SEMA3F

Summary

SEMA3F (semaphorin 3F, HGNC:10728) is a protein-coding gene on chromosome 3p21.31, encoding Semaphorin-3F (Q13275). May play a role in cell motility and cell adhesion.

This gene encodes a member of the semaphorin III family of secreted signaling proteins that are involved in axon guidance during neuronal development. The encoded protein contains an N-terminal Sema domain, an immunoglobulin loop and a C-terminal basic domain. This gene is expressed by the endothelial cells where it was found to act in an autocrine fashion to induce apoptosis, inhibit cell proliferation and survival, and function as an anti-tumorigenic agent. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 6405 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism (Strong, GenCC)
• GWAS associations: 37
• Clinical variants (ClinVar): 337 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_004186

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10728
Approved symbol	SEMA3F
Name	semaphorin 3F
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	SEMAK, Sema4
Ensembl gene	ENSG00000001617
Ensembl biotype	protein_coding
OMIM	601124
Entrez	6405

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 retained_intron

ENST00000002829, ENST00000413852, ENST00000414301, ENST00000420831, ENST00000426511, ENST00000434342, ENST00000450338, ENST00000470737, ENST00000493743, ENST00000858140, ENST00000923328, ENST00000923329, ENST00000923330, ENST00000923331, ENST00000961513, ENST00000961514

RefSeq mRNA: 3 — MANE Select: NM_004186 NM_001318798, NM_001318800, NM_004186

CCDS: CCDS2811, CCDS82779, CCDS82780

Canonical transcript exons

ENST00000002829 — 19 exons

Exon	Start	End
ENSE00000380982	50185443	50185531
ENSE00000768695	50174052	50174114
ENSE00000768696	50174231	50174350
ENSE00000768697	50175096	50175188
ENSE00000768699	50182284	50182403
ENSE00000768700	50182644	50182783
ENSE00000768703	50183420	50183564
ENSE00000768704	50184592	50184814
ENSE00000768706	50185666	50185707
ENSE00000768707	50185889	50186046
ENSE00000768709	50186281	50186348
ENSE00000768710	50186613	50186746
ENSE00001911603	50187705	50189075
ENSE00001933741	50155324	50155564
ENSE00002021109	50159575	50159734
ENSE00003482432	50183186	50183255
ENSE00003554145	50173793	50173953
ENSE00003603741	50182904	50183018
ENSE00003786809	50176768	50176861

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.5551 / max 327.9523, expressed in 1429 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36680	11.4696	1297
36679	7.0046	1148
36681	2.4362	955
36682	0.9490	538
36678	0.4217	256
36683	0.2287	103
36685	0.0346	16
202756	0.0108	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	99.80	gold quality
gingival epithelium	UBERON:0001949	98.69	gold quality
lower esophagus mucosa	UBERON:0035834	98.37	gold quality
gingiva	UBERON:0001828	98.29	gold quality
squamous epithelium	UBERON:0006914	98.20	gold quality
tongue squamous epithelium	UBERON:0006919	98.13	gold quality
pancreatic ductal cell	CL:0002079	98.01	gold quality
esophagus squamous epithelium	UBERON:0006920	97.54	gold quality
skin of hip	UBERON:0001554	96.90	gold quality
epithelium of esophagus	UBERON:0001976	96.90	gold quality
pharyngeal mucosa	UBERON:0000355	96.84	gold quality
esophagus mucosa	UBERON:0002469	96.63	gold quality
penis	UBERON:0000989	96.45	gold quality
upper leg skin	UBERON:0004262	96.14	gold quality
hair follicle	UBERON:0002073	95.94	gold quality
type B pancreatic cell	CL:0000169	95.57	silver quality
skin of abdomen	UBERON:0001416	95.56	gold quality
zone of skin	UBERON:0000014	95.10	gold quality
skin of leg	UBERON:0001511	95.05	gold quality
cervix epithelium	UBERON:0004801	95.01	gold quality
oviduct epithelium	UBERON:0004804	94.99	gold quality
nasal cavity epithelium	UBERON:0005384	94.94	gold quality
nipple	UBERON:0002030	94.81	gold quality
body of tongue	UBERON:0011876	94.71	gold quality
mammalian vulva	UBERON:0000997	94.62	gold quality
epithelium of nasopharynx	UBERON:0001951	94.45	gold quality
oral cavity	UBERON:0000167	94.04	gold quality
parotid gland	UBERON:0001831	94.04	gold quality
vagina	UBERON:0000996	93.72	gold quality
renal medulla	UBERON:0000362	93.21	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.11
E-MTAB-6678	no	2.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, FOXO3, ID2, RORA, SNAI1, TCF3, ZEB1

miRNA regulators (miRDB)

