SEMA4G

Summary

SEMA4G (semaphorin 4G, HGNC:10735) is a protein-coding gene on chromosome 10q24.31, encoding Semaphorin-4G (Q9NTN9). Cell surface receptor for PLXNB2.

Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 57715 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 25 total
• MANE Select transcript: NM_017893

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10735
Approved symbol	SEMA4G
Name	semaphorin 4G
Location	10q24.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20590, KIAA1619
Ensembl gene	ENSG00000095539
Ensembl biotype	protein_coding
OMIM	618991
Entrez	57715

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000210633, ENST00000370250, ENST00000476171, ENST00000484128, ENST00000517724, ENST00000518124, ENST00000518244, ENST00000518948, ENST00000519756, ENST00000521006, ENST00000897610, ENST00000897611, ENST00000897612

RefSeq mRNA: 3 — MANE Select: NM_017893 NM_001203244, NM_001393925, NM_017893

CCDS: CCDS55724, CCDS7501, CCDS91320

Canonical transcript exons

ENST00000210633 — 15 exons

Exon	Start	End
ENSE00000721411	100978849	100979018
ENSE00000721419	100980122	100980344
ENSE00000721422	100980578	100980693
ENSE00000721426	100980822	100980997
ENSE00000721429	100981168	100981229
ENSE00000811365	100979102	100979271
ENSE00000811366	100979848	100979992
ENSE00001279632	100983305	100985616
ENSE00001958635	100972529	100973036
ENSE00003534396	100973547	100973609
ENSE00003561002	100973129	100973277
ENSE00003608339	100978295	100978388
ENSE00003611971	100977632	100977730
ENSE00003656829	100978527	100978640
ENSE00003971307	100969504	100969591

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 97.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.5372 / max 309.1859, expressed in 1239 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106618	6.3537	1231
106619	0.1835	70

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	97.55	gold quality
rectum	UBERON:0001052	97.38	gold quality
right lobe of liver	UBERON:0001114	95.59	gold quality
cortical plate	UBERON:0005343	95.07	gold quality
ileal mucosa	UBERON:0000331	93.53	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.15	gold quality
cerebellar hemisphere	UBERON:0002245	92.66	gold quality
cerebellar cortex	UBERON:0002129	92.50	gold quality
transverse colon	UBERON:0001157	91.77	gold quality
body of pancreas	UBERON:0001150	90.68	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.40	gold quality
cerebellum	UBERON:0002037	90.13	gold quality
liver	UBERON:0002107	89.54	gold quality
small intestine	UBERON:0002108	88.93	gold quality
right ovary	UBERON:0002118	86.66	gold quality
left ovary	UBERON:0002119	86.63	gold quality
right lobe of thyroid gland	UBERON:0001119	86.43	gold quality
skin of leg	UBERON:0001511	86.22	gold quality
body of stomach	UBERON:0001161	85.78	gold quality
intestine	UBERON:0000160	85.65	gold quality
colonic mucosa	UBERON:0000317	85.58	gold quality
metanephros cortex	UBERON:0010533	85.55	gold quality
left lobe of thyroid gland	UBERON:0001120	85.32	gold quality
duodenum	UBERON:0002114	85.26	gold quality
right adrenal gland cortex	UBERON:0035827	85.04	gold quality
mucosa of sigmoid colon	UBERON:0004993	84.88	gold quality
pancreas	UBERON:0001264	84.84	gold quality
right uterine tube	UBERON:0001302	84.69	gold quality
colonic epithelium	UBERON:0000397	84.56	gold quality
large intestine	UBERON:0000059	84.50	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

109 targeting SEMA4G, 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-4262	100.00	73.26	3931
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-520G-5P	99.99	66.76	658
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-1229-3P	99.97	66.49	906
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-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650

Literature-anchored findings (GeneRIF, showing 2)

• These findings provide evidence that the miR-608 rs4919510 polymorphism may modify cancer susceptibility in a type-specific manner. Furthermore, SEMA4G may function as an oncogene or tumour suppressor to regulate tumour development in a type-specific manner. Further studies with experimental evaluations are warranted. (PMID:28653886)
• Variants in TPO rs2048722, PTCSC2 rs925489 and SEMA4G rs4919510 affect thyroid carcinoma susceptibility risk. (PMID:36737753)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sema4ga	ENSDARG00000076595
danio_rerio	sema4gb	ENSDARG00000088143
mus_musculus	Sema4g	ENSMUSG00000025207
rattus_norvegicus	Sema4g	ENSRNOG00000014650

Paralogs (19): SEMA3F (ENSG00000001617), SEMA3G (ENSG00000010319), SEMA3B (ENSG00000012171), SEMA3A (ENSG00000075213), SEMA3C (ENSG00000075223), SEMA5B (ENSG00000082684), SEMA6A (ENSG00000092421), 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-4G — Q9NTN9 (reviewed: Q9NTN9)

All UniProt accessions (3): Q9NTN9, E5RGX4, H0YBN3

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor for PLXNB2. May play a role in axon guidance.

