NTF3

Summary

NTF3 (neurotrophin 3, HGNC:8023) is a protein-coding gene on chromosome 12p13.31, encoding Neurotrophin-3 (P20783). Seems to promote the survival of visceral and proprioceptive sensory neurons.

The protein encoded by this gene is a member of the neurotrophin family, that controls survival and differentiation of mammalian neurons. This protein is closely related to both nerve growth factor and brain-derived neurotrophic factor. It may be involved in the maintenance of the adult nervous system, and may affect development of neurons in the embryo when it is expressed in human placenta. NTF3-deficient mice generated by gene targeting display severe movement defects of the limbs. The mature peptide of this protein is identical in all mammals examined including human, pig, rat and mouse.

Source: NCBI Gene 4908 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 35 total
• MANE Select transcript: NM_001102654

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8023
Approved symbol	NTF3
Name	neurotrophin 3
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	NGF2
Ensembl gene	ENSG00000185652
Ensembl biotype	protein_coding
OMIM	162660
Entrez	4908

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000331010, ENST00000423158, ENST00000535299, ENST00000541234, ENST00000543548, ENST00000544836

RefSeq mRNA: 2 — MANE Select: NM_001102654 NM_001102654, NM_002527

CCDS: CCDS44806, CCDS8538

Canonical transcript exons

ENST00000423158 — 2 exons

Exon	Start	End
ENSE00001740540	5494194	5495299
ENSE00002263308	5432108	5432342

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 92.30.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9533 / max 155.7519, expressed in 618 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123611	2.7042	603
123610	0.2491	153

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	92.30	gold quality
tibial artery	UBERON:0007610	92.29	gold quality
aorta	UBERON:0000947	91.06	gold quality
right coronary artery	UBERON:0001625	89.94	gold quality
ascending aorta	UBERON:0001496	89.75	gold quality
thoracic aorta	UBERON:0001515	89.61	gold quality
left coronary artery	UBERON:0001626	88.43	gold quality
descending thoracic aorta	UBERON:0002345	88.07	gold quality
coronary artery	UBERON:0001621	87.07	gold quality
right ovary	UBERON:0002118	83.14	gold quality
left ovary	UBERON:0002119	82.41	gold quality
blood vessel layer	UBERON:0004797	82.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.18	gold quality
saphenous vein	UBERON:0007318	80.62	gold quality
cervix squamous epithelium	UBERON:0006922	80.48	gold quality
right lobe of liver	UBERON:0001114	80.46	gold quality
mucosa of stomach	UBERON:0001199	79.88	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.68	gold quality
ectocervix	UBERON:0012249	79.31	gold quality
ovary	UBERON:0000992	78.63	gold quality
endocervix	UBERON:0000458	77.48	gold quality
vagina	UBERON:0000996	77.22	gold quality
cerebellar hemisphere	UBERON:0002245	75.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	75.57	gold quality
cerebellar cortex	UBERON:0002129	75.52	gold quality
triceps brachii	UBERON:0001509	74.75	gold quality
gluteal muscle	UBERON:0002000	74.72	gold quality
calcaneal tendon	UBERON:0003701	74.72	gold quality
cerebellum	UBERON:0002037	74.53	gold quality
urethra	UBERON:0000057	74.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, OPTN, POU4F3, SOX9, SP1, SP4, SRY, ZNF175

miRNA regulators (miRDB)

93 targeting NTF3, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• NGF and NT-3 concentrations are increased in children with hydrocephalus. (PMID:11580868)
• Human eosinophils produce neurotrophin 3 on immunologic stimuli. (PMID:11877300)
• Results suggest that the G(- 3004)-A3 haplotype has a modest effect of giving susceptibility to schizophrenia. (PMID:11920853)
• The gene expression of this protein was studied in the developing human tooth. (PMID:12397373)
• NT3 is significantly decreased in the myenteric plexus of patients with active Crohn’s disease and ulcerative colitis. (PMID:12598727)
• Fibroblasts genetically modified to express human neurotrophin-3 (NT-3) were placed in, and distal to, the lesion cavity in chronic spinal cord injured rats; grafted animals exhibited significant growth of corticospinal axons (PMID:12710933)
• 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)
• Monocytes, produce, store and release nerve growth factor, brain-derived neurotrophic factor and NT-3 (PMID:15544837)
• In transgenic mlc/NT-3 mice following nerve injury, NT-3 plays an important role during the early stages of spindle denervation that ultimately effects reinnervation by group II and gamma fibers. (PMID:15589528)
• Circulating neurotrophin-3 levels increased in early neonatal life, possibly due to exposure to various stimuli soon after birth (PMID:15770067)
• The present data on neurotrophin-specific transcriptional down-regulation of NT3 in human Chronic obstructive pulmonary disease (COPD)indicate a pathophysiological role for neurotrophins in COPD. (PMID:15843147)
• Human bronchial smooth muscle cells can express NGF, BDNF and NT-3. Expression may be differently regulated by inflammatory cytokines. Might have potential role in airway inflammation. (PMID:16441896)
• Light and electron microscopy immunohistochemistry showed that tonsillar samples were positive for NT3. (PMID:16786155)
• With electrical stimulation of forepaw in experimental spinal cord injury, NT3-treated animals showed extensive activation of brain structures that included contralateral cortex, thalamus, caudate putamen, hippocampus, and periaqueductal gray. (PMID:17112518)
• These findings suggest that the NT-3 signaling system may play a role in the pathophysiology of BD. (PMID:17234344)
• These results demonstrate functional interchangeability between the pro-peptides of nerve growth factor and NT-3 with respect to their role in assisting oxidative folding of the mature part. (PMID:17698064)
• neurotrophins (NT)and high affinity NT receptor proteins were more abundantly expressed in idiopatic pulmonary fibrosis/usual interstitial pneumoniae than non specific pneumonia and respiratory bronchiolitis-associated interstitial lung disease patients (PMID:18069415)
• NTF3 might be involved in the molecular basis of the age-dependent changes in ADHD symptoms throughout life span. (PMID:18179783)
• NT-3, NT-4, