SEMA6D Gene

HGNC Family	Semaphorins (SEMA)
Name	sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D
Description	Semaphorins are a large family, including both secreted and membrane associated proteins, many of which have been implicated as inhibitors or chemorepellents in axon pathfinding, fasciculation and branching, and target selection. All semaphorins possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Additional sequence motifs C-terminal to the semaphorin domain allow classification into distinct subfamilies. Results demonstrate that transmembrane semaphorins, like the secreted ones, can act as repulsive axon guidance cues. This gene encodes a class 6 vertebrate transmembrane semaphorin that demonstrates alternative splicing. Several transcript variants have been identified and expression of the distinct encoded isoforms is thought to be regulated in a tissue- and development-dependent manner. [provided by RefSeq, Nov 2010]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSEMA6D is a member of the class VI semaphorin family whose alternatively spliced isoforms are dynamically expressed in a tissue‐ and development‐dependent manner. Early studies demonstrated that, during embryogenesis, SEMA6D localizes to specific brain regions—including areas surrounding the lateral ventricles, striatum, midbrain, and pons—where its extracellular domain mediates axonal extension inhibition and growth cone collapse, thereby contributing to proper neuronal circuit formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn gastric carcinoma, elevated SEMA6D expression has been observed at both the protein and mRNA levels. Immunohistochemical analyses reveal that SEMA6D, particularly when co‐localized with Snail (a well‐known promoter of epithelial–mesenchymal transition), correlates with more aggressive clinicopathological features such as poorer differentiation, increased invasion, and lymph node metastasis, suggesting its potential role as a biomarker and pathogenic driver in gastric cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of chronic liver disease, serum concentrations of SEMA6D rise significantly in patients with chronic hepatitis C and correlate with fibrosis stage. Notably, SEMA6D levels decrease following effective antiviral therapies, underscoring its promise as a non‐invasive marker for liver injury and fibrosis severity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSEMA6D has also been implicated in oncologic chemoresistance. In osteosarcoma, for example, increased SEMA6D expression is associated with cisplatin resistance. Mechanistically, a regulatory axis involving circUBAP2 and miR-506-3p modulates SEMA6D levels, influencing cell proliferation, migration, invasion, and apoptosis, and thereby contributing to tumor survival against chemotherapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncological roles, genetic imaging studies have linked SEMA6D to the development of reading-related neural structures—such as alterations in cortical thickness and gyrification in regions including the fusiform and supramarginal gyri—suggesting that genetic variability in SEMA6D can impact cognitive processes. Complementarily, recent work in murine models has revealed that SEMA6D in amygdalar interneurons is essential for synaptic maturation and proper gamma-aminobutyric acid transmission, thereby coordinating anxiogenic, metabolic, and inflammatory responses through modulation of sympathetic activity and neural circuit homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xianghu Qu, Handong Wei, Yun Zhai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification, characterization, and functional study of the two novel human members of the semaphorin gene family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M206451200"}], "href": "https://doi.org/10.1074/jbc.M206451200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12110693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12110693"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xiang-Yang Zhao, Lin Chen, Qian Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of semaphorin 6D in gastric carcinoma and its significance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Gastroenterol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3748/wjg.v12.i45.7388"}], "href": "https://doi.org/10.3748/wjg.v12.i45.7388"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17143962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17143962"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sixuan Qu, Zhaoli Yang, Hongdi Tao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Semaphorin 6D and Snail are highly expressed in gastric cancer and positively correlated with malignant clinicopathological indexes]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi (2019)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31814570"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31814570"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Neven Papic, Snjezana Zidovec Lepej, Lana Gorenec, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The association of semaphorins 3C, 5A and 6D with liver fibrosis stage in chronic hepatitis C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0209481"}], "href": "https://doi.org/10.1371/journal.pone.0209481"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30592759"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30592759"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lin Dong, Fangfei Qu "}, {"type": "b", "children": [{"type": "t", "text": "CircUBAP2 promotes SEMA6D expression to enhance the cisplatin resistance in osteosarcoma through sponging miR-506-3p by activating Wnt/β-catenin signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Histol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10735-020-09883-8"}], "href": "https://doi.org/10.1007/s10735-020-09883-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32472335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32472335"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tina Thomas, Meaghan V Perdue, Shiva Khalaf, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuroimaging genetic associations between "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "SEMA6D"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": ", brain structure, and reading skills."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Exp Neuropsychol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/13803395.2021.1912300"}], "href": "https://doi.org/10.1080/13803395.2021.1912300"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33960276"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33960276"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yoshimitsu Nakanishi, Mayuko Izumi, Hiroaki Matsushita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Semaphorin 6D tunes amygdalar circuits for emotional, metabolic, and inflammatory outputs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2024.06.017"}], "href": "https://doi.org/10.1016/j.neuron.2024.06.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39002542"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39002542"}]}]}]}
Proteins	SEM6D_HUMAN
NCBI Gene ID	80031
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

SEMA6D has 5,939 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 118 datasets.

Click the + buttons to view associations for SEMA6D from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

SEMA6D Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by SEMA6D gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of SEMA6D gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of SEMA6D gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of SEMA6D gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of SEMA6D gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of SEMA6D gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of SEMA6D gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of SEMA6D gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of SEMA6D gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of SEMA6D gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of SEMA6D gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of SEMA6D gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of SEMA6D gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with SEMA6D gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of SEMA6D gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of SEMA6D gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of SEMA6D gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of SEMA6D gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of SEMA6D gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing SEMA6D protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing SEMA6D protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with SEMA6D protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with SEMA6D protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing SEMA6D protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of SEMA6D gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with SEMA6D gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with SEMA6D gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with SEMA6D gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by SEMA6D gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with SEMA6D gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with SEMA6D gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with SEMA6D gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with SEMA6D gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with SEMA6D gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with SEMA6D gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at SEMA6D gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of SEMA6D gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of SEMA6D gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing SEMA6D from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with SEMA6D gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.