67 targeting SEMA3F, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
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-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-451B	99.55	68.28	1380

Literature-anchored findings (GeneRIF, showing 40)

• SEMA3F and VEGF have antagonistic actions affecting motility in primary tumor cell (PMID:12659673)
• SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells (PMID:15520858)
• SEMA3F suppresses lung neoplasm progression in an experimental model (PMID:15967098)
• Results suggest that p53 negatively regulates tumor vessel formation and cell growth via the SEMA3F-NRP2 pathway. (PMID:17308083)
• combinations of sema3A and sema3F may be able to inhibit tumor angiogenesis more effectively than single semaphorins. (PMID:17569671)
• Semaphorin 3F mRNA forms a G quartet-containing structure, which is recognized with high affinity and specificity by the RGG box domain of the fragile X mental retardation protein. (PMID:17693432)
• Transient SEMA-3F gene transfection may inhibit the proliferation of Tca8113 cells. (PMID:18476556)
• ABL2/ARG is a novel mediator of SEMA3F-induced RhoA inactivation and collapsing activity. (PMID:18660502)
• Sema3F inhibits tumor development from MDA-MB-435 and MDA-MB-231 and but not MCF-7 or MDA-MB-68 cancer cells. It inhibits tumor angiogenesis in all of the formed tumors. The inhibition is correlated with the expression of neuropilins of the tumors cells. (PMID:18818766)
• SEMA3F loss was associated with changes in cell signaling: increased phospho-AKT in normoxia and hypoxia-induced factor 1alpha protein. Exogenous addition of SEMA3F could modulate ZEB-1-induced angiogenesis in a chorioallantoic membrane assay. (PMID:19177200)
• Semaphorin3F reverses Multicellular resistance by regulating alpha(v)beta3 (PMID:19657188)
• These data indicate that polymorphisms in SEMA3F are associated with prostate cancer risk and poor prognosis in Hispanic and nonHispanic white men (PMID:19683737)
• Soluble neuropilin-2Fc did not inhibit repulsion but increased the repellent effect of semaphorin 3F. (PMID:19790074)
• SEMA3F, CLEC16A, LAMA3, and PCSK2 variants have roles in myocardial infarction in Japanese individuals (PMID:20036365)
• semaphorin-3B and semaphorin-3F have roles in ovarian cancer (PMID:20124444)
• Metastatic tumor cells overexpress c-myc, leading to upregulation of Id2 expression; the aberrantly elevated amount of Id2 represses SEMA3F expression and, as a consequence, enhances the ability of tumor cells to migrate and invade. (PMID:20388805)
• Endogenous SEMA3F acts as a suppressor of the growth and metastasis of human colorectal cancer cells. (PMID:21349996)
• It was concluded that hypoxia regulates VEGF and SE MA3F activities through transcriptional repression of their common receptor NRP2, providing a novel mechanism by which hypoxia induces tumor angiogenesis, growth and metastasis. (PMID:21610314)
• This study demonstrated a marked loss of noradrenergic and sensory nerve fibers in polyp mucosa, which was associated with a strong increase of semaphorin 3F and 3A. (PMID:22093159)
• showed that transcription of SEMA3F is directly regulated by RORalpha (PMID:22350413)
• we found that merlin regulated expression of SEMA3F through Rho GTPase family member Rac1 (PMID:22431917)
• A functional role for Semaphorin 3F in the outer retina where it acts as a vasorepulsive cue to maintain physiologic avascularity. (PMID:23603393)
