SEMA3C

Summary

SEMA3C (semaphorin 3C, HGNC:10725) is a protein-coding gene on chromosome 7q21.11, encoding Semaphorin-3C (Q99985). Binds to plexin family members and plays an important role in the regulation of developmental processes.

This gene encodes a secreted glycoprotein that belongs to the semaphorin class 3 family of neuronal guidance cues. The encoded protein contains an N-terminal sema domain, integrin and immunoglobulin-like domains, and a C-terminal basic domain. Homodimerization and proteolytic cleavage of the C-terminal propeptide are necessary for the function of the encoded protein. It binds a neuropilin co-receptor before forming a heterotrimeric complex with an associated plexin. An increase in the expression of this gene correlates with an increase in cancer cell invasion and adhesion. Naturally occurring mutations in this gene are associated with Hirschsprung disease.

Source: NCBI Gene 10512 — RefSeq curated summary.

At a glance

• GWAS associations: 40
• Clinical variants (ClinVar): 263 total
• Phenotypes (HPO): 19
• MANE Select transcript: NM_006379

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10725
Approved symbol	SEMA3C
Name	semaphorin 3C
Location	7q21.11
Locus type	gene with protein product
Status	Approved
Aliases	SemE
Ensembl gene	ENSG00000075223
Ensembl biotype	protein_coding
OMIM	602645
Entrez	10512

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 15 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000265361, ENST00000411788, ENST00000419255, ENST00000427167, ENST00000458729, ENST00000459652, ENST00000470581, ENST00000475955, ENST00000487621, ENST00000878446, ENST00000878447, ENST00000878448, ENST00000878449, ENST00000953787, ENST00000953788, ENST00000953789, ENST00000953790, ENST00000953791, ENST00000953792, ENST00000953793, ENST00000953794, ENST00000953795

RefSeq mRNA: 3 — MANE Select: NM_006379 NM_001350120, NM_001350121, NM_006379

CCDS: CCDS5596

Canonical transcript exons

ENST00000265361 — 18 exons

Exon	Start	End
ENSE00000454552	80765155	80765243
ENSE00000698637	80748898	80749028
ENSE00000698638	80751269	80751336
ENSE00000698640	80758331	80758488
ENSE00000698641	80761616	80761657
ENSE00000698642	80789306	80789528
ENSE00000698650	80818299	80818418
ENSE00001129553	80827425	80827487
ENSE00001429726	80918828	80919051
ENSE00001798358	80742538	80745307
ENSE00003468038	80805639	80805758
ENSE00003507036	80916679	80916819
ENSE00003528947	80798092	80798236
ENSE00003547215	80800757	80800826
ENSE00003555958	80810611	80810701
ENSE00003616439	80828585	80828745
ENSE00003638212	80802665	80802779
ENSE00003647434	80804106	80804248

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.0487 / max 1693.0540, expressed in 1525 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84540	38.4976	1401
84545	11.0518	1213
84539	10.6951	1128
84541	7.3340	1260
84543	4.3538	1081
84542	3.1096	1032
84544	2.3488	885
84533	0.2396	101
84546	0.2331	116
84525	0.2271	67

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mammary duct	UBERON:0001765	99.11	gold quality
synovial joint	UBERON:0002217	99.11	gold quality
calcaneal tendon	UBERON:0003701	98.80	gold quality
cortical plate	UBERON:0005343	98.60	gold quality
cartilage tissue	UBERON:0002418	98.59	gold quality
epithelium of mammary gland	UBERON:0003244	98.29	gold quality
germinal epithelium of ovary	UBERON:0001304	98.16	gold quality
skin of hip	UBERON:0001554	97.90	gold quality
endometrium epithelium	UBERON:0004811	97.86	gold quality
vena cava	UBERON:0004087	97.63	gold quality
layer of synovial tissue	UBERON:0007616	97.10	gold quality
cauda epididymis	UBERON:0004360	96.90	gold quality
biceps brachii	UBERON:0001507	96.84	gold quality
parietal pleura	UBERON:0002400	96.79	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.78	gold quality
bronchial epithelial cell	CL:0002328	96.66	gold quality
pigmented layer of retina	UBERON:0001782	96.62	gold quality
tendon	UBERON:0000043	96.61	gold quality
urethra	UBERON:0000057	96.27	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.06	gold quality
upper leg skin	UBERON:0004262	96.00	gold quality
heart right ventricle	UBERON:0002080	95.70	gold quality
seminal vesicle	UBERON:0000998	95.57	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.52	gold quality
epithelium of bronchus	UBERON:0002031	95.51	gold quality
thoracic mammary gland	UBERON:0005200	95.43	gold quality
mammary gland	UBERON:0001911	95.42	gold quality
myocardium	UBERON:0002349	95.28	gold quality
pons	UBERON:0000988	95.19	gold quality
bronchus	UBERON:0002185	95.13	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	37.18
E-CURD-114	yes	12.12
E-CURD-112	no	2.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP4, CTNNB1, GATA6

miRNA regulators (miRDB)

190 targeting SEMA3C, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-518E-5P	100.00	67.66	954
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-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959

Literature-anchored findings (GeneRIF, showing 40)

• correlation of gene expression with histopathological findings and clinical outcome in ovarian and breast cancer patients (PMID:12174914)
• 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)
• S3C from macrophages and fibroblasts, which is selectively directed against sympathetic nerve fibers, could be one element responsible for reduced sympathetic innervation in rheumatoid arthritis tissue (PMID:15077297)
• sema3A and sema3C have opposite roles in neoplasm invasiveness and adhesion (PMID:17390026)
• mutations in GATA6 are genetic causes of congenital heart diseases involving outflow tract defects, as a result of the disruption of the direct regulation of semaphorin 3C-plexin A2 signaling (PMID:19666519)
• cleavage of semaphorin 3C induced by ADAMTS1 promotes the migration of breast cancer cells, indicating that the co-expression of these molecules in tumors may contribute to the metastatic program (PMID:19915008)
• The role of the motoneuronal Sema3 code could be to set population-specific axon sensitivity to limb-derived chemotropic Sema3 proteins, therefore specifying stereotyped motor nerve trajectories in their target field. (PMID:22899844)
• Capillary-like tubular formation was reduced by the addition of culture media of sema3C miRNA cells. (PMID:22924992)
• SEMA3C is a novel adipokine regulated by weight changes. (PMID:23666167)
• Glioma stem cells preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/nuclear factor (NF)-kB signaling. (PMID:25464848)
• p65-Sema3C, but not FR-sema3C, rendered A549 lung cancer cells resistant to serum deprivation, suggesting that previously reported protumorigenic activities of sema3C may be due to p65-Sema3C produced by tumor cells (PMID:25808871)
• Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability. (PMID:25839327)
• SEMA3C expression increased in the transition from normal to malignant breast lesions and correlated with microvessel density and tumour grade and is differentially regulated in the development of breast versus oral neoplasia. (PMID:25910410)
• Increased levels of Sema3C protein may be associated with the progression of glioma tumor and have potential as a prognostic marker for outcome of glioma patients. (PMID:26032848)
• Data show significant increases in semaphorin3C, 3D and their receptor neuropilin-2 in degenerate samples which were shown to contain nerves and blood vessels, compared to non-degenerate samples without nerves and blood vessels. (PMID:26286962)
• SEMA3C plays a role in the progression of breast cancer and may positively influence breast cancer cell adhesion, invasion and proliferation, as well as being associated with grade of disease and estrogen receptor status. (PMID:26977026)
• The exploratory genome-wide association studies confirmed APOE and identified the novel loci: rs2525776 near SEMA3C (P = 1 x 10(-8), OR = 3.3 [2.1-5.1]). (PMID:26993346)
• in situ hybridization analysis revealed that Sema 3C and Sema 3F are expressed at the RNA level in the endometriosis affected peritoneum (PMID:27558236)
• FR-sema3C could perhaps be used for the treatment of AMD. (PMID:28036336)
• Androgen receptor transcriptionally regulates semaphorin 3C in a GATA2-dependent manner in prostate tumor cells. (PMID:28038451)
• Aberrant expression of sema3c is correlated with poor prognosis of pancreatic ductal adenocarcinoma patients and promotes tumor growth and metastasis by activating ERK1/2 signaling pathway. (PMID:28315433)
• we show that SEMA3C promotes migration and invasion in vitro and cell dissemination in vivo. (PMID:28904399)
• In the absence of neuropilins, plexin-A4 formed complexes with plexin-D1, and was required in addition to plexin-D1 to enable Sema3C-induced signal transduction. (PMID:29661844)
• 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)
• Both, anti-angiogenic and anti-tumorigenic activities of Sema3C were enhanced by the treatment of sodium valproate and, importantly, were not attributed to the cytotoxic effects. (PMID:31726800)
• Increased Expression of Sema3C Indicates a Poor Prognosis and Is Regulated by miR-142-5p in Glioma. (PMID:32238705)
• Whole-genome sequencing of glioblastoma reveals enrichment of non-coding constraint mutations in known and novel genes. (PMID:32513296)
• Semaphorin 3 C is a Novel Adipokine Representing Exercise-Induced Improvements of Metabolism in Metabolically Healthy Obese Young Males. (PMID:32561824)
• Semaphorin-3C Is Upregulated in Polycystic Kidney Epithelial Cells and Inhibits Angiogenesis of Glomerular Endothelial Cells. (PMID:32610315)
• MiR-146a Regulates Migration and Invasion by Targeting NRP2 in Circulating-Tumor Cell Mimicking Suspension Cells. (PMID:33396906)
• MAOA promotes prostate cancer cell perineural invasion through SEMA3C/PlexinA2/NRP1-cMET signaling. (PMID:33420365)
• SEMA3C induces androgen synthesis in prostatic stromal cells through paracrine signaling. (PMID:33503318)
• Effect of semaphorin 3C gene variants in multifactorial Hirschsprung disease. (PMID:33557656)
• LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C. (PMID:33568674)
• Whole-genome sequencing identifies functional noncoding variation in SEMA3C that cosegregates with dyslexia in a multigenerational family. (PMID:34076780)
• Semaphorin 3C exacerbates liver fibrosis. (PMID:37055018)
• Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma. (PMID:37080989)
• Semaphorin 3C promotes de novo steroidogenesis in prostate cancer cells. (PMID:37800655)
• Clinically-observed FOXA1 mutations upregulate SEMA3C through transcriptional derepression in prostate cancer. (PMID:38528115)
• Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression. (PMID:38956074)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sema3c	ENSDARG00000034300
mus_musculus	Sema3c	ENSMUSG00000028780
rattus_norvegicus	Sema3c	ENSRNOG00000006526

