NGF

Summary

NGF (nerve growth factor, HGNC:7808) is a protein-coding gene on chromosome 1p13.2, encoding Beta-nerve growth factor (P01138). Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems.

This gene is a member of the NGF-beta family and encodes a secreted protein which homodimerizes and is incorporated into a larger complex. This protein has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy, type 5 (HSAN5), and dysregulation of this gene’s expression is associated with allergic rhinitis.

Source: NCBI Gene 4803 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary sensory and autonomic neuropathy (Strong, ClinGen) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 167 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes
• MANE Select transcript: NM_002506

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7808
Approved symbol	NGF
Name	nerve growth factor
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134259
Ensembl biotype	protein_coding
OMIM	162030
Entrez	4803

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000369512, ENST00000675637, ENST00000676038, ENST00000679806, ENST00000680116, ENST00000680540, ENST00000680752, ENST00000681124, ENST00000871201, ENST00000871202, ENST00000871203, ENST00000871204, ENST00000871205, ENST00000929056, ENST00000970250, ENST00000970251

RefSeq mRNA: 1 — MANE Select: NM_002506 NM_002506

CCDS: CCDS882

Canonical transcript exons

ENST00000369512 — 3 exons

Exon	Start	End
ENSE00001020911	115338204	115338249
ENSE00001020912	115293627	115293750
ENSE00001450208	115285917	115286807

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 94.67.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2617 / max 74.0482, expressed in 766 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13980	3.1546	749
13981	0.1071	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	94.67	gold quality
left uterine tube	UBERON:0001303	86.55	gold quality
right ovary	UBERON:0002118	86.05	gold quality
right atrium auricular region	UBERON:0006631	86.05	gold quality
apex of heart	UBERON:0002098	85.58	gold quality
cardiac atrium	UBERON:0002081	85.09	gold quality
ascending aorta	UBERON:0001496	85.04	gold quality
left ovary	UBERON:0002119	84.87	gold quality
thoracic aorta	UBERON:0001515	84.86	gold quality
aorta	UBERON:0000947	83.68	gold quality
tibial artery	UBERON:0007610	82.92	gold quality
popliteal artery	UBERON:0002250	82.90	gold quality
heart left ventricle	UBERON:0002084	81.87	gold quality
omental fat pad	UBERON:0010414	81.82	gold quality
peritoneum	UBERON:0002358	81.79	gold quality
cardiac ventricle	UBERON:0002082	81.78	gold quality
heart	UBERON:0000948	81.49	gold quality
ovary	UBERON:0000992	81.15	gold quality
descending thoracic aorta	UBERON:0002345	81.09	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.62	gold quality
left coronary artery	UBERON:0001626	80.42	gold quality
coronary artery	UBERON:0001621	79.62	gold quality
vena cava	UBERON:0004087	78.69	silver quality
myocardium	UBERON:0002349	78.65	gold quality
body of uterus	UBERON:0009853	78.62	gold quality
right coronary artery	UBERON:0001625	77.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	77.49	gold quality
tibial nerve	UBERON:0001323	76.48	gold quality
left ventricle myocardium	UBERON:0006566	74.15	gold quality
endocervix	UBERON:0000458	74.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.18

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CDKN1A	Activation
CTSS	Activation
GCH1	Activation
SCN9A	Activation

Upstream regulators (CollecTRI, top): AP1, AR, ASCL1, CEBPD, CREB1, CREM, CUX1, DNMT3B, EGR1, EGR3, EGR4, FOS, HAND1, HES1, ID2, ID3, ING4, JUN, JUNB, JUND, KLF7, LRRFIP1, NEUROD6, NFATC4, NFE2L2, NFKB2, NFKB, NR1H4, NR4A1, NR4A2, NR5A1, NRG1, POU2F2, POU4F1, RARB, RELA, SP1, TFAP2A, TP53, VDR

miRNA regulators (miRDB)

37 targeting NGF, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-568	99.98	69.86	2084
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-548AR-3P	99.85	71.26	3889
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-32-3P	99.36	68.20	2517

Literature-anchored findings (GeneRIF, showing 40)

