SEMA4D

Summary

SEMA4D (semaphorin 4D, HGNC:10732) is a protein-coding gene on chromosome 9q22.2, encoding Semaphorin-4D (Q92854). Cell surface receptor for PLXNB1 and PLXNB2 that plays an important role in cell-cell signaling.

Enables identical protein binding activity; semaphorin receptor binding activity; and transmembrane signaling receptor activity. Involved in several processes, including positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; regulation of neuron projection development; and regulation of primary metabolic process. Located in microtubule organizing center; nucleoplasm; and plasma membrane.

Source: NCBI Gene 10507 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 196 total
• Phenotypes (HPO): 55
• Druggable target: yes
• MANE Select transcript: NM_001371194

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10732
Approved symbol	SEMA4D
Name	semaphorin 4D
Location	9q22.2
Locus type	gene with protein product
Status	Approved
Aliases	CD100, coll-4, FLJ39737
Ensembl gene	ENSG00000187764
Ensembl biotype	protein_coding
OMIM	601866
Entrez	10507

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 36 protein_coding, 5 retained_intron, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000339861, ENST00000356444, ENST00000418828, ENST00000420101, ENST00000420670, ENST00000420681, ENST00000420987, ENST00000422704, ENST00000429836, ENST00000433650, ENST00000438547, ENST00000450295, ENST00000455551, ENST00000464051, ENST00000469653, ENST00000474258, ENST00000475255, ENST00000482128, ENST00000486935, ENST00000492386, ENST00000537934, ENST00000540183, ENST00000540475, ENST00000544513, ENST00000858567, ENST00000858568, ENST00000858569, ENST00000858570, ENST00000858571, ENST00000858572, ENST00000858573, ENST00000858574, ENST00000858575, ENST00000858576, ENST00000858577, ENST00000917881, ENST00000917882, ENST00000917883, ENST00000917884, ENST00000917885, ENST00000917886, ENST00000917887, ENST00000917888, ENST00000917889, ENST00000917890, ENST00000917891, ENST00000947512

RefSeq mRNA: 11 — MANE Select: NM_001371194 NM_001142287, NM_001371194, NM_001371195, NM_001371196, NM_001371197, NM_001371198, NM_001371199, NM_001371200, NM_001371201, NM_001371202, NM_006378

CCDS: CCDS47991, CCDS6685

Canonical transcript exons

ENST00000422704 — 16 exons

Exon	Start	End
ENSE00001364475	89388636	89388792
ENSE00001365232	89393562	89393655
ENSE00001371945	89386367	89386482
ENSE00001381319	89392423	89392536
ENSE00001383236	89388872	89389047
ENSE00001384069	89391264	89391415
ENSE00001384090	89387386	89387608
ENSE00001405010	89402871	89403016
ENSE00001416368	89405351	89405699
ENSE00001424804	89455888	89455953
ENSE00001432732	89399276	89399338
ENSE00002237006	89497919	89498113
ENSE00002253755	89377235	89379629
ENSE00002278000	89396737	89396835
ENSE00003553839	89381174	89381346
ENSE00003578303	89381055	89381098