Paralogs (19): SEMA3F (ENSG00000001617), SEMA3G (ENSG00000010319), SEMA3B (ENSG00000012171), SEMA3A (ENSG00000075213), 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-3C — Q99985 (reviewed: Q99985)

Alternative names: Semaphorin-E

All UniProt accessions (3): Q99985, F2Z2Y0, F8WEP9

UniProt curated annotations — full annotation on UniProt →

Function. Binds to plexin family members and plays an important role in the regulation of developmental processes. Required for normal cardiovascular development during embryogenesis. Functions as attractant for growing axons, and thereby plays an important role in axon growth and axon guidance.

Subunit / interactions. Interacts with PLXND1.

Subcellular location. Secreted.

Tissue specificity. Expressed intensely in the heart, skeletal muscle, colon, small intestine, ovary, testis, and prostate. Faint expression ubiquitously among other organs, including brain.

Similarity. Belongs to the semaphorin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99985-1	1	yes
Q99985-2	2

RefSeq proteins (3): NP_001337049, NP_001337050, NP_006370* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	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

Pfam: PF01403, PF07679

UniProt features (24 total): glycosylation site 7, disulfide bond 6, splice variant 3, domain 2, sequence variant 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99985-F1	85.69	0.69

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): 101–112, 130–139, 266–378, 290–338, 514–532, 643–709

Glycosylation sites (7): 465, 585, 586, 81, 123, 252, 268

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 424 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_GLAND_MORPHOGENESIS, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_SALIVARY_GLAND_DEVELOPMENT

