SEMA4A

Summary

SEMA4A (semaphorin 4A, HGNC:10729) is a protein-coding gene on chromosome 1q22, encoding Semaphorin-4A (Q9H3S1). Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling.

This gene encodes a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. The encoded protein is a single-pass type I membrane protein containing an immunoglobulin-like C2-type domain, a PSI domain and a sema domain. It inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons. It is an activator of T-cell-mediated immunity and suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mutations in this gene are associated with retinal degenerative diseases including retinitis pigmentosa type 35 (RP35) and cone-rod dystrophy type 10 (CORD10). Multiple alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 64218 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited retinal dystrophy (Moderate, GenCC) — +6 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 685 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 91
• MANE Select transcript: NM_022367

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10729
Approved symbol	SEMA4A
Name	semaphorin 4A
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	SemB, FLJ12287, CORD10
Ensembl gene	ENSG00000196189
Ensembl biotype	protein_coding
OMIM	607292
Entrez	64218

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 23 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000355014, ENST00000368282, ENST00000368284, ENST00000368285, ENST00000414683, ENST00000435124, ENST00000438830, ENST00000462892, ENST00000466698, ENST00000469065, ENST00000470306, ENST00000484155, ENST00000485575, ENST00000487358, ENST00000633494, ENST00000872469, ENST00000872470, ENST00000872471, ENST00000872472, ENST00000872473, ENST00000920832, ENST00000920833, ENST00000920834, ENST00000920835, ENST00000920836, ENST00000920837, ENST00000950311, ENST00000950312, ENST00000950313, ENST00000950314

RefSeq mRNA: 8 — MANE Select: NM_022367 NM_001193300, NM_001193301, NM_001193302, NM_001370567, NM_001370568, NM_001370569, NM_001370571, NM_022367

CCDS: CCDS1132, CCDS53378

Canonical transcript exons

ENST00000368285 — 15 exons

Exon	Start	End
ENSE00001054479	156175556	156175656
ENSE00001054480	156158719	156158824
ENSE00001446772	156153585	156153764
ENSE00001446774	156176405	156177744
ENSE00003474176	156154550	156154717
ENSE00003487912	156158388	156158486
ENSE00003490971	156174822	156174940
ENSE00003545965	156160443	156160559
ENSE00003592525	156172826	156173006
ENSE00003623497	156158070	156158132
ENSE00003627082	156161346	156161518
ENSE00003647461	156160905	156161029
ENSE00003661897	156162944	156163094
ENSE00003681619	156175086	156175243
ENSE00003784807	156156414	156156574

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 95.54.

FANTOM5 (CAGE): breadth broad, TPM avg 13.9016 / max 654.4916, expressed in 826 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5697	10.6620	455
5696	1.7546	253
5688	0.5255	143
5695	0.2820	178
5691	0.1816	70
5693	0.1699	85
5692	0.1065	53
5689	0.0639	24
5698	0.0549	28
5687	0.0408	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.54	gold quality
mononuclear cell	CL:0000842	95.18	gold quality
leukocyte	CL:0000738	95.17	gold quality
granulocyte	CL:0000094	93.97	gold quality
bone marrow cell	CL:0002092	92.56	gold quality
blood	UBERON:0000178	92.52	gold quality
lower esophagus mucosa	UBERON:0035834	92.46	gold quality
type B pancreatic cell	CL:0000169	90.87	gold quality
amygdala	UBERON:0001876	90.51	gold quality
nucleus accumbens	UBERON:0001882	90.43	gold quality
esophagus mucosa	UBERON:0002469	90.32	gold quality
skin of abdomen	UBERON:0001416	90.26	gold quality
left lobe of thyroid gland	UBERON:0001120	89.82	gold quality
pigmented layer of retina	UBERON:0001782	89.79	gold quality
olfactory bulb	UBERON:0002264	89.50	gold quality
skin of leg	UBERON:0001511	89.29	gold quality
cingulate cortex	UBERON:0003027	89.29	gold quality
anterior cingulate cortex	UBERON:0009835	89.28	gold quality
lymph node	UBERON:0000029	88.97	gold quality
thyroid gland	UBERON:0002046	88.97	gold quality
sural nerve	UBERON:0015488	88.91	gold quality
tongue squamous epithelium	UBERON:0006919	88.90	silver quality
right lobe of thyroid gland	UBERON:0001119	88.78	gold quality
caudate nucleus	UBERON:0001873	88.42	gold quality
spleen	UBERON:0002106	88.12	gold quality
parotid gland	UBERON:0001831	87.86	gold quality
temporal lobe	UBERON:0001871	87.83	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.72	gold quality
putamen	UBERON:0001874	87.72	gold quality
metanephros cortex	UBERON:0010533	87.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	46.20
E-ANND-3	yes	14.67
E-MTAB-9067	yes	12.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting SEMA4A, 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-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-5094	98.63	67.11	1062
HSA-MIR-6076	98.61	65.69	637
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4632-5P	97.82	65.38	1470