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 99.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.1300 / max 509.9313, expressed in 1280 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101331	17.9109	1268
101321	0.7609	78
101311	0.4247	142
101330	0.2538	136
101312	0.2229	78
101310	0.1614	94
101324	0.1462	56
101320	0.0851	37
101323	0.0552	31
101322	0.0516	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.12	gold quality
spinal cord	UBERON:0002240	98.61	gold quality
granulocyte	CL:0000094	97.85	gold quality
corpus callosum	UBERON:0002336	97.23	gold quality
lower esophagus mucosa	UBERON:0035834	96.89	gold quality
blood	UBERON:0000178	96.83	gold quality
leukocyte	CL:0000738	96.29	gold quality
monocyte	CL:0000576	96.26	gold quality
inferior vagus X ganglion	UBERON:0005363	96.20	gold quality
mononuclear cell	CL:0000842	96.14	gold quality
lymph node	UBERON:0000029	95.81	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.75	gold quality
medial globus pallidus	UBERON:0002477	95.73	gold quality
globus pallidus	UBERON:0001875	95.31	gold quality
metanephros cortex	UBERON:0010533	95.19	gold quality
substantia nigra	UBERON:0002038	95.10	gold quality
spleen	UBERON:0002106	95.07	gold quality
midbrain	UBERON:0001891	94.84	gold quality
gastrocnemius	UBERON:0001388	94.46	gold quality
subthalamic nucleus	UBERON:0001906	94.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.08	gold quality
vermiform appendix	UBERON:0001154	94.03	gold quality
amygdala	UBERON:0001876	94.00	gold quality
Ammon’s horn	UBERON:0001954	93.88	gold quality
putamen	UBERON:0001874	93.85	gold quality
bone marrow cell	CL:0002092	93.60	gold quality
muscle of leg	UBERON:0001383	93.60	gold quality
right frontal lobe	UBERON:0002810	93.12	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.98	gold quality
buccal mucosa cell	CL:0002336	92.95	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	22.51
E-ANND-3	yes	9.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPE, HIF1A

miRNA regulators (miRDB)

91 targeting SEMA4D, 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-3120-5P	100.00	65.56	965
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481

Literature-anchored findings (GeneRIF, showing 40)

• Leukemic & normal CD5+ B cells express CD100; upon interaction between CD100 & Plexin-B1, both increase their proliferative activity & life span. CD100/Plexin-B1 crosstalk is not malignancy related but reproduces a mechanism used by normal CD5+ B cells. (PMID:12406905)
• Soluble CD100 induces a progressive decrease in process extension of oligodendrocytes, followed by their death and the death of multipotent neural precursors. (PMID:14707103)
• up-modulation of the survival receptor CD100 is restricted to proliferating B-cell leukemia cells (PMID:15613544)
• demonstrate that Sema4D is angiogenic in vitro and in vivo and that this effect is mediated by its high-affinity receptor, Plexin B1, and that biologic effects elicited by Plexin B1 require coupling and activation of the Met tyrosine kinase (PMID:15632204)
• Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway (PMID:16055703)
• Data show that semaphorin 4D (Sema4D), a protein originally shown to regulate axonal growth cone guidance in the developing central nervous system, is highly expressed in cell lines derived from head and neck squamous cell carcinomas. (PMID:16754882)
• semaphorin 4D has a role in platelet responses to vascular injury (PMID:17244710)
• Multivariate analysis revealed that CD100 expression and tumor size were independent prognosticators for overall survival. (PMID:17520683)
• CD100-CD72 interaction can be the mechanism by which NK cell communicate with B cells. (PMID:17786190)
• a novel mechanism by which plexin-mediated signaling can be regulated and explains how Sema4D can exert different biological activities through the differential association of its receptor with ErbB-2 and Met. (PMID:18025083)
• show here that activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation creates docking sites for the SH2 domains of phospholipase Cgamma. (PMID:19805522)
• neither Sema3A nor Sema4D likely influence the susceptibility to Alzheimer’s disease (PMID:19957197)
• crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto) (PMID:20877282)
• dysregulations in CD100 expression and release could play a role in SSc development and/or maintenance. (PMID:21244334)
• Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D. (PMID:21538148)
• Sema4D potentiates the invasiveness of pancreatic cancer cells. The binding of Sema4D to plexinB1 induced small GTPase Ras homolog gene family, member A activation and resulted in the phosphorylation of MAPK and Akt. (PMID:21812859)
• From the data obtained in this study, SEMA4D may have a role in more aggressive and potentially metastatic breast tumours. (PMID:21925246)
• CD72 mRNA expression level correlates with Sema4D expression in peripheral blood mononuclear cells in immune thrombocytopenia. (PMID:22111667)
• Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth. (PMID:22189792)
• The expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). (PMID:22652457)
• copy number loss of the Sema4D gene region may play a role in the etiology of acetabular dysplasia (PMID:23335257)
• Lycorine hydrochloride suppressed the expression of several key angiogenic genes, including VE-cadherin and Sema4D, and reduced Akt phosphorylation in Hey1B cells. (PMID:23376478)
• The membrane-proximal cytoplasmic domain of Sema4D contains a binding site for calmodulin within the polybasic region Arg762-Lys779, that regulates Sema4D exodomain shedding in platelets. (PMID:23564909)
• There was an increased level of plasma soluble Sema4 in the Sema4D(high) population of T-cells suggesting a potential role of these T-cells in heart failure. (PMID:23741311)
• Elevated plasma soluble Sema4D/CD100 levels are associated with disease severity in patients of hemorrhagic fever with renal syndrome. (PMID:24040126)
• CD100 may have a role in atherosclerotic plaque development, and may possibly be employed in targeted treatments of these atheromas. (PMID:24098722)
• results suggest that the contribution of Sema4D in platelets applies to ITAM-containing receptors as a class (PMID:24131822)
• SEMA4D might possibly serve as a reliable tool for early and accurate prediction of EOC poor prognosis. (PMID:24289594)
• Sema4D contributes to enhanced invasion and tumor progression through increased motility of cervical cancer and VEGF-C/-D-mediated lymphangiogenesis. (PMID:24603190)
• Data suggest that CD100 seems to be involved in hepatitis C virus (HCV) clearance by natural killer (NK) cells. (PMID:25108441)
• Sema4D could play an important role in promoting tumor proliferation, migration and metastasis in the NSCLC, by influencing the Akt protein phosphorylation. Inhibition of Sema4D may be a useful approach for the treatment of NSCLC. (PMID:25135716)
• A positive feedback loop involving sSema4D/IL-6 and TNFalpha/ADAMTS-4 may contribute to the pathogenesis of rheumatoid arthritis. (PMID:25707877)
• Suggest that HIF-1alpha and Sema4D expression correlates with histological tumor type, TNM stage, and lymphatic metastasis in colorectal carcinoma. (PMID:25717256)
• Results show that decreased expression of Sema4D, plexin-B1 and -B2 was associated with local recurrence and poor prognosis of breast neoplasm. (PMID:26035216)
• Plexin-B1 induces cutaneous squamous cell carcinoma cell proliferation, migration, and invasion by interacting with Sema4D. Plexin-B1 might serve as a useful biomarker and/or as a novel therapeutic target for cSCC. (PMID:26051877)
• Blocking of CD100, plexin B1 and/or B2 in adhesion experiments have shown that both CD100 and plexins act as adhesion molecules involved in monocyte-endothelial cell binding. (PMID:26275342)
• Tax and semaphorin 4D released from lymphocytes infected with human lymphotropic virus type 1 and inhibit neurite growth in a neuron cell line. (PMID:26389656)
• Serum sSema4D levels are increased in patients with atrial fibrillation and are independently associated with atrial remodeling (PMID:26417899)
• This assay specifically and reproducibly measured cSEMA4D saturation and expression levels. Evaluation of the SEMA4D-specific PD markers were critical in determining the clinical saturation threshold of cSEMA4D by VX15/2503 (PMID:26566052)
• sema 4D was the direct target of miR-214 and was negatively regulated by miR-214 in ovarian cancer cells (PMID:26718213)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000067801
mus_musculus	Sema4d	ENSMUSG00000021451
rattus_norvegicus	Sema4d	ENSRNOG00000013679

Paralogs (19): SEMA3F (ENSG00000001617), SEMA3G (ENSG00000010319), SEMA3B (ENSG00000012171), SEMA3A (ENSG00000075213), 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), SEMA4A (ENSG00000196189)

Protein

Protein identifiers

Semaphorin-4D — Q92854 (reviewed: Q92854)