GO Biological Process (22): neural crest cell migration (GO:0001755), somitogenesis (GO:0001756), blood vessel remodeling (GO:0001974), outflow tract septum morphogenesis (GO:0003148), cardiac right ventricle morphogenesis (GO:0003215), pulmonary myocardium development (GO:0003350), immune response (GO:0006955), axon guidance (GO:0007411), response to xenobiotic stimulus (GO:0009410), post-embryonic development (GO:0009791), neural tube development (GO:0021915), positive regulation of cell migration (GO:0030335), negative chemotaxis (GO:0050919), limb bud formation (GO:0060174), dichotomous subdivision of terminal units involved in salivary gland branching (GO:0060666), semaphorin-plexin signaling pathway (GO:0071526), cardiac endothelial to mesenchymal transition (GO:0140074), positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis (GO:1905312), outflow tract morphogenesis (GO:0003151), nervous system development (GO:0007399), heart development (GO:0007507), cell differentiation (GO:0030154)

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

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chordate embryonic development	2
anatomical structure formation involved in morphogenesis	2
signaling receptor binding	2
neural crest cell development	1
mesenchymal cell migration	1
anterior/posterior pattern specification	1
segmentation	1
somite development	1
tissue remodeling	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
cardiac ventricle morphogenesis	1
striated muscle tissue development	1
venous blood vessel development	1
immune system process	1
response to stimulus	1
axonogenesis	1
neuron projection guidance	1
response to chemical	1
multicellular organism development	1
multicellular organismal process	1
nervous system development	1
tube development	1
epithelium development	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
chemotaxis	1
limb morphogenesis	1
branching involved in salivary gland morphogenesis	1
dichotomous subdivision of an epithelial terminal unit	1
cell surface receptor signaling pathway	1
mesenchymal cell differentiation	1
cardiac neural crest cell migration involved in outflow tract morphogenesis	1
positive regulation of cell migration	1
regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis	1
heart morphogenesis	1
anatomical structure morphogenesis	1
system development	1
receptor ligand activity	1

Protein interactions and networks

STRING

1130 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA3C	NRP2	O60462	992
SEMA3C	PLXND1	Q9Y4D7	987
SEMA3C	NRP1	O14786	979
SEMA3C	PLXNA1	Q9UIW2	958
SEMA3C	PLXNA2	O75051	954
SEMA3C	PLXNA3	P51805	870
SEMA3C	GATA6	P78327	827
SEMA3C	PLXNA4	Q9HCM2	759
SEMA3C	NTN1	O95631	636
SEMA3C	PLXNB2	O15031	629
SEMA3C	PLXNB1	O43157	596
SEMA3C	PLXNB3	Q9ULL4	581
SEMA3C	EFNB1	P98172	574
SEMA3C	VEGFC	P49767	519
SEMA3C	EFNB2	P52799	510

IntAct

63 interactions, top by confidence:

A	B	Type	Score
SURF2	RPL5	psi-mi:“MI:0914”(association)	0.800
NRP1	CSNK2A2	psi-mi:“MI:0914”(association)	0.790
SDC2	PDPK1	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
HDGFL2	CDC7	psi-mi:“MI:0914”(association)	0.530
NIFK	RSL1D1	psi-mi:“MI:0914”(association)	0.530
SEMA3C	TTC38	psi-mi:“MI:0915”(physical association)	0.500
SEMA3C	PDIA3	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
Srp72		psi-mi:“MI:0914”(association)	0.350
Rrbp1	PIPSL	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
SDC2	METTL8	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
IGFL3	CBX4	psi-mi:“MI:0914”(association)	0.350
CCL3L1	QSOX1	psi-mi:“MI:0914”(association)	0.350
SLURP1	MANBA	psi-mi:“MI:0914”(association)	0.350
C1orf54	AGRN	psi-mi:“MI:0914”(association)	0.350
C1QTNF7	AGRN	psi-mi:“MI:0914”(association)	0.350
EDDM3B	PLXNB2	psi-mi:“MI:0914”(association)	0.350
VNN1	SMAD7	psi-mi:“MI:0914”(association)	0.350

BioGRID (64): SEMA3C (Affinity Capture-MS), SEMA3C (Affinity Capture-MS), SEMA3C (Affinity Capture-MS), SEMA3C (Affinity Capture-MS), SEMA3C (Affinity Capture-MS), SEMA3C (Negative Genetic), SEMA3C (Affinity Capture-RNA), SEMA3C (Synthetic Lethality), SEMA3C (Proximity Label-MS), SEMA3C (Proximity Label-MS), SEMA3C (Affinity Capture-MS), SEMA3F (Affinity Capture-MS), SEMA3A (Affinity Capture-MS), SEMA3C (Affinity Capture-MS), SEMA3C (Affinity Capture-MS)

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

3 interactions.