• Data suggest that SEMA3F C-terminal domain exhibits high-affinity binding of neuropilin-1 (NRP1; thus inhibiting binding of vascular endothelial growth factor A to NRP1); this interaction may be involved in anti-angiogenic activity of SEMA3F. (PMID:24079887)
• Data indicate that semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) are expressed in the thymus. (PMID:25068647)
• Our findings demonstrate the ability of SEMA3F to inhibit the stemness of human CRC cells by suppressing Rac1 activation, which suggests a novel therapeutic approach for colorectal cancer (PMID:25529012)
• SEMA3F functions as a suppressor of colorectal cancer metastasis by down-regulating the ASCL2-CXCR4 signaling axis. (PMID:25866254)
• SEMA3F may represent an antilymphangiogenic metastasis suppressor gene widely lost during cancer progression, hence serving as a prognostic biomarker and an attractive target for therapeutic intervention to halt metastasis. (PMID:25952650)
• Infantile hemangioma-derived stem cells and endothelial cells are inhibited by SEMA3E and SEMA3F. (PMID:26086095)
• SEMA3F-NRP2 interactions inhibit intracellular PI-3K activity, mTORC2-dependent signaling, RhoA activity and cytoskeletal stress fiber formation. (PMID:26156437)
• Study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy. (PMID:26447612)
• SEMA3F was downregulated in colorectal cancer tissues as compared to matched adjacent non-tumor tissues (PMID:26722466)
• A new SEMA3F transcript is expressed in all breast cell lines and breast cancer biopsies, and is translated into a new semaphorin 3F isoform. (PMID:26784191)
• in situ hybridization analysis revealed that Sema 3C and Sema 3F are expressed at the RNA level in the endometriosis affected peritoneum (PMID:27558236)
• Semaphorin 3F placenta tissue expression was significantly reduced in preeclampsia. In addition, semaphorin 3F level at delivery was significantly lower in serum, amniotic fluid and venous umbilical blood of preeclamptic patients compared with normal pregnant women. (PMID:28350837)
• There is a positive association between the expression of AKAP12 and Semaphorin 3F in prostate cancer, suggesting that the activation of Semaphorin 3F by AKAP12 may be involved in prostate cancer progression and metastasis. (PMID:28698137)
• SEMA3F plays a role as a tumor suppressor in Oral squamous cell carcinoma cell proliferation, migration and invasion. (PMID:29299034)
• Familial chronic megacolon appears to be associated with SEMA3F, which is associated with genes impacting enteric nerve or pacemaker function. (PMID:30663199)
• SEMA 3F is recommended as an important therapeutic agent for the prevention of pathological angiogenesis. SEMA 3F may offer an effective and efficient anti-angiogenic intervention that can be administered at a lower dose alternative to typical VEGF blocking agents. (PMID:31420803)
• The level of SEMA3F was significantly higher in normal prostate tissues compared with that in prostate cancer cells. (PMID:31563162)
• SEMA3F was significantly upregulated in hepatocellular carcinoma tissue and was associated with poor survival. SEMA3F promoted hepatocellular carcinoma metastasis by activating focal adhesion pathway. (PMID:31968181)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sema3fa	ENSDARG00000011163
danio_rerio	sema3fb	ENSDARG00000055373
mus_musculus	Sema3f	ENSMUSG00000034684
rattus_norvegicus	Sema3f	ENSRNOG00000017704