Alternative names: A8, BB18, GR3

All UniProt accessions (7): A0A0C4DG45, C9JD54, C9JFP1, C9JYS7, E9PFD9, Q92854, F5H044

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor for PLXNB1 and PLXNB2 that plays an important role in cell-cell signaling. Regulates GABAergic synapse development. Promotes the development of inhibitory synapses in a PLXNB1-dependent manner. Modulates the complexity and arborization of developing neurites in hippocampal neurons by activating PLXNB1 and interaction with PLXNB1 mediates activation of RHOA. Promotes the migration of cerebellar granule cells. Plays a role in the immune system; induces B-cells to aggregate and improves their viability (in vitro). Induces endothelial cell migration through the activation of PTK2B/PYK2, SRC, and the phosphatidylinositol 3-kinase-AKT pathway.

Subunit / interactions. Homodimer. Interacts with PLXNB2. Interacts with PLXNB1.

Subcellular location. Cell membrane.

Tissue specificity. Strongly expressed in skeletal muscle, peripheral blood lymphocytes, spleen, and thymus and also expressed at lower levels in testes, brain, kidney, small intestine, prostate, heart, placenta, lung and pancreas, but not in colon and liver.

Similarity. Belongs to the semaphorin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92854-1	1	yes
Q92854-2	2

RefSeq proteins (11): NP_001135759, NP_001358123, NP_001358124, NP_001358125, NP_001358126, NP_001358127, NP_001358128, NP_001358129, NP_001358130, NP_001358131, NP_006369 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR002165	Plexin_repeat	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013151	Immunoglobulin_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

Pfam: PF00047, PF01403, PF01437

UniProt features (106 total): strand 45, helix 12, turn 11, glycosylation site 9, disulfide bond 8, mutagenesis site 5, domain 3, topological domain 2, splice variant 2, sequence variant 2, signal peptide 1, chain 1, modified residue 1, transmembrane region 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1OLZ	X-RAY DIFFRACTION	2
3OL2	X-RAY DIFFRACTION	2.99

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92854-F1	81.38	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.

Post-translational modifications (1): 833

Disulfide bonds (8): 97–108, 126–135, 257–370, 281–326, 503–520, 509–553, 512–529, 576–624

Glycosylation sites (9): 49, 77, 139, 191, 329, 379, 419, 613, 632

Mutagenesis-validated functional residues (5):

Position	Phenotype
100–101	abolishes plxnb1 binding.
181–182	abolishes plxnb1 binding.
244	abolishes homodimerization, abolishes collapse of growth cones and reduces plxnb1 binding; when associated with s-246.
246	abolishes homodimerization, abolishes collapse of growth cones and reduces plxnb1 binding; when associated with n-244.
395	strongly reduces plxnb1 binding.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-416550	Sema4D mediated inhibition of cell attachment and migration
R-HSA-416572	Sema4D induced cell migration and growth-cone collapse
R-HSA-416700	Other semaphorin interactions
R-HSA-1266738	Developmental Biology
R-HSA-373755	Semaphorin interactions
R-HSA-400685	Sema4D in semaphorin signaling
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 544 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_COLLATERAL_SPROUTING, CAR_TNFRSF25, GOBP_BONE_TRABECULA_MORPHOGENESIS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_PHOSPHORYLATION, GNF2_CASP8, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, PEREZ_TP63_TARGETS, MODULE_45, MODULE_64, REACTOME_OTHER_SEMAPHORIN_INTERACTIONS

GO Biological Process (30): negative regulation of transcription by RNA polymerase II (GO:0000122), neural crest cell migration (GO:0001755), positive regulation of protein phosphorylation (GO:0001934), immune response (GO:0006955), cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), axon guidance (GO:0007411), regulation of cell shape (GO:0008360), positive regulation of cell migration (GO:0030335), regulation of cell projection organization (GO:0031344), positive regulation of Rho protein signal transduction (GO:0035025), negative regulation of apoptotic process (GO:0043066), positive regulation of GTPase activity (GO:0043547), ossification involved in bone maturation (GO:0043931), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of collateral sprouting (GO:0048672), regulation of dendrite morphogenesis (GO:0048814), negative chemotaxis (GO:0050919), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), bone trabecula morphogenesis (GO:0061430), leukocyte aggregation (GO:0070486), semaphorin-plexin signaling pathway (GO:0071526), positive regulation of inhibitory synapse assembly (GO:1905704), nervous system development (GO:0007399), axonogenesis (GO:0007409), cell differentiation (GO:0030154), positive regulation of axonogenesis (GO:0050772), regulation of synapse assembly (GO:0051963), regulation of biological quality (GO:0065008), positive regulation of intracellular signal transduction (GO:1902533)

GO Molecular Function (9): transmembrane signaling receptor activity (GO:0004888), signaling receptor binding (GO:0005102), semaphorin receptor binding (GO:0030215), signaling receptor activity (GO:0038023), neuropilin binding (GO:0038191), identical protein binding (GO:0042802), chemorepellent activity (GO:0045499), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (10): semaphorin receptor complex (GO:0002116), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), centrosome (GO:0005813), plasma membrane (GO:0005886), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), postsynaptic membrane (GO:0045211), GABA-ergic synapse (GO:0098982), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Sema4D in semaphorin signaling	2
Semaphorin interactions	2
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling receptor binding	3
cellular anatomical structure	3
protein binding	2
microtubule organizing center	2
cilium	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
neural crest cell development	1
mesenchymal cell migration	1
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
immune system process	1
response to stimulus	1
cellular process	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
axonogenesis	1
neuron projection guidance	1
regulation of cell morphogenesis	1
regulation of biological quality	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
cell projection organization	1
regulation of cellular component organization	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
ossification	1
bone maturation	1

Protein interactions and networks

STRING

1140 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA4D	PLXNB1	O43157	999
SEMA4D	CD72	P21854	998
SEMA4D	PLXNB2	O15031	998
SEMA4D	RND1	Q92730	920
SEMA4D	PLXNA2	O75051	882
SEMA4D	RRAS	P10301	850
SEMA4D	PLXNC1	O60486	848
SEMA4D	PLXNB3	Q9ULL4	846
SEMA4D	ARHGEF11	O15085	783
SEMA4D	MET	P08581	763
SEMA4D	PLXND1	Q9Y4D7	745
SEMA4D	PLXNA4	Q9HCM2	707
SEMA4D	ARHGEF12	Q9NZN5	664
SEMA4D	EFNB3	Q15768	661
SEMA4D	RASA1	P20936	648

IntAct

36 interactions, top by confidence:

A	B	Type	Score
SEMA4D	PLXNB2	psi-mi:“MI:0407”(direct interaction)	0.560
PLXNB3	SEMA4D	psi-mi:“MI:0407”(direct interaction)	0.560
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
CRK	SEMA4D	psi-mi:“MI:0915”(physical association)	0.490
SEMA4D	CRK	psi-mi:“MI:0915”(physical association)	0.490
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SEMA4D	CD72	psi-mi:“MI:0407”(direct interaction)	0.440
PTPRC	SEMA4D	psi-mi:“MI:0915”(physical association)	0.400
SCGB2A2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
ST8SIA4	NRP1	psi-mi:“MI:0914”(association)	0.350
VCAM1	APOA1	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
ST8SIA4	FAM234B	psi-mi:“MI:0914”(association)	0.350
KLRC1	METTL15	psi-mi:“MI:0914”(association)	0.350
CST9L	QSOX1	psi-mi:“MI:0914”(association)	0.350
C1orf54	AGRN	psi-mi:“MI:0914”(association)	0.350
VCAM1	ATP2A1	psi-mi:“MI:0914”(association)	0.350
LCN6	COCH	psi-mi:“MI:0914”(association)	0.350
DNAJC25-GNG10	CHST10	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): SEMA4D (Two-hybrid), SEMA4D (Affinity Capture-MS), SEMA4D (Affinity Capture-MS), SEMA4D (Affinity Capture-MS), SEMA4D (Affinity Capture-MS), SEMA4D (Affinity Capture-RNA), CD72 (Affinity Capture-Western), SEMA4D (Proximity Label-MS), SEMA4D (Proximity Label-MS), SEMA4D (Protein-RNA), SEMA4D (Affinity Capture-MS), SEMA4D (Affinity Capture-MS), SEMA4D (Affinity Capture-RNA), PTPRC (Affinity Capture-Western), SEMA4D (Proximity Label-MS)