A	Effect	B	Mechanism
SEMA3C	up-regulates	NRP2	binding
GATA6	“up-regulates quantity by expression”	SEMA3C	“transcriptional regulation”
SEMA3C	“up-regulates activity”	PLXNA2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Metabolism of carbohydrates and carbohydrate derivatives	5	12.8×	2e-03
Extracellular matrix organization	6	8.1×	2e-03
PIP3 activates AKT signaling	5	7.1×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	155
Likely benign	73
Benign	15

Top pathogenic / likely-pathogenic (0)

SpliceAI

4070 predictions. Top by Δscore:

Variant	Effect	Δscore
7:80748894:TCA:T	donor_loss	1.0000
7:80748895:CAC:C	donor_loss	1.0000
7:80748897:CCT:C	donor_gain	1.0000
7:80749027:TG:T	acceptor_gain	1.0000
7:80749029:C:CC	acceptor_gain	1.0000
7:80749033:C:CT	acceptor_gain	1.0000
7:80749037:C:CT	acceptor_gain	1.0000
7:80749038:A:T	acceptor_gain	1.0000
7:80749042:A:AC	acceptor_gain	1.0000
7:80749042:A:C	acceptor_gain	1.0000
7:80749050:C:CT	acceptor_gain	1.0000
7:80749051:G:T	acceptor_gain	1.0000
7:80761658:C:CC	acceptor_gain	1.0000
7:80765149:TCAAA:T	donor_loss	1.0000
7:80765150:CAAAC:C	donor_loss	1.0000
7:80765151:AAAC:A	donor_loss	1.0000
7:80765152:AACC:A	donor_loss	1.0000
7:80765153:ACCTT:A	donor_loss	1.0000
7:80765154:C:G	donor_loss	1.0000
7:80765165:T:TA	donor_gain	1.0000
7:80765239:CCGAT:C	acceptor_gain	1.0000
7:80765240:CGAT:C	acceptor_gain	1.0000
7:80765240:CGATC:C	acceptor_gain	1.0000
7:80765243:TC:T	acceptor_loss	1.0000
7:80765244:C:CC	acceptor_gain	1.0000
7:80765245:T:C	acceptor_loss	1.0000
7:80765249:T:TC	acceptor_gain	1.0000
7:80789301:TTTAC:T	donor_loss	1.0000
7:80789302:TTA:T	donor_loss	1.0000
7:80789303:TA:T	donor_loss	1.0000

AlphaMissense

4978 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:80745221:G:C	C643W	1.000
7:80745222:C:G	C643S	1.000
7:80745222:C:T	C643Y	1.000
7:80745223:A:G	C643R	1.000
7:80745223:A:T	C643S	1.000
7:80745229:A:C	Y641D	1.000
7:80748931:C:A	W603C	1.000
7:80748931:C:G	W603C	1.000
7:80748933:A:G	W603R	1.000
7:80748933:A:T	W603R	1.000
7:80748966:A:G	C592R	1.000
7:80751288:G:C	C564W	1.000
7:80751289:C:G	C564S	1.000
7:80751289:C:T	C564Y	1.000
7:80751290:A:G	C564R	1.000
7:80751290:A:T	C564S	1.000
7:80751324:T:A	R552S	1.000
7:80751324:T:G	R552S	1.000
7:80758357:A:C	C539W	1.000
7:80758358:C:G	C539S	1.000
7:80758358:C:T	C539Y	1.000
7:80758359:A:G	C539R	1.000
7:80758359:A:T	C539S	1.000
7:80758372:C:A	W534C	1.000
7:80758372:C:G	W534C	1.000
7:80758374:A:G	W534R	1.000
7:80758374:A:T	W534R	1.000
7:80758378:G:C	C532W	1.000
7:80758379:C:A	C532F	1.000
7:80758379:C:G	C532S	1.000

dbSNP variants (sampled 300 via entrez): RS1000005298 (7:80883541 A>G), RS1000017837 (7:80897891 G>C), RS1000025827 (7:80819189 AT>A,ATT), RS1000062571 (7:80838651 A>T), RS1000073424 (7:80888196 T>A,C), RS1000083319 (7:80760163 G>T), RS1000093480 (7:80857505 T>C), RS1000093518 (7:80796925 T>A,C), RS1000096329 (7:80853412 T>C), RS1000110650 (7:80817127 T>A,C), RS1000113172 (7:80773901 G>C), RS1000145971 (7:80774992 C>G,T), RS1000148335 (7:80876951 G>A,T), RS1000187176 (7:80878374 G>A), RS1000202325 (7:80919680 C>T)