Literature-anchored findings (GeneRIF, showing 31)

• Mutations within the SEMA4A gene cause various retinal degnerative diseases. (PMID:16199541)
• Dendritic cell-derived SEM4A is not only critical for T helper type (Th)1 cells but also for Th17 cell differentiation, and multiple sclerosis patients with high Sema4A levels exhibit Th17 cell skewing. (PMID:22491253)
• mutations in SEMA4A may cause susceptibility to light exposure, oxidative stress, and ER stress, which may be involved in the progression and pathology of RP. (PMID:22956603)
• Sema4A plays an inhibitory role in T helper (Th)2-type allergic diseases, such as allergic asthma, in a fraction of Sema4a-deficient transgenic mice. (PMID:23007237)
• These results indicate the importance of the Sema4A protein conformation in human and mouse retina homeostasis. (PMID:23360997)
• Germline variants in SEMA4A predispose to familial colorectal cancer type X. (PMID:25307848)
• PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may regulate Sema4A expression in retinal pigment epithelial cells and thereby contribute to the maintenance of retinal structure and function. (PMID:25515530)
• Data suggest that increased expression of semaphorin 4A (Sema4A) is required to promote inflammation of rheumatoid arthritis (RA). (PMID:26303122)
• Sema4A activated the Akt pathway via Plexin D1 receptor in lung fibroblasts.Lung fibroblasts show elevated levels of Sema4A expression in systemic sclerosis patients. (PMID:26648031)
• In this review, we summarized the current findings on neuroimmune Sema4A and Sema4D molecules in chronic inflammation underlying many diseases and discussed their positive or negative impacts on the implicated molecular and cellular processes (PMID:27554682)
• SEMA 4A confers doxorubicin resistance on hepatocellular carcinoma by inducing epithelialemesenchymal transition. (PMID:27697528)
• Suggest a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A regulating cell migration via Scrib. (PMID:28007914)
• Here we show three families with retinal degeneration in which unaffected family members are either homozygous or heterozygous for the variant. The p.R713Q variant in SEMA4A is insufficient to cause either autosomal recessive or autosomal dominant retinitis pigmentosa and is unlikely to be pathogenic. (PMID:28805479)
• Human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. H-ferritin can block Sema4A-mediated cytotoxicity. Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. (PMID:29457657)
• ILT-4 is a receptor for hSEMA4A)on activated CD4(+) T cells. hSEMA4A is highly expressed in human asthmatic lung tissue. (PMID:29467366)
• Advanced peri-implantitis lesions showed higher levels of gene expression for Sem3A and Sem4D and lower levels of Sem4A in comparison to tissues obtained from a healthy dental implant. (PMID:29763494)
• Hypoxic induction of Sema4A contributes to the abnormal proliferation and apoptosis of breast cancer cells. (PMID:30270262)
• In this study, we found that the levels of sSEMA4A were significantly elevated in patients with CRSwNPs and asthma, and that SEMA4A was especially highly expressed in eosinophils in nasal polyps. We also demonstrated that SEMA4A in eosinophils can be cleaved by ADAMTS4, suggesting that eosinophils are a major source of SEMA4A in serum from these patients. (PMID:30342889)
• this study shows that semaphorin 4A acts in a feed-forward loop with NF-kappaB pathway to exacerbate catabolic effect of IL-1beta on chondrocytes (PMID:30685700)
• Sema4A plays direct and dual roles in promoting inflammation and fibrosis in systemic sclerosis. (PMID:31012544)
• Sema4A exerts a Treg cell phenotype-stabilizing effect, defined as an increase in percentage and numbers of CD4+CD25+Foxp3+ cells, on human Peripheral Blood Mononuclear Cells populations, and CD4+ T cells. (PMID:31236543)
• T-cell specific upregulation of Sema4A as risk factor for autoimmunity in systemic lupus erythematosus and rheumatoid arthritis. (PMID:31876207)
• Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase. (PMID:32169103)
• Sema4D and 4A seem to play a critical role in the pathogenesis of some autoimmune diseases, such as multiple sclerosis. (PMID:32244055)
• Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner. (PMID:32971928)
• Semaphorin 4A restricts tumor progression by inhibiting angiogenesis of oral squamous cell carcinoma cells. (PMID:33460983)
• Identifying Function Determining Residues in Neuroimmune Semaphorin 4A. (PMID:35328445)
• The possible involvement of sema3A and sema4A in the pathogenesis of multiple sclerosis. (PMID:35460904)
• Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8[+] T cell cytotoxicity and proliferation. (PMID:37205755)
• Semaphorin4A promotes lung cancer by activation of NF-kappaB pathway mediated by PlexinB1. (PMID:37901456)
• Semaphorin 4A Maintains Trophoblastic Function via Activating the STAT3 Pathway. (PMID:39062540)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sema4a	ENSMUSG00000028064
rattus_norvegicus	Sema4a	ENSRNOG00000019737