ESM2 similar proteins: A0M8R7, A0M8S8, A1X150, B2RXS4, B3DK56, E2RK30, O15031, O45657, O60486, P08581, P08F94, P16056, P97523, Q00PJ8, Q07DV8, Q07DY1, Q07DZ1, Q07E01, Q07E24, Q07E37, Q07E48, Q09YH7, Q09YI9, Q09YK0, Q09YL1, Q09YN5, Q108U6, Q2IBA6, Q2IBC0, Q2IBD8, Q2IBF2, Q2IBG7, Q2QL89, Q2QLA9, Q2QLC0, Q2QLE0, Q2QLF1, Q2QLG5, Q2QLH6, Q60PR7

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
SEMA4D	up-regulates	PLXNB1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	128
Likely benign	26
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

2547 predictions. Top by Δscore:

Variant	Effect	Δscore
9:89381050:CTCA:C	donor_loss	1.0000
9:89381051:TCA:T	donor_loss	1.0000
9:89381052:CACCC:C	donor_loss	1.0000
9:89381053:AC:A	donor_gain	1.0000
9:89381054:CC:C	donor_gain	1.0000
9:89381096:CCC:C	acceptor_gain	1.0000
9:89381097:CCC:C	acceptor_gain	1.0000
9:89381168:CCATA:C	donor_loss	1.0000
9:89381169:CATA:C	donor_loss	1.0000
9:89381170:ATAC:A	donor_loss	1.0000
9:89381171:TACCT:T	donor_loss	1.0000
9:89381172:A:AG	donor_loss	1.0000
9:89381173:CCTG:C	donor_gain	1.0000
9:89381342:TTGCC:T	acceptor_gain	1.0000
9:89381347:C:CC	acceptor_gain	1.0000
9:89381350:CG:C	acceptor_gain	1.0000
9:89381351:G:C	acceptor_gain	1.0000
9:89386361:CTTTA:C	donor_loss	1.0000
9:89386362:TTTA:T	donor_loss	1.0000
9:89386363:TTAC:T	donor_loss	1.0000
9:89386364:TACCT:T	donor_loss	1.0000
9:89386365:A:C	donor_loss	1.0000
9:89386366:C:CA	donor_loss	1.0000
9:89386366:CCTT:C	donor_gain	1.0000
9:89386478:CCGGT:C	acceptor_gain	1.0000
9:89386479:CGGT:C	acceptor_gain	1.0000
9:89386479:CGGTC:C	acceptor_gain	1.0000
9:89386482:TCTGC:T	acceptor_loss	1.0000
9:89386483:C:CC	acceptor_gain	1.0000
9:89386483:CTGC:C	acceptor_loss	1.0000