• On immunologic stimuli, human eosinophils secrete nerve growth factor that promotes elongation of neurites. (PMID:11877300)
• Results support the involvement of NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome, implying neuroimmune and adipoimmune pathways in the pathobiology of these cardiovascular disorders. (PMID:11935372)
• Phenotypic knockout of nerve growth factor (NGF) activity in transgenic anti-NGF mice (AD11 mice) results in a progressive neurodegenerative phenotype. (PMID:12205295)
• The gene expression of this protein was studied in the developing human tooth. (PMID:12397373)
• correlation between the activity of systemic lupus erythematosus and the levels of NGF in serum (PMID:12453472)
• NGF modulates cytokine mRNA expression in immune cells. (NGF) (PMID:12531456)
• Interleukin-10 and nerve growth factor have reciprocal upregulatory effects on intestinal epithelial cells. (PMID:12676754)
• Data suggest that activation of bronchial eosinophils by neurotrophins (nerve growth factor, brain-derived neurotrophic factor, neurotrophins-3 and -4) might play a role in the regulation of eosinophilic inflammation in allergic asthma. (PMID:12900521)
• Circulating levels in Behcet disease are not different from normal values. (PMID:12918708)
• histamine may enhance nerve growth factor production by inducing c-Fos expression in keratinocytes. (PMID:12925217)
• NGF might have a crucial role in the auditory pathway, promoting the survival and preventing the degeneration of sensorineural cells. (PMID:14587217)
• NGF is expressed in human pancreatic beta cells and modulates insulin secretion through a paracrine/autocrine loop, similar to the one observed in cultured rat beta cells (PMID:14708938)
• Zinc(II) in native beta-NGF plays an important role in the structure and the biological activity of the protein (PMID:14970904)
• mutation causes loss of pain perception (PMID:14976160)
• acts as a co-receptor and molecular switch governing the p75NTR-mediated pro-apoptotic signal induced by proNGF (PMID:14985763)
• determined the 2.4 A crystal structure of NGF complexed with the extracellular domain of p75; the complex is composed of an NGF homodimer asymmetrically bound to a single p75 (PMID:15131306)
• expression of NGF and its receptors, TrkA and p75NTR, in hepatocellular carcinomas (HCC); NGF and its receptors are thought to have a role in cellular interactions involving HCC cells, hepatic stellate cells, arterial cells and nerve cells in HCC tissues (PMID:15523689)
• Monocytes, produce, store and release NGF, brain-derived neurotrophic factor and neurotrophin 3 (PMID:15544837)
• pro-NGF purified from AD human brains can induce apoptosis in neuronal cell cultures through its interaction with the p75NTR receptor (PMID:15681836)
• NGF is indeed involved in growth initiation of human primordial follicles. (PMID:15829579)
• p62 regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination (PMID:16079148)
• NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels (PMID:16319926)
• Overexpression in salivary adenoid cystic carcinoma may constitute a reason for perineural invasion (PMID:16546643)
• Light and electron microscopy immunohistochemistry showed that tonsillar samples were positive for NGF. (PMID:16786155)
• Here, we show the first evidence of NGF-TrkA autocrine loop and clinical significance of Nerve growth factor(NGF)overexpression in oesophageal squamous cell carcinoma(OESCC). (PMID:16832412)
• non-fat cells in human adipose tissue contribute to most of the release of NGF seen during primary culture of adipose tissue explants from obese women (PMID:16839849)
• Findings report, for the first time, the expression pattern of NGF and TrkA proteins in human scalp skin and hair follicle. (PMID:16919030)
• SNP associated with ADHD in the 5’ pro-NGF sequence may affect intracellular processing and secretion of NGF. (PMID:17192954)
• a NGF/BEX2/NF-kappaB pathway is involved in regulating apoptosis in breast cancer cells and in modulating response to tamoxifen in primary tumors (PMID:17638883)
• We show here high expression of TRKA in Hodgkin-Reed/Sternberg cell lines as compared to normal B cells and other B cell lymphomas, without major increases in TRKA gene dosage. (PMID:17673289)
• has mitogenic and motogenic effects on oral mucosal keratinocytes. Differential expression throughout the epithelium suggests a role in epithelial differentiation (PMID:17850422)
• Nerve growth factor was only detected in liver tissue with hepatocellular carcinoma present. (PMID:17854142)
• NGF concentration in CSF is a useful marker of brain damage following severe TBI (PMID:17881264)
• Late preweaning exposure of rats to chlorpyrifos and methyl parathion affect expression of nerve growth factor in hippocampus and cerebral cortex. (PMID:17893397)
• The NGF mRNA levels at baseline in the interstitial cystitis patients were significantly greater than those in the controls. NGF expression plays an important role in the pathogenesis of IC. (PMID:17905097)
• These results newly demonstrate the cardiac prosurvival action of NGF and provide mechanistic information on the signaling pathway (PMID:17992191)
• These data support a role for NGF-induced cell apoptosis in LLS formation in vitro. (PMID:18068123)
• N-terminal Vps10p domain of sortilin, which is responsible for the interaction with the neurotrophins, adopts a beta-propeller fold, and that the N-terminal regions of sortilin, pro-NGF and pro-BDNF are mainly intrinsically disordered regions (PMID:18191449)
• Targeting NGF in breast cancer may have therapeutic ramifications. (PMID:18199526)
• Variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes showing a synergistic epistatic interaction. (PMID:18203754)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ngfb	ENSDARG00000014050
danio_rerio	ngfa	ENSDARG00000058961
mus_musculus	Ngf	ENSMUSG00000027859
rattus_norvegicus	Ngf	ENSRNOG00000016571