Disease associations

OMIM: gene MIM:602645 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001561	Polyhydramnios
HP:0001824	Weight loss
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002251	Aganglionic megacolon
HP:0003270	Abdominal distention
HP:0004322	Short stature
HP:0004387	Enterocolitis
HP:0005214	Intestinal obstruction
HP:0011968	Feeding difficulties
HP:0012719	Functional abnormality of the gastrointestinal tract
HP:0031369	Colon perforation
HP:0034754	Bilious emesis
HP:0100806	Sepsis
HP:6000224	Delayed passage of meconium

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000386_1	Bilirubin levels	2.000000e-06
GCST003081_11	Glucocorticoid-induced osteonecrosis (age 10 years and older)	5.000000e-06
GCST003452_16	Posterior cortical atrophy and Alzheimer’s disease	1.000000e-08
GCST003660_13	HDL cholesterol	1.000000e-08
GCST005170_30	Intraocular pressure	6.000000e-12
GCST005331_3	CSF tryptophan concentration in tuberculous meningitis	6.000000e-06
GCST005580_10	Intraocular pressure	6.000000e-15
GCST005580_39	Intraocular pressure	5.000000e-13
GCST005790_6	Rosacea symptom severity	1.000000e-07
GCST006005_13	High density lipoprotein cholesterol levels	5.000000e-21
GCST006065_8	Glaucoma (primary open-angle)	7.000000e-09
GCST006394_12	Intraocular pressure	4.000000e-11
GCST006395_5	Glaucoma	2.000000e-06
GCST006585_2762	Blood protein levels	7.000000e-08
GCST007094_112	Diastolic blood pressure	1.000000e-09
GCST008075_12	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-45
GCST008075_147	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-51
GCST008075_98	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-08
GCST008084_166	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-08
GCST008084_63	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-08
GCST008085_189	HDL cholesterol levels in current drinkers	5.000000e-06
GCST008085_71	HDL cholesterol levels in current drinkers	2.000000e-07
GCST009103_4	Resistance to antihypertensive treatment in hypertension	2.000000e-06
GCST009391_95	Metabolite levels	3.000000e-06
GCST009725_47	Intraocular pressure	4.000000e-11
GCST009726_12	Glaucoma	3.000000e-08
GCST011348_13	High density lipoprotein cholesterol levels	1.000000e-18
GCST90002403_576	Red blood cell count	3.000000e-09
GCST90011770_11	Glaucoma (primary open-angle)	1.000000e-14
GCST90020025_352	Waist-to-hip ratio adjusted for BMI	6.000000e-09

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004695	intraocular pressure measurement
EFO:0008534	tryptophan measurement
EFO:0009180	rosacea severity measurement
EFO:0006336	diastolic blood pressure
EFO:0004329	alcohol drinking
EFO:1002006	treatment-resistant hypertension
EFO:0010473	cyclic adenosine monophosphate measurement
EFO:0004305	erythrocyte count
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7779029	Toxicity	3	irinotecan	Non-Small Cell Lung Carcinoma

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7779029	SEMA3C	3	0.00	1	irinotecan
rs11979430	SEMA3C		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Air Pollutants	increases expression, decreases expression, increases abundance	4
Estradiol	affects cotreatment, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
bisphenol A	decreases expression, decreases methylation	2
mercuric bromide	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
bisphenol S	decreases expression, decreases methylation	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Calcitriol	increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
alpha phellandrene	decreases expression	1
titanium dioxide	affects expression	1
ascorbate-2-phosphate	affects cotreatment, increases expression, affects binding	1
arsenite	affects binding, decreases reaction	1
afimoxifene	increases expression	1
sulforaphane	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	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_D8A0	Ubigene A-549 SEMA3C KO	Cancer cell line	Male

Clinical trials (associated diseases)

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