Subunit / interactions. Interacts with PLXNB2.

Subcellular location. Cell membrane.

Similarity. Belongs to the semaphorin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NTN9-1	1	yes
Q9NTN9-2	2
Q9NTN9-3	3

RefSeq proteins (3): NP_001190173, NP_001380854, NP_060363* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR002165	Plexin_repeat	Repeat
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016201	PSI	Domain
IPR027231	Semaphorin	Family
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036352	Semap_dom_sf	Homologous_superfamily

Pfam: PF01403, PF01437

UniProt features (28 total): disulfide bond 7, glycosylation site 6, domain 3, compositionally biased region 2, modified residue 2, topological domain 2, splice variant 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NTN9-F1	80.35	0.61

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 (2): 795, 837

Disulfide bonds (7): 104–115, 133–142, 270–377, 294–337, 508–525, 517–534, 584–632

Glycosylation sites (6): 55, 111, 126, 388, 542, 598

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 172 (showing top): TTTGTAG_MIR520D, AREB6_03, GOBP_NEUROGENESIS, HNF1_Q6, FOXO1_01, CTATGCA_MIR153, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, RODRIGUES_NTN1_TARGETS_DN, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_TAXIS, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, BLALOCK_ALZHEIMERS_DISEASE_UP, TCCCCAC_MIR491, RYTAAWNNNTGAY_UNKNOWN, TANAKA_METHYLATED_IN_ESOPHAGEAL_CARCINOMA

GO Biological Process (7): neural crest cell migration (GO:0001755), axon guidance (GO:0007411), positive regulation of cell migration (GO:0030335), negative chemotaxis (GO:0050919), semaphorin-plexin signaling pathway (GO:0071526), nervous system development (GO:0007399), 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)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling receptor binding	2
neural crest cell development	1
mesenchymal cell migration	1
axonogenesis	1
neuron projection guidance	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
chemotaxis	1
cell surface receptor signaling pathway	1
system development	1
cellular developmental process	1
receptor ligand activity	1
negative chemotaxis	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA4G	PLXNB2	O15031	741
SEMA4G	PLXNC1	O60486	516
SEMA4G	ENTPD7	Q9NQZ7	456
SEMA4G	DLG4	P78352	449
SEMA4G	USP17L20	D6RJB6	447
SEMA4G	PLXND1	Q9Y4D7	447
SEMA4G	CPN1	P15169	402
SEMA4G	RRAS	P10301	364
SEMA4G	PKD2L1	Q9P0L9	347
SEMA4G	NACC2	Q96BF6	342
SEMA4G	KLHL4	Q9C0H6	325
SEMA4G	TUBGCP4	Q9UGJ1	323
SEMA4G	PAGR1	Q9BTK6	318
SEMA4G	MRPL43	Q8N983	310
SEMA4G	ZNF587B	E7ETH6	293

IntAct

51 interactions, top by confidence:

A	B	Type	Score
SEMA4G	TRIP13	psi-mi:“MI:0915”(physical association)	0.560
GOPC	SEMA4G	psi-mi:“MI:0915”(physical association)	0.560
SEMA4G	GOPC	psi-mi:“MI:0915”(physical association)	0.560
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
TMX1	NRP1	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
EVA1C	STK25	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
LRRTM2	SEMA4G	psi-mi:“MI:0915”(physical association)	0.400
SEMA4G	ATXN1	psi-mi:“MI:0915”(physical association)	0.370
SHARPIN	MAP3K7	psi-mi:“MI:0914”(association)	0.350
TNIP1	UMAD1	psi-mi:“MI:0914”(association)	0.350
CD81	STX3	psi-mi:“MI:0914”(association)	0.350
CD81	PVR	psi-mi:“MI:0914”(association)	0.350
CD81	CD276	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
PCDHB3	ESYT2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PTCH1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
IL5RA	POTEF	psi-mi:“MI:0914”(association)	0.350
LCN6	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (53): SEMA4G (Two-hybrid), SEMA4G (Two-hybrid), SEMA4G (Two-hybrid), SEMA4G (Two-hybrid), SEMA4G (Two-hybrid), SEMA4G (Two-hybrid), SEMA4G (Affinity Capture-MS), RBPMS (Two-hybrid), SEMA4G (Affinity Capture-MS), SEMA4G (Affinity Capture-MS), DEGS1 (Two-hybrid), CREB3L1 (Two-hybrid), ARL13B (Two-hybrid), TNFRSF10D (Two-hybrid), SEMA4G (Affinity Capture-MS)