Paralogs (3): BDNF (ENSG00000176697), NTF3 (ENSG00000185652), NTF4 (ENSG00000225950)

Protein

Protein identifiers

Beta-nerve growth factor — P01138 (reviewed: P01138)

All UniProt accessions (2): A0A7P0TAZ6, P01138

UniProt curated annotations — full annotation on UniProt →

Function. Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades to regulate neuronal proliferation, differentiation and survival. The immature NGF precursor (proNGF) functions as a ligand for the heterodimeric receptor formed by SORCS2 and NGFR, and activates cellular signaling cascades that lead to inactivation of RAC1 and/or RAC2, reorganization of the actin cytoskeleton and neuronal growth cone collapse. In contrast to mature NGF, the precursor form (proNGF) promotes neuronal apoptosis (in vitro). Inhibits metalloproteinase-dependent proteolysis of platelet glycoprotein VI. Binds lysophosphatidylinositol and lysophosphatidylserine between the two chains of the homodimer. The lipid-bound form promotes histamine relase from mast cells, contrary to the lipid-free form.

Subunit / interactions. Homodimer. The homodimer interacts with a single NTRK1 chain. The homodimer interacts with a single NGFR chain. The NGF dimer interacts with a single SORCS2 chain (via extracellular domain). The NGF precursor (proNGF) binds to a receptor complex formed by SORT1 and NGFR, which leads to NGF endocytosis. Both mature NGF and the immature NGF precursor (proNGF) interact with SORCS2 and with the heterodimer formed by SORCS2 and NGFR (via extracellular domains). The NGF precursor (proNGF) has much higher affinity for SORCS2 than mature NGF. The NGF precursor (proNGF) has much higher affinity for SORT1 than mature NGF. Interacts with ADAM10 in a divalent cation-dependent manner. Interaction with SORCS3.

Subcellular location. Secreted. Endosome lumen.

Disease relevance. Neuropathy, hereditary sensory and autonomic, 5 (HSAN5) [MIM:608654] A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN5 patients manifest loss of pain perception and impaired temperature sensitivity, ulcers, and in some cases self-mutilation. The autonomic involvement is variable. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the NGF-beta family.

RefSeq proteins (1): NP_002497* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002072	Nerve_growth_factor-rel	Domain
IPR019846	Nerve_growth_factor_CS	Conserved_site
IPR020408	Nerve_growth_factor-like	Family
IPR020425	Nerve_growth_factor_bsu	Family
IPR020437	Nerve_growth_factor_bsu_mml	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00243

UniProt features (31 total): strand 9, sequence variant 6, disulfide bond 3, binding site 3, sequence conflict 2, turn 2, glycosylation site 2, signal peptide 1, propeptide 1, helix 1, chain 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9TPP	X-RAY DIFFRACTION	1.8
1WWW	X-RAY DIFFRACTION	2.2
1SG1	X-RAY DIFFRACTION	2.4
9TQ6	X-RAY DIFFRACTION	2.4
4ZBN	X-RAY DIFFRACTION	2.45
4EDW	X-RAY DIFFRACTION	2.48
4EDX	X-RAY DIFFRACTION	2.5
2IFG	X-RAY DIFFRACTION	3.4
5JZ7	X-RAY DIFFRACTION	3.4
6YW8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01138-F1	73.55	0.37