AlphaMissense

5668 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:89389011:A:G	W271R	1.000
9:89389011:A:T	W271R	1.000
9:89392503:A:C	F181C	1.000
9:89388678:C:A	W355C	0.999
9:89388678:C:G	W355C	0.999
9:89388994:T:A	K276N	0.999
9:89388994:T:G	K276N	0.999
9:89389009:C:A	W271C	0.999
9:89389009:C:G	W271C	0.999
9:89392502:A:C	F181L	0.999
9:89392502:A:T	F181L	0.999
9:89392504:A:G	F181L	0.999
9:89393596:A:C	F158L	0.999
9:89393596:A:T	F158L	0.999
9:89393598:A:G	F158L	0.999
9:89396758:G:C	F131L	0.999
9:89396758:G:T	F131L	0.999
9:89396760:A:G	F131L	0.999
9:89396827:G:C	C108W	0.999
9:89396828:C:G	C108S	0.999
9:89396829:A:G	C108R	0.999
9:89396829:A:T	C108S	0.999
9:89399300:A:C	C97W	0.999
9:89399301:C:G	C97S	0.999
9:89399302:A:G	C97R	0.999
9:89399302:A:T	C97S	0.999
9:89387537:G:C	F393L	0.998
9:89387537:G:T	F393L	0.998
9:89387539:A:G	F393L	0.998
9:89387544:A:G	L391P	0.998

dbSNP variants (sampled 300 via entrez): RS1000007036 (9:89494634 G>A,T), RS1000008314 (9:89432352 C>G,T), RS1000009548 (9:89474878 G>C,T), RS1000009939 (9:89477981 G>A), RS1000031902 (9:89396118 G>A), RS1000040581 (9:89362646 G>C), RS1000043558 (9:89467511 A>C,G,T), RS1000059596 (9:89494380 C>A), RS1000065993 (9:89472841 C>A,G), RS1000070254 (9:89489773 C>T), RS1000072069 (9:89360493 C>G,T), RS1000076122 (9:89467756 T>C), RS1000078280 (9:89433526 G>C), RS1000103659 (9:89396347 G>A), RS1000155404 (9:89429678 C>T)

Disease associations

OMIM: gene MIM:601866 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000083	Renal insufficiency
HP:0000554	Uveitis
HP:0000716	Depression
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000989	Pruritus
HP:0001081	Cholelithiasis
HP:0001298	Encephalopathy
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001402	Hepatocellular carcinoma
HP:0001409	Portal hypertension
HP:0001433	Hepatosplenomegaly
HP:0001541	Ascites
HP:0001635	Congestive heart failure
HP:0001733	Pancreatitis
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001879	Abnormal eosinophil morphology
HP:0001945	Fever
HP:0002027	Abdominal pain
HP:0002202	Pleural effusion
HP:0002240	Hepatomegaly
HP:0002608	Celiac disease
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002960	Autoimmunity
HP:0003073	Hypoalbuminemia
HP:0003459	Polyclonal elevation of IgM

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004255_1	Body mass index	1.000000e-08
GCST004611_45	High light scatter reticulocyte count	7.000000e-10
GCST004612_101	High light scatter reticulocyte percentage of red cells	7.000000e-10
GCST004619_66	Reticulocyte fraction of red cells	2.000000e-09
GCST004622_22	Reticulocyte count	4.000000e-09
GCST006585_1141	Blood protein levels	2.000000e-187
GCST010002_323	Refractive error	3.000000e-08
GCST010703_339	Brain morphology (MOSTest)	3.000000e-10
GCST011011_42	Youthful appearance (self-reported)	6.000000e-09
GCST90002385_387	High light scatter reticulocyte count	1.000000e-12
GCST90002386_429	High light scatter reticulocyte percentage of red cells	2.000000e-14
GCST90002397_685	Mean spheric corpuscular volume	5.000000e-13
GCST90002405_462	Reticulocyte count	3.000000e-13
GCST90002406_327	Reticulocyte fraction of red cells	1.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007986	reticulocyte count
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630887 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
pepinemab	Binding	9.35	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
arsenite	increases methylation	1
lycorine	decreases expression	1
butyraldehyde	decreases expression	1
tobacco tar	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
beta-methylcholine	affects 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	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Amiodarone	increases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	increases expression	1
Carbamazepine	affects expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8P6	Abcam HCT 116 SEMA4D KO	Cancer cell line	Male
CVCL_B9RJ	Abcam A-549 SEMA4D KO	Cancer cell line	Male

Clinical trials (associated diseases)

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