Paralogs (19): 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), SEMA4A (ENSG00000196189)

Protein

Protein identifiers

Semaphorin-3F — Q13275 (reviewed: Q13275)

Alternative names: Sema III/F, Semaphorin IV

All UniProt accessions (6): C9IYS6, C9J1V2, C9J4H5, C9JPG5, Q13275, H7C4A2

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in cell motility and cell adhesion.

Subcellular location. Secreted.

Tissue specificity. Expressed abundantly but differentially in a variety of neural and nonneural tissues. There is high expression in mammary gland, kidney, fetal brain, and lung and lower expression in heart and liver.

Similarity. Belongs to the semaphorin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13275-1	1	yes
Q13275-2	2

RefSeq proteins (3): NP_001305727, NP_001305729, NP_004177* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR003598	Ig_sub2	Domain
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

UniProt features (19 total): disulfide bond 6, sequence variant 2, sequence conflict 2, domain 2, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13275-F1	84.06	0.65

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (6): 300–412, 324–372, 548–566, 678–746, 104–115, 133–142

Glycosylation sites (2): 53, 126

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 265 (showing top): GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION, RORA1_01, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_NEURON_PROJECTION_EXTENSION_INVOLVED_IN_NEURON_PROJECTION_GUIDANCE, AREB6_03, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_CRANIAL_NERVE_MORPHOGENESIS, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, MODULE_16, GOBP_CRANIAL_NERVE_DEVELOPMENT

GO Biological Process (20): neural crest cell migration (GO:0001755), axon guidance (GO:0007411), facial nerve structural organization (GO:0021612), trigeminal nerve structural organization (GO:0021637), nerve development (GO:0021675), branchiomotor neuron axon guidance (GO:0021785), positive regulation of cell migration (GO:0030335), ventral trunk neural crest cell migration (GO:0036486), negative regulation of axon extension involved in axon guidance (GO:0048843), axon extension involved in axon guidance (GO:0048846), negative chemotaxis (GO:0050919), sympathetic ganglion development (GO:0061549), semaphorin-plexin signaling pathway (GO:0071526), sympathetic neuron projection extension (GO:0097490), sympathetic neuron projection guidance (GO:0097491), regulation of postsynapse organization (GO:0099175), neural crest cell migration involved in autonomic nervous system development (GO:1901166), signal transduction (GO:0007165), trunk neural crest cell migration (GO:0036484), system development (GO:0048731)

GO Molecular Function (5): semaphorin receptor binding (GO:0030215), neuropilin binding (GO:0038191), chemorepellent activity (GO:0045499), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), glutamatergic synapse (GO:0098978), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neuron projection guidance	2
cranial nerve structural organization	2
anatomical structure development	2
neural crest cell migration	2
signaling receptor binding	2
neural crest cell development	1
mesenchymal cell migration	1
axonogenesis	1
facial nerve morphogenesis	1
trigeminal nerve morphogenesis	1
nervous system development	1
motor neuron axon guidance	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
trunk neural crest cell migration	1
negative regulation of axon extension	1
regulation of axon extension involved in axon guidance	1
axon extension involved in axon guidance	1
negative regulation of chemotaxis	1
axon guidance	1
axon extension	1
chemotaxis	1
sympathetic nervous system development	1
ganglion development	1
cell surface receptor signaling pathway	1
neuron projection extension	1
regulation of synapse organization	1
postsynapse organization	1
autonomic nervous system development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
trunk segmentation	1
multicellular organism development	1
receptor ligand activity	1
negative chemotaxis	1
protein binding	1

Protein interactions and networks

STRING

992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA3F	NRP2	O60462	999
SEMA3F	PLXNA3	P51805	999
SEMA3F	NRP1	O14786	994
SEMA3F	PLXNA1	Q9UIW2	990
SEMA3F	PLXNA4	Q9HCM2	815
SEMA3F	NRCAM	Q92823	741
SEMA3F	PLXND1	Q9Y4D7	673
SEMA3F	ROBO2	Q9HCK4	665
SEMA3F	FMR1	Q06787	660
SEMA3F	PLXNA2	O75051	626
SEMA3F	PLXNB1	O43157	602
SEMA3F	UNC5A	Q6ZN44	596
SEMA3F	EPHB2	P29323	580
SEMA3F	EFNA5	P52803	572
SEMA3F	GNAT1	P11488	571

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
SEMA3C	ZZEF1	psi-mi:“MI:0914”(association)	0.350
SLC35G2	SEMA3F	psi-mi:“MI:0915”(physical association)	0.000
UBA1	SEMA3F	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): SEMA3F (Affinity Capture-RNA), SEMA3F (Affinity Capture-RNA), SEMA3F (Reconstituted Complex), SEMA3F (Affinity Capture-MS), SEMA3F (Affinity Capture-MS), SEMA3F (Reconstituted Complex), SEMA3F (Affinity Capture-MS), SEMA3F (Affinity Capture-RNA), SEMA3F (Proximity Label-MS), SEMA3F (Affinity Capture-MS), SEMA3F (Two-hybrid), SEMA3F (Reconstituted Complex)