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), SEMA4D (ENSG00000187764)

Protein

Protein identifiers

Semaphorin-4A — Q9H3S1 (reviewed: Q9H3S1)

Alternative names: Semaphorin-B

All UniProt accessions (5): A0A0J9YVY6, Q9H3S1, Q5TCI4, Q5TCI6, Q5TCJ7

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling. Regulates glutamatergic and GABAergic synapse development. Promotes the development of inhibitory synapses in a PLXNB1-dependent manner and promotes the development of excitatory synapses in a PLXNB2-dependent manner. Plays a role in priming antigen-specific T-cells, promotes differentiation of Th1 T-helper cells, and thereby contributes to adaptive immunity. Promotes phosphorylation of TIMD2. Inhibits angiogenesis. Promotes axon growth cone collapse. Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons.

Subunit / interactions. Interacts with PLXNB1, PLXNB2, PLXNB3, PLXND1 and TIMD2.

Subcellular location. Cell membrane.

Disease relevance. Retinitis pigmentosa 35 (RP35) [MIM:610282] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry. Cone-rod dystrophy 10 (CORD10) [MIM:610283] An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the semaphorin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3S1-1	1	yes
Q9H3S1-2	2

RefSeq proteins (8): NP_001180229, NP_001180230, NP_001180231, NP_001357496, NP_001357497, NP_001357498, NP_001357500, NP_071762* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR002165	Plexin_repeat	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016201	PSI	Domain
IPR027231	Semaphorin	Family
IPR036352	Semap_dom_sf	Homologous_superfamily

Pfam: PF01403, PF01437

UniProt features (30 total): disulfide bond 7, glycosylation site 4, sequence variant 4, sequence conflict 3, domain 3, topological domain 2, splice variant 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3S1-F1	85.05	0.64

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 (7): 113–124, 142–151, 269–379, 293–339, 497–514, 506–523, 580–624

Glycosylation sites (4): 120, 135, 496, 607

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-416700	Other semaphorin interactions
R-HSA-1266738	Developmental Biology
R-HSA-373755	Semaphorin interactions
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 507 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, MODULE_255, GOBP_SYNAPSE_ASSEMBLY, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, REACTOME_OTHER_SEMAPHORIN_INTERACTIONS, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, MODULE_317, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (18): angiogenesis (GO:0001525), neural crest cell migration (GO:0001755), axon guidance (GO:0007411), regulation of cell shape (GO:0008360), regulation of endothelial cell migration (GO:0010594), negative regulation of angiogenesis (GO:0016525), positive regulation of cell migration (GO:0030335), T-helper 1 cell differentiation (GO:0045063), negative chemotaxis (GO:0050919), semaphorin-plexin signaling pathway (GO:0071526), positive regulation of excitatory synapse assembly (GO:1904891), positive regulation of inhibitory synapse assembly (GO:1905704), adaptive immune response (GO:0002250), T cell differentiation involved in immune response (GO:0002292), immune system process (GO:0002376), nervous system development (GO:0007399), axonogenesis (GO:0007409), 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 (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of cell migration	2
positive regulation of synapse assembly	2
immune response	2
signaling receptor binding	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
neural crest cell development	1
mesenchymal cell migration	1
axonogenesis	1
neuron projection guidance	1
regulation of cell morphogenesis	1
regulation of biological quality	1
endothelial cell migration	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cell migration	1
positive regulation of cell motility	1
alpha-beta T cell activation involved in immune response	1
T cell differentiation involved in immune response	1
T-helper 1 type immune response	1
T-helper cell differentiation	1
chemotaxis	1
cell surface receptor signaling pathway	1
excitatory synapse assembly	1
regulation of excitatory synapse assembly	1
inhibitory synapse assembly	1
regulation of inhibitory synapse assembly	1
T cell activation involved in immune response	1
T cell differentiation	1
biological_process	1
system development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
cellular developmental process	1
receptor ligand activity	1
negative chemotaxis	1
binding	1
membrane	1

Protein interactions and networks

STRING

950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA4A	NRP1	O14786	942
SEMA4A	PLXND1	Q9Y4D7	937
SEMA4A	PLXNB1	O43157	795
SEMA4A	PRPF3	O43395	787
SEMA4A	AIPL1	Q9NZN9	774
SEMA4A	PITPNM3	Q9BZ71	767
SEMA4A	CERKL	Q49MI3	747
SEMA4A	ABCA4	P78363	731
SEMA4A	ZNF513	Q8N8E2	712
SEMA4A	FSCN2	O14926	712
SEMA4A	IMPG2	Q9BZV3	706
SEMA4A	GUCY2D	Q02846	705
SEMA4A	CRX	O43186	697
SEMA4A	PRPH2	P23942	694
SEMA4A	PTEN	P60484	694

IntAct

33 interactions, top by confidence:

A	B	Type	Score
SEMA4A	PLXND1	psi-mi:“MI:0407”(direct interaction)	0.680
PLXND1	SEMA4A	psi-mi:“MI:0407”(direct interaction)	0.680
	SEMA4A	psi-mi:“MI:0407”(direct interaction)	0.440
PLXNB1	SEMA4A	psi-mi:“MI:0407”(direct interaction)	0.440
PLXNB2	SEMA4A	psi-mi:“MI:0407”(direct interaction)	0.440
PLXNB3	SEMA4A	psi-mi:“MI:0407”(direct interaction)	0.440
SEMA4A	DDX54	psi-mi:“MI:0915”(physical association)	0.370
SEMA4A	TMEM192	psi-mi:“MI:0914”(association)	0.350
SEMA4A	CNTNAP1	psi-mi:“MI:0914”(association)	0.350
BRAF	SEMA4A	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	SEMA4A	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	SEMA4A	psi-mi:“MI:2364”(proximity)	0.270
SEMA4A	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	SEMA4A	psi-mi:“MI:2364”(proximity)	0.270
SPOP	SEMA4A	psi-mi:“MI:2364”(proximity)	0.270
SEMA4A	SPOP	psi-mi:“MI:2364”(proximity)	0.270
SEMA4A	EGFR	psi-mi:“MI:2364”(proximity)	0.270
SEMA4A	PTEN	psi-mi:“MI:2364”(proximity)	0.270
SEMA4A	PTPN11	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (14): SEMA4A (Proximity Label-MS), SIRT5 (Affinity Capture-MS), SEMA4C (Affinity Capture-MS), TMEM192 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), SEMA4B (Affinity Capture-MS), GMCL1 (Affinity Capture-MS), ERLEC1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), SEMA4A (Affinity Capture-RNA), SEMA4A (Co-fractionation), SEMA4A (Co-fractionation), SEMA4A (Co-fractionation), SEMA4A (Two-hybrid)

