugada syndrome (MONDO:0015263), Kallmann syndrome (MONDO:0018800), skeletal dysplasia (MONDO:0018230)

Orphanet (4): Kallmann syndrome (Orphanet:478), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), CHARGE syndrome (Orphanet:138), Cataract-intellectual disability-hypogonadism syndrome (Orphanet:1387)

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000175	Cleft palate
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000639	Nystagmus
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000823	Delayed puberty
HP:0000830	Anterior hypopituitarism
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001279	Syncope
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001335	Bimanual synkinesia

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001154_7	Attention deficit hyperactivity disorder	8.000000e-06
GCST001199_4	Iris characteristics	7.000000e-11
GCST001199_5	Iris characteristics	3.000000e-06
GCST001366_3	Prion diseases	3.000000e-06
GCST001762_361	Obesity-related traits	9.000000e-06
GCST001877_51	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	4.000000e-06
GCST005022_17	Major depression and alcohol dependence	2.000000e-11
GCST006110_34	Nose morphology	8.000000e-06
GCST006979_129	Heel bone mineral density	4.000000e-15
GCST008151_82	Waist circumference	3.000000e-07
GCST008160_35	Waist circumference	3.000000e-07
GCST010002_256	Refractive error	7.000000e-11
GCST010320_14	PR interval	5.000000e-10
GCST010321_33	PR interval	7.000000e-11
GCST010702_82	Subcortical volume (MOSTest)	5.000000e-09
GCST010703_199	Brain morphology (MOSTest)	1.000000e-11
GCST011176_22	Stroke	8.000000e-07
GCST90011892_7	Retinitis pigmentosa	1.000000e-05

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0005116	urinary metabolite measurement
EFO:0009270	heel bone mineral density
EFO:0004462	PR interval
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D058747	CHARGE Syndrome	C09.218.458.341.186.500.250; C10.597.751.418.341.186.500.250; C10.597.751.941.162.625.250; C11.270.147.500; C11.966.075.375.250; C16.131.077.299.250; C16.320.165; C23.888.592.763.393.341.186.500.500; C23.888.592.763.941.162.625.500
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
C536028	Martsolf syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	5
trichostatin A	affects cotreatment, decreases expression, increases expression	3
(+)-JQ1 compound	decreases expression, affects cotreatment	3
Estradiol	increases expression, decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases abundance, affects splicing, increases expression	2
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction, increases expression	2
Temozolomide	affects response to substance, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Cadmium	increases abundance, increases expression	2
Endosulfan	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	decreases methylation	1
methylmercuric chloride	decreases expression	1
deoxynivalenol	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	decreases expression	1
evodiamine	decreases reaction, increases expression, decreases expression	1
chromium hexavalent ion	increases expression, affects cotreatment, increases activity, decreases reaction	1
corosolic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
mirdametinib	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
ferrostatin-1	decreases reaction, increases expression	1
Dasatinib	decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT00701077	PHASE3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	PHASE3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT02933437	PHASE2	UNKNOWN	The Response To Ajmaline Provocation in Healthy Subjects
NCT07146880	PHASE2	NOT_YET_RECRUITING	Empagliflozin as a Potential Therapeutic Solution for Patients With Brugada Syndrome
NCT00064987	PHASE2	TERMINATED	Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00392756	PHASE1	COMPLETED	Examination of Idiopathic Hypogonadotropic Hypogonadism (IHH)and Kallmann Syndrome (KS)
NCT00493961	PHASE1	COMPLETED	Studying the Effects of 7 Days of Gonadotropin Releasing Hormone (GnRH) Treatment in Men With Hypogonadism
NCT00914823	PHASE1	COMPLETED	Kisspeptin Administration in the Adult
NCT01438034	PHASE1	COMPLETED	Kisspeptin in the Evaluation of Delayed Puberty
NCT03118479	PHASE1	TERMINATED	Effect of Varying Testosterone Levels on Insulin Sensitivity in Men With Idiopathic Hypogonadotropic Hypogonadism (IHH)
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT02014961	Not specified	UNKNOWN	Worm Study: Modifier Genes in Sudden Cardiac Death
NCT02052765	Not specified	COMPLETED	AnalyST & Brugada Syndrome - Feasibility Study
NCT02302274	Not specified	COMPLETED	Diagnostic Value and Safety of Flecainide Infusion Test in Brugada Syndrome
NCT02344277	Not specified	COMPLETED	Evaluation of Subcutaneous Implantable Cardiac Defibrillator in Brugada Patients
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02641431	Not specified	COMPLETED	Epicardial Ablation in Brugada Syndrome
NCT02704416	Not specified	COMPLETED	Ablation in Brugada Syndrome for the Prevention of VF
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03435393	Not specified	UNKNOWN	Ripple Mapping for Epicardial Mapping of Brugada Syndrome
NCT03485508	Not specified	UNKNOWN	The Brugada Syndrome: a Follow-up Study
NCT03491475	Not specified	UNKNOWN	Echocardiography During Ajmaline Test
NCT03524079	Not specified	COMPLETED	Right Ventricle Morphology and Hemodynamics in BrS
NCT03764592	Not specified	COMPLETED	VF Mapping in Brugada and Early Repolarization Syndromes
NCT03775954	Not specified	RECRUITING	Fetal Electrophysiologic Abnormalities in High-Risk Pregnancies Associated With Fetal Demise