ESM2 similar proteins: A0M8R7, A0M8S8, A7MB70, O08665, O09126, O42236, O88632, O95025, P08581, P16056, P97523, Q07DV8, Q07DY1, Q07DZ1, Q07E24, Q07E37, Q07E48, Q09YH7, Q09YK0, Q09YL1, Q108U6, Q13275, Q14563, Q24323, Q26473, Q2IBA6, Q2IBD8, Q2IBF2, Q2IBG7, Q2QL89, Q2QLA9, Q2QLC0, Q2QLE0, Q2QLF1, Q2QLG5, Q2QLH6, Q5RE75, Q62181, Q63548, Q75ZY9

Diamond homologs: A7MB70, D3ZTD8, O08665, O09126, O15041, O35464, O42236, O42237, O88632, O95025, O95754, P70275, Q13214, Q13275, Q13591, Q14563, Q17330, Q24322, Q24323, Q26473, Q26972, Q4LFA9, Q5EA85, Q5R7F5, Q5RE75, Q60519, Q62177, Q62178, Q62179, Q62181, Q62217, Q63548, Q64151, Q76KF0, Q8BH34, Q8NFY4, Q90607, Q90663, Q90665, Q92854

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SEMA3F	up-regulates	NRP2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	193
Likely benign	114
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2986 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50173785:A:AG	acceptor_gain	1.0000
3:50173786:C:G	acceptor_gain	1.0000
3:50173788:CACA:C	acceptor_loss	1.0000
3:50173788:CACAG:C	acceptor_gain	1.0000
3:50173789:ACAGA:A	acceptor_gain	1.0000
3:50173790:C:G	acceptor_gain	1.0000
3:50173790:CAG:C	acceptor_gain	1.0000
3:50173790:CAGA:C	acceptor_loss	1.0000
3:50173791:A:AG	acceptor_gain	1.0000
3:50173791:A:C	acceptor_loss	1.0000
3:50173791:AGA:A	acceptor_gain	1.0000
3:50173792:G:GA	acceptor_gain	1.0000
3:50173792:G:T	acceptor_gain	1.0000
3:50173792:GA:G	acceptor_gain	1.0000
3:50173792:GAGC:G	acceptor_gain	1.0000
3:50173792:GAGCT:G	acceptor_gain	1.0000
3:50173903:GAC:G	donor_gain	1.0000
3:50173949:TCATT:T	donor_gain	1.0000
3:50173950:CATT:C	donor_gain	1.0000
3:50173951:ATT:A	donor_gain	1.0000
3:50173951:ATTGT:A	donor_loss	1.0000
3:50173952:TT:T	donor_gain	1.0000
3:50173952:TTG:T	donor_loss	1.0000
3:50173953:TGTA:T	donor_loss	1.0000
3:50173954:G:GG	donor_gain	1.0000
3:50173954:GTAAG:G	donor_loss	1.0000
3:50174115:G:GG	donor_gain	1.0000
3:50174348:CAG:C	donor_loss	1.0000
3:50174352:T:A	donor_loss	1.0000
3:50175091:CTCA:C	acceptor_loss	1.0000

AlphaMissense

5110 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:50173883:G:C	R68P	1.000
3:50174088:T:A	C104S	1.000
3:50174088:T:C	C104R	1.000
3:50174089:G:C	C104S	1.000
3:50174090:C:G	C104W	1.000
3:50174283:T:C	L130P	1.000
3:50174291:T:C	C133R	1.000
3:50174292:G:A	C133Y	1.000
3:50174293:C:G	C133W	1.000
3:50174318:T:A	C142S	1.000
3:50174318:T:C	C142R	1.000
3:50174319:G:A	C142Y	1.000
3:50174319:G:C	C142S	1.000
3:50174320:C:G	C142W	1.000
3:50182314:A:T	D225V	1.000
3:50182344:G:C	R235P	1.000
3:50182398:T:C	L253P	1.000
3:50182773:G:C	R298P	1.000
3:50182778:T:A	C300S	1.000
3:50182778:T:C	C300R	1.000
3:50182779:G:A	C300Y	1.000
3:50182779:G:C	C300S	1.000
3:50182780:C:G	C300W	1.000
3:50182907:G:C	D303H	1.000
3:50182908:A:T	D303V	1.000
3:50182914:G:A	G305D	1.000
3:50182940:T:A	W314R	1.000
3:50182940:T:C	W314R	1.000
3:50182942:G:C	W314C	1.000
3:50182942:G:T	W314C	1.000