ESM2 similar proteins: A5PJN5, A6QQ07, B2RXS4, O08590, O15031, O35632, O95497, O95498, P09172, P14616, P15101, P19801, P26011, P36633, P43251, P83548, Q3SZL5, Q3V5L5, Q4R7M2, Q58CQ9, Q5FVF9, Q5R8R3, Q5XI31, Q64237, Q64716, Q6PD26, Q765H6, Q76HN1, Q8AV84, Q8BG22, Q8CIF4, Q8IRR1, Q8JZQ5, Q8NFI3, Q8SQG7, Q91ZJ9, Q9BDJ5, Q9DA79, Q9DBX3, Q9H3S1

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of axonogenesis	5	181.6×	3e-08
synapse assembly	5	72.1×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	399
Likely benign	207
Benign	12

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3361	NM_022367.4(SEMA4A):c.1049T>G (p.Phe350Cys)	Pathogenic
813238	NM_022367.4(SEMA4A):c.745dup (p.Glu249fs)	Pathogenic
813239	NM_022367.4(SEMA4A):c.985C>T (p.Gln329Ter)	Pathogenic
3028253	NM_022367.4(SEMA4A):c.1377G>C (p.Glu459Asp)	Likely pathogenic

SpliceAI

2044 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156156409:A:AG	acceptor_gain	1.0000
1:156156409:AACAG:A	acceptor_gain	1.0000
1:156156411:CAGG:C	acceptor_loss	1.0000
1:156156412:A:AC	acceptor_loss	1.0000
1:156156412:A:AG	acceptor_gain	1.0000
1:156156412:AG:A	acceptor_gain	1.0000
1:156156412:AGG:A	acceptor_gain	1.0000
1:156156412:AGGG:A	acceptor_gain	1.0000
1:156156413:G:A	acceptor_loss	1.0000
1:156156413:G:GA	acceptor_gain	1.0000
1:156156413:GG:G	acceptor_gain	1.0000
1:156156413:GGG:G	acceptor_gain	1.0000
1:156156413:GGGG:G	acceptor_gain	1.0000
1:156156562:GC:G	donor_gain	1.0000
1:156156573:TGG:T	donor_loss	1.0000
1:156156575:G:C	donor_loss	1.0000
1:156156575:G:GG	donor_gain	1.0000
1:156156576:T:A	donor_loss	1.0000
1:156158063:C:G	acceptor_gain	1.0000
1:156158129:TGAGG:T	donor_loss	1.0000
1:156158130:GAG:G	donor_gain	1.0000
1:156158133:G:C	donor_loss	1.0000
1:156158133:G:GG	donor_gain	1.0000
1:156158134:T:A	donor_loss	1.0000
1:156160436:A:AG	acceptor_gain	1.0000
1:156160437:C:G	acceptor_gain	1.0000
1:156160439:CTA:C	acceptor_loss	1.0000
1:156160441:A:AG	acceptor_gain	1.0000
1:156160441:A:T	acceptor_loss	1.0000
1:156160441:AGAT:A	acceptor_gain	1.0000