Antibody-complex structures (SAbDab): 3 — 4EDW, 4EDX, 5JZ7

Functional residue map

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

Ligand- & substrate-binding residues (3): 173 (in other chain); 209; 209

Disulfide bonds (3): 189–231, 136–201, 179–229

Glycosylation sites (2): 69, 114

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-167021	PLC-gamma1 signalling
R-HSA-167044	Signalling to RAS
R-HSA-167060	NGF processing
R-HSA-170968	Frs2-mediated activation
R-HSA-170984	ARMS-mediated activation
R-HSA-177504	Retrograde neurotrophin signalling
R-HSA-187042	TRKA activation by NGF
R-HSA-187706	Signalling to p38 via RIT and RIN
R-HSA-193648	NRAGE signals death through JNK
R-HSA-193670	p75NTR negatively regulates cell cycle via SC1
R-HSA-193681	Ceramide signalling
R-HSA-198203	PI3K/AKT activation
R-HSA-198745	Signalling to STAT3
R-HSA-205017	NFG and proNGF binds to p75NTR
R-HSA-205025	NADE modulates death signalling
R-HSA-205043	NRIF signals cell death from the nucleus
R-HSA-209543	p75NTR recruits signalling complexes
R-HSA-209560	NF-kB is activated and signals survival
R-HSA-209563	Axonal growth stimulation

MSigDB gene sets: 415 (showing top): PID_SHP2_PATHWAY, GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_CIRCADIAN_RHYTHM, REACTOME_RETROGRADE_NEUROTROPHIN_SIGNALLING, MODULE_92, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_CELL_MATURATION, GOBP_REGULATION_OF_COLLATERAL_SPROUTING, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEURON_PROJECTION_EXTENSION, MODULE_255, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, LFA1_Q6, KEGG_MAPK_SIGNALING_PATHWAY

GO Biological Process (30): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), peripheral nervous system development (GO:0007422), circadian rhythm (GO:0007623), negative regulation of cell population proliferation (GO:0008285), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), positive regulation of gene expression (GO:0010628), positive regulation of neuron projection development (GO:0010976), positive regulation of neuron maturation (GO:0014042), sensory perception of pain (GO:0019233), nerve development (GO:0021675), positive regulation of protein ubiquitination (GO:0031398), nerve growth factor signaling pathway (GO:0038180), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of neuron differentiation (GO:0045666), positive regulation of axon extension (GO:0045773), positive regulation of Ras protein signal transduction (GO:0046579), regulation of neurotransmitter secretion (GO:0046928), neurotrophin TRK receptor signaling pathway (GO:0048011), positive regulation of collateral sprouting (GO:0048672), axon extension (GO:0048675), neuron projection morphogenesis (GO:0048812), modulation of chemical synaptic transmission (GO:0050804), regulation of release of sequestered calcium ion into cytosol (GO:0051279), neuron apoptotic process (GO:0051402), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of ERK1 and ERK2 cascade (GO:0070374), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), signal transduction (GO:0007165), neuron projection development (GO:0031175), regulation of neuron differentiation (GO:0045664)

GO Molecular Function (9): nerve growth factor receptor binding (GO:0005163), growth factor activity (GO:0008083), metalloendopeptidase inhibitor activity (GO:0008191), lipid binding (GO:0008289), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297), enzyme inhibitor activity (GO:0004857), signaling receptor binding (GO:0005102), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi lumen (GO:0005796), cytosol (GO:0005829), synaptic vesicle (GO:0008021), axon (GO:0030424), dendrite (GO:0030425), endosome lumen (GO:0031904), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by NTRK1 (TRKA)	4
Cell death signalling via NRAGE, NRIF and NADE	3
p75 NTR receptor-mediated signalling	3
Signalling to ERKs	2
Prolonged ERK activation events	2
p75NTR signals via NF-kB	2
Expression and Processing of Neurotrophins	1
Activation of TRKA receptors	1
p75NTR regulates axonogenesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nervous system development	2
neurotrophin signaling pathway	2
positive regulation of cell growth	2
positive regulation of developmental growth	2
positive regulation of axonogenesis	2
binding	2
cellular anatomical structure	2
intracellular organelle lumen	2
neuron projection	2
enzyme-linked receptor protein signaling pathway	1
system development	1
rhythmic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
extrinsic apoptotic signaling pathway	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
regulation of neuron maturation	1
neuron maturation	1
positive regulation of cell maturation	1
sensory perception	1
anatomical structure development	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
cellular response to nerve growth factor stimulus	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
regulation of axon extension	1
axon extension	1
Ras protein signal transduction	1