dbSNP variants (sampled 300 via entrez): RS1000019306 (3:50189463 A>G), RS1000079164 (3:50189206 T>G), RS1000136800 (3:50162940 C>A,T), RS1000167279 (3:50170545 G>C), RS1000195766 (3:50171598 C>T), RS1000239012 (3:50170206 G>A,T), RS1000350662 (3:50165410 C>G), RS1000508707 (3:50183814 T>TG), RS1000694880 (3:50171782 C>T), RS1000751531 (3:50176713 A>C,G,T), RS1000826679 (3:50163949 G>A), RS1000843349 (3:50158516 C>T), RS1000906831 (3:50189476 C>G), RS1001046771 (3:50183315 C>G,T), RS1001072645 (3:50165157 A>G)

Disease associations

OMIM: gene MIM:601124 | disease phenotypes: MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism	Strong	Autosomal dominant

Mondo (2): hearing loss disorder (MONDO:0005365), hypogonadotropic hypogonadism (MONDO:0018555)

Orphanet (1): Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000044	Hypogonadotropic hypogonadism

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST005316_114	Intelligence (MTAG)	6.000000e-15
GCST005316_129	Intelligence (MTAG)	2.000000e-09
GCST005316_293	Intelligence (MTAG)	1.000000e-14
GCST005316_294	Intelligence (MTAG)	2.000000e-22
GCST005951_49	Body mass index	1.000000e-08
GCST006269_792	General cognitive ability	3.000000e-09
GCST006269_801	General cognitive ability	7.000000e-09
GCST006412_2	Intraocular pressure	5.000000e-07
GCST006920_7	Regular attendance at a gym or sports club	6.000000e-10
GCST007044_11	Extremely high intelligence	4.000000e-08
GCST007325_72	General risk tolerance (MTAG)	6.000000e-10
GCST007335_7	Age at first sexual intercourse	3.000000e-11
GCST007336_2	Age at first birth	1.000000e-12
GCST007336_4	Age at first birth	9.000000e-15
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST007565_88	Morning person	7.000000e-19
GCST008129_41	Body mass index	9.000000e-26
GCST009524_124	Household income (MTAG)	3.000000e-08
GCST009524_204	Household income (MTAG)	6.000000e-09
GCST009524_227	Household income (MTAG)	1.000000e-19
GCST009725_79	Intraocular pressure	2.000000e-07
GCST009726_22	Glaucoma	8.000000e-08
GCST010002_422	Refractive error	4.000000e-14
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST011703_58	Smoking initiation	1.000000e-10
GCST012008_1	Lateral thalamic nuclei volume	2.000000e-14

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004340	body mass index
EFO:0004695	intraocular pressure measurement
EFO:0009592	social interaction measurement
EFO:0008579	risk-taking behaviour
EFO:0009749	age at first sexual intercourse measurement
EFO:0009101	age at first birth measurement
EFO:0008328	chronotype measurement
EFO:0009695	household income
EFO:0004346	neuroimaging measurement
EFO:0005670	smoking initiation
EFO:0006935	thalamus volume
EFO:0010100	multisite chronic pain
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression	3
Acetaminophen	increases expression	2
Air Pollutants	increases abundance, affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation	2
Calcitriol	increases expression, decreases reaction, increases response to substance	2
Valproic Acid	affects expression, increases methylation	2
Cyclosporine	decreases methylation, increases expression	2
Aflatoxin B1	increases expression, affects expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
trichostatin A	decreases expression	1
sodium arsenite	affects methylation	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	increases phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
seocalcitol	increases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
clothianidin	decreases expression	1
belinostat	decreases expression	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)