ESM2 similar proteins: A2AJ76, B0S5N4, B2RXS4, D3ZLH5, D3ZPX4, F1MMS9, O15031, O75326, O75578, O95754, P08514, P08648, P11688, P17852, P26006, P38570, P51805, P53711, P60882, P70206, P70208, Q13214, Q13683, Q27977, Q3UH93, Q4LFA9, Q5STE3, Q60519, Q61738, Q62177, Q62179, Q62470, Q63258, Q64151, Q7Z7M0, Q8NDA2, Q9C0C4, Q9NPR2, Q9NS98, Q9NTN9

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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1726 predictions. Top by Δscore:

Variant	Effect	Δscore
10:100977630:A:AG	acceptor_gain	1.0000
10:100977630:AGAC:A	acceptor_gain	1.0000
10:100977631:G:GG	acceptor_gain	1.0000
10:100977631:GACG:G	acceptor_gain	1.0000
10:100977731:G:GG	donor_gain	1.0000
10:100978289:CCCTA:C	acceptor_loss	1.0000
10:100978293:A:AG	acceptor_gain	1.0000
10:100978293:AG:A	acceptor_gain	1.0000
10:100978293:AGGAT:A	acceptor_gain	1.0000
10:100978294:G:GA	acceptor_gain	1.0000
10:100978294:GG:G	acceptor_gain	1.0000
10:100978294:GGA:G	acceptor_gain	1.0000
10:100978294:GGAT:G	acceptor_gain	1.0000
10:100978294:GGATG:G	acceptor_gain	1.0000
10:100978388:GGTG:G	donor_loss	1.0000
10:100978389:G:GA	donor_loss	1.0000
10:100978389:G:GG	donor_gain	1.0000
10:100978390:T:G	donor_loss	1.0000
10:100978950:G:GT	donor_gain	1.0000
10:100979100:AG:A	acceptor_gain	1.0000
10:100979101:GG:G	acceptor_gain	1.0000
10:100979101:GGGA:G	acceptor_gain	1.0000
10:100979229:GCC:G	donor_gain	1.0000
10:100979258:C:G	donor_gain	1.0000
10:100979269:GTG:G	donor_gain	1.0000
10:100979844:CTAGG:C	acceptor_loss	1.0000
10:100979845:TA:T	acceptor_loss	1.0000
10:100979846:A:AG	acceptor_gain	1.0000
10:100979846:A:C	acceptor_loss	1.0000
10:100979846:AG:A	acceptor_gain	1.0000

AlphaMissense

5397 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:100973555:G:C	W94C	1.000
10:100973555:G:T	W94C	1.000
10:100977638:T:A	C115S	1.000
10:100977639:G:C	C115S	1.000
10:100979138:T:A	W284R	1.000
10:100979138:T:C	W284R	1.000
10:100973583:T:A	C104S	0.999
10:100973584:G:C	C104S	0.999
10:100977638:T:C	C115R	0.999
10:100977640:C:G	C115W	0.999
10:100977646:C:A	N117K	0.999
10:100977646:C:G	N117K	0.999
10:100977693:G:A	C133Y	0.999
10:100977695:G:T	G134W	0.999
10:100977707:T:A	F138I	0.999
10:100977707:T:C	F138L	0.999
10:100977709:C:A	F138L	0.999
10:100977709:C:G	F138L	0.999
10:100978559:T:C	F188L	0.999
10:100978560:T:G	F188C	0.999
10:100978561:C:A	F188L	0.999
10:100978561:C:G	F188L	0.999
10:100979013:T:A	C270S	0.999
10:100979014:G:C	C270S	0.999
10:100979140:G:C	W284C	0.999
10:100979140:G:T	W284C	0.999
10:100979155:A:C	K289N	0.999
10:100979155:A:T	K289N	0.999
10:100980191:T:C	F400L	0.999
10:100980193:T:A	F400L	0.999

dbSNP variants (sampled 300 via entrez): RS1000038219 (10:100976030 G>A), RS1000263318 (10:100980496 A>G), RS1000336668 (10:100969778 G>A,T), RS1000469814 (10:100986024 G>T), RS1001397510 (10:100968114 G>T), RS1001745445 (10:100985696 A>G,T), RS1002338010 (10:100967879 G>C), RS1002588925 (10:100977830 G>A), RS1003102647 (10:100971535 C>G,T), RS1003167771 (10:100984188 C>T), RS1003301865 (10:100969377 T>A,C), RS1003332961 (10:100969237 G>A,C), RS1003548536 (10:100976830 T>C), RS1003712073 (10:100982598 C>G), RS1003743134 (10:100982311 G>A)

Disease associations

OMIM: gene MIM:618991 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006921_7	Regular attendance at a pub or social club	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	2
Nickel	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases methylation	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Flame Retardants	decreases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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