Protein interactions and networks

STRING

3919 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NGF	NGFR	P08138	999
NGF	NTRK2	Q16620	999
NGF	NTRK1	P04629	999
NGF	NTRK3	Q16288	998
NGF	SORT1	Q99523	990
NGF	GFRA1	P56159	949
NGF	GDNF	P39905	925
NGF	NTF4	P34130	922
NGF	TRPA1	O75762	916
NGF	GAP43	P17677	905
NGF	TAC1	P20366	874
NGF	EGF	P01133	867
NGF	CALM1	P02593	867
NGF	CALML4	Q96GE6	866
NGF	CALML6	Q8TD86	863

IntAct

30 interactions, top by confidence:

A	B	Type	Score
Ngfr	NGF	psi-mi:“MI:0407”(direct interaction)	0.720
NGF	Ngfr	psi-mi:“MI:0407”(direct interaction)	0.720
Ngfr	NGF	psi-mi:“MI:0915”(physical association)	0.720
NGF	NTRK1	psi-mi:“MI:0407”(direct interaction)	0.680
SORT1	NGF	psi-mi:“MI:0407”(direct interaction)	0.680
SORT1	NGF	psi-mi:“MI:0915”(physical association)	0.680
EIF2S2	NGF	psi-mi:“MI:0915”(physical association)	0.560
APP	NGF	psi-mi:“MI:0915”(physical association)	0.560
NGF	APP	psi-mi:“MI:0915”(physical association)	0.560
NGFR	NGF	psi-mi:“MI:0407”(direct interaction)	0.540
NGFR	NGF	psi-mi:“MI:0915”(physical association)	0.540
NGF	NGF	psi-mi:“MI:0407”(direct interaction)	0.440
SORCS3	NGF	psi-mi:“MI:0407”(direct interaction)	0.440
NGF	SORCS3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (19): NGF (Reconstituted Complex), NGFR (Reconstituted Complex), NTRK1 (Reconstituted Complex), NGF (Reconstituted Complex), SORT1 (Reconstituted Complex), ITGA9 (Reconstituted Complex), ITGB1 (Reconstituted Complex), NGF (Reconstituted Complex), NTRK1 (Reconstituted Complex), NGFR (Reconstituted Complex), NGF (Reconstituted Complex), NGF (Co-crystal Structure), CHRM4 (Affinity Capture-Western), S (Reconstituted Complex), NGF (Co-fractionation)

ESM2 similar proteins: A6MFL5, A6MFL6, A6MFL7, F8RKW5, O73797, P01138, P01139, P05200, P13600, P18280, P19093, P20181, P20675, P20783, P21617, P25427, P25428, P25435, P34128, Q06AV0, Q1W7Q6, Q29074, Q2XXL6, Q3HXX4, Q3HXX5, Q3HXX6, Q3HXX7, Q3HXX8, Q3HXX9, Q3HXY0, Q3HXY1, Q3HXY2, Q3HXY3, Q3HXY4, Q3HXY5, Q3HXY6, Q3HXY7, Q3HXY8, Q3HXY9, Q3HXZ0

Diamond homologs: A6MFL5, A6MFL6, A6MFL7, B8QCG6, F8RKW5, O18752, O18753, O18755, O70183, O73797, O93474, O97759, P01138, P01139, P01140, P05200, P0DMD1, P13600, P14082, P18280, P19093, P20181, P20675, P20783, P21237, P21617, P23363, P23560, P24727, P25427, P25428, P25429, P25433, P25435, P30894, P34128, P34129, P61898, P61899, Q02193

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
NGF	up-regulates	NGFR	binding
THBS1	up-regulates	NGF	binding
NGF	up-regulates	NTRK1	binding
NGF	“up-regulates quantity by expression”	GCH1	“transcriptional regulation”
NGF	“up-regulates quantity by expression”	SCN9A	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	92
Likely benign	51
Benign	8

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2181214	NM_002506.3(NGF):c.241C>T (p.Arg81Ter)	Pathogenic
29802	NM_002506.3(NGF):c.680_682delinsA (p.Thr227fs)	Pathogenic
14045	NM_002506.3(NGF):c.661C>T (p.Arg221Trp)	Likely pathogenic

SpliceAI

943 predictions. Top by Δscore:

Variant	Effect	Δscore
1:115293749:CT:C	acceptor_gain	0.9900
1:115293751:C:CC	acceptor_gain	0.9900
1:115338203:CCG:C	donor_gain	0.9900
1:115338202:A:AC	donor_gain	0.9800
1:115338203:C:CC	donor_gain	0.9800
1:115286808:C:CG	acceptor_loss	0.9700
1:115286809:T:C	acceptor_loss	0.9700
1:115300395:A:AC	donor_gain	0.9700
1:115300396:C:CC	donor_gain	0.9700
1:115338196:TGAC:T	donor_loss	0.9700
1:115338197:GACT:G	donor_loss	0.9700
1:115338198:ACT:A	donor_loss	0.9700
1:115338199:CTCA:C	donor_loss	0.9700
1:115338200:TCACC:T	donor_loss	0.9700
1:115338201:C:CG	donor_loss	0.9700
1:115338202:A:T	donor_loss	0.9700
1:115338203:C:CA	donor_loss	0.9700
1:115293746:AAACT:A	acceptor_gain	0.9600
1:115293748:ACT:A	acceptor_gain	0.9500
1:115293749:CTC:C	acceptor_gain	0.9500
1:115293750:TCT:T	acceptor_gain	0.9500
1:115306416:C:CT	acceptor_gain	0.9500
1:115293747:AACTC:A	acceptor_loss	0.9400
1:115293750:TC:T	acceptor_loss	0.9400
1:115293751:C:A	acceptor_loss	0.9400
1:115293752:T:G	acceptor_loss	0.9400
1:115294599:A:AC	donor_gain	0.9400
1:115287907:A:AC	donor_gain	0.9300
1:115287908:C:CC	donor_gain	0.9300
1:115335986:T:A	donor_gain	0.9300

AlphaMissense

1580 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:115286205:C:A	W197C	1.000
1:115286205:C:G	W197C	1.000
1:115286389:C:G	C136S	1.000
1:115286390:A:T	C136S	1.000
1:115286103:A:C	C231W	0.999
1:115286104:C:G	C231S	0.999
1:115286104:C:T	C231Y	0.999
1:115286105:A:G	C231R	0.999
1:115286105:A:T	C231S	0.999
1:115286128:A:T	I223N	0.999
1:115286136:C:A	W220C	0.999
1:115286136:C:G	W220C	0.999
1:115286138:A:G	W220R	0.999
1:115286138:A:T	W220R	0.999
1:115286175:A:C	F207L	0.999
1:115286175:A:T	F207L	0.999
1:115286177:A:G	F207L	0.999
1:115286193:A:C	C201W	0.999
1:115286194:C:G	C201S	0.999
1:115286194:C:T	C201Y	0.999
1:115286195:A:T	C201S	0.999
1:115286230:C:G	C189S	0.999
1:115286231:A:T	C189S	0.999
1:115286260:C:G	C179S	0.999
1:115286261:A:T	C179S	0.999
1:115286275:A:C	F174C	0.999
1:115286275:A:G	F174S	0.999
1:115286370:C:A	W142C	0.999
1:115286370:C:G	W142C	0.999
1:115286389:C:T	C136Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000057445 (1:115288275 T>C), RS1000064682 (1:115336765 C>A,T), RS1000090354 (1:115289179 T>A,C), RS1000090837 (1:115330325 C>A), RS1000201839 (1:115324262 A>T), RS1000212465 (1:115315646 G>A), RS1000271381 (1:115336907 G>A,C), RS1000356014 (1:115318186 T>C), RS1000433170 (1:115288081 T>G), RS1000474631 (1:115295195 T>A,C), RS1000594856 (1:115305526 T>C), RS1000631096 (1:115330499 G>A), RS1000648399 (1:115312688 A>G), RS1000730085 (1:115299795 A>C), RS1000740594 (1:115329740 C>T)

Disease associations

OMIM: gene MIM:162030 | disease phenotypes: MIM:608654, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary sensory and autonomic neuropathy	Strong	Autosomal recessive
hereditary sensory and autonomic neuropathy type 5	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary sensory and autonomic neuropathy	Strong	AR

Mondo (4): hereditary sensory and autonomic neuropathy type 5 (MONDO:0012092), peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease (MONDO:0015626), hereditary sensory and autonomic neuropathy (MONDO:0015364)

Orphanet (2): Hereditary sensory and autonomic neuropathy type 5 (Orphanet:64752), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000164	Abnormality of the dentition
HP:0000168	Abnormality of the gingiva
HP:0000272	Malar flattening
HP:0000490	Deeply set eye
HP:0000970	Anhidrosis
HP:0001058	Poor wound healing
HP:0001256	Mild intellectual disability
HP:0001954	Recurrent fever
HP:0002014	Diarrhea
HP:0002019	Constipation
HP:0002378	Hand tremor
HP:0002495	Impaired vibratory sensation
HP:0002661	Painless fractures due to injury
HP:0002754	Osteomyelitis
HP:0002757	Recurrent fractures
HP:0002758	Osteoarthritis
HP:0003040	Arthropathy
HP:0003095	Septic arthritis
HP:0003419	Low back pain
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0006121	Acral ulceration
HP:0007021	Pain insensitivity
HP:0007249	Decreased number of small peripheral myelinated nerve fibers
HP:0007328	Impaired pain sensation
HP:0009830	Peripheral neuropathy
HP:0010829	Impaired temperature sensation
HP:0011463	Childhood onset

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001928_1	Pediatric non-alcoholic fatty liver disease activity score	7.000000e-06
GCST003720_14	Migraine	9.000000e-09
GCST003720_23	Migraine	4.000000e-24
GCST003721_1	Migraine without aura	7.000000e-09
GCST003927_1	Dysmenorrheic pain	4.000000e-14
GCST003986_7	Migraine	2.000000e-13
GCST004227_3	Obstetric antiphospholipid syndrome	4.000000e-06
GCST006636_5	Menstruation quality of life impact (dysmenorrhea)	8.000000e-12
GCST006637_1	Pain medicine use during menstruation	2.000000e-13
GCST006656_1	Dysmenorrheic pain severity	1.000000e-19
GCST007094_183	Diastolic blood pressure	1.000000e-11
GCST007099_65	Systolic blood pressure	1.000000e-07
GCST007201_84	Schizophrenia	4.000000e-07
GCST010866_18	Coronary artery disease	9.000000e-11
GCST90002403_15	Red blood cell count	2.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007889	dysmenorrheic pain measurement
EFO:0007010	drug use measurement
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D009477	Hereditary Sensory and Autonomic Neuropathies	C10.500.250; C10.574.500.493; C10.668.829.800.175; C16.131.666.310; C16.320.400.415

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1649058 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2239622	Dosage	3	methadone	Heroin Dependence;Opioid-Related Disorders

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2239622	NGF	3	0.75	1	methadone

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	IC50	1000	nM	CHEMBL1397270

PubChem BioAssay actives

1 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7,10-dimethyl-2,4-dioxobenzo[g]pteridine-8-carbaldehyde	700919: Inhibition of NGF binding to p75NTR	ic50	1.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Copper	affects binding, increases expression	2
Nicotine	increases expression, increases secretion	2
Cadmium Chloride	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	decreases reaction, increases phosphorylation	1
mangiferin	increases secretion	1
sulforaphane	decreases phosphorylation, decreases reaction, increases activity, increases expression	1
sodium arsenite	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
manganese chloride	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression, decreases reaction	1
beclomethasone 17-monopropionate	decreases reaction, increases secretion, decreases secretion	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases expression, decreases reaction	1
methanandamide	decreases reaction, increases expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
U 0126	decreases reaction, increases expression	1
pyrazolanthrone	decreases reaction, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression	1
jinfukang	decreases expression, increases reaction	1
NSC 689534	affects binding, increases expression	1
Calcimycin	affects cotreatment, decreases reaction, increases expression, decreases expression	1
Temozolomide	decreases expression	1
Edaravone	increases expression, decreases reaction	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Berberine	decreases expression, decreases reaction, increases expression	1
Calcitriol	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1648454	Binding	Induction of neurotrophic factor mRNA expression in human 1321N1 cells at 100 uM by RT-PCR analysis relative to beta-actin mRNA expression	Lyconadins D and E, and complanadine E, new Lycopodium alkaloids from Lycopodium complanatum. — Bioorg Med Chem

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 2 spontaneously immortalized cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4P7	SEES3-1V human NGF, clone1	Embryonic stem cell	Male
CVCL_A4P8	SEES3-1V human NGF, clone2	Embryonic stem cell	Male
CVCL_A4P9	SEES3-1V human NGF, clone3	Embryonic stem cell	Male
CVCL_DF65	NGC0211	Spontaneously immortalized cell line	Male
CVCL_DF66	NGC-0295	Spontaneously immortalized cell line	Male
CVCL_UG27	UKWNLi002-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.