AlphaMissense

4950 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156161382:T:A	W283R	1.000
1:156161382:T:C	W283R	1.000
1:156161384:G:C	W283C	0.999
1:156161384:G:T	W283C	0.999
1:156158106:T:A	C113S	0.997
1:156158107:G:C	C113S	0.997
1:156158402:C:A	N126K	0.997
1:156158402:C:G	N126K	0.997
1:156158463:T:C	F147L	0.997
1:156158465:C:A	F147L	0.997
1:156158465:C:G	F147L	0.997
1:156161010:G:C	R264P	0.997
1:156161015:G:C	A266P	0.997
1:156161399:G:C	K288N	0.997
1:156161399:G:T	K288N	0.997
1:156158394:T:A	C124S	0.996
1:156158395:G:C	C124S	0.996
1:156158788:T:C	F178L	0.996
1:156158790:T:A	F178L	0.996
1:156158790:T:G	F178L	0.996
1:156161016:C:A	A266D	0.996
1:156161024:T:A	C269S	0.996
1:156161025:G:C	C269S	0.996
1:156158449:G:A	C142Y	0.995
1:156158450:C:G	C142W	0.995
1:156161022:T:A	V268D	0.995
1:156161349:G:C	D272H	0.995
1:156161383:G:C	W283S	0.995
1:156161389:C:T	T285I	0.995
1:156161400:G:C	A289P	0.995

dbSNP variants (sampled 300 via entrez): RS1000094743 (1:156171314 A>T), RS1000123553 (1:156174404 G>A,T), RS1000307629 (1:156168533 T>A,C), RS1000391863 (1:156173571 G>C), RS1000496831 (1:156146164 A>G), RS1000609090 (1:156152803 G>A,T), RS1000640225 (1:156152560 G>A,C), RS1000763011 (1:156173928 T>G), RS1000784756 (1:156146362 A>G), RS1000830876 (1:156159155 G>A), RS1000971072 (1:156146994 G>A), RS1001047014 (1:156166545 T>C), RS1001107605 (1:156159323 G>C,T), RS1001231613 (1:156174028 T>C), RS1001304346 (1:156151570 C>T)

Disease associations

OMIM: gene MIM:607292 | disease phenotypes: MIM:610282, MIM:610283, MIM:268000, MIM:120970, MIM:114500, MIM:108985

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited retinal dystrophy	Moderate	Autosomal recessive
cone-rod dystrophy	Supportive	Autosomal dominant
familial colorectal cancer type X	Supportive	Autosomal dominant
retinitis pigmentosa	Supportive	Autosomal dominant
retinitis pigmentosa 35	Limited	Unknown
cone-rod dystrophy 10	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Lynch syndrome	Disputed	AD

Mondo (10): retinitis pigmentosa 35 (MONDO:0012463), cone-rod dystrophy 10 (MONDO:0012464), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), cone-rod dystrophy (MONDO:0015993), optic atrophy (MONDO:0003608), colorectal cancer (MONDO:0005575), polyp of colon (MONDO:0021400), helicoid peripapillary chorioretinal degeneration (MONDO:0007176), familial colorectal cancer type X (MONDO:0018604)

Orphanet (5): Cone rod dystrophy (Orphanet:1872), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Helicoid peripapillary chorioretinal degeneration (Orphanet:86813), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000608	Macular degeneration
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001123	Visual field defect
HP:0001250	Seizure
HP:0001252	Hypotonia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006624_23	Systolic blood pressure	2.000000e-10
GCST009325_67	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	8.000000e-22
GCST90002402_494	Platelet count	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004309	platelet count

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D003111	Colonic Polyps	C23.300.825.411.235
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C564597	Cone-Rod Dystrophy 10 (supp.)
C565206	Retinitis Pigmentosa 35 (supp.)
C566236	Sveinsson Chorioretinal Atrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
bromoacetate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
jinfukang	decreases expression	1
Sunitinib	decreases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Vehicle Emissions	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Hydralazine	affects cotreatment, increases expression	1
Methotrexate	decreases expression	1
Niclosamide	increases expression	1
Ozone	increases expression, increases abundance	1
Silicon Dioxide	increases expression	1
Urethane	increases expression	1
Zinc	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	affects expression, increases abundance	1

Cellosaurus cell lines

5 cell lines: 5 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_RK83	SU223-A2	Induced pluripotent stem cell	Female
CVCL_RK84	SU223-A4	Induced pluripotent stem cell	Female
CVCL_RK85	SU223-A7	Induced pluripotent stem cell	Female
CVCL_RK86	SU223-B3	Induced pluripotent stem cell	Female
CVCL_RK87	SU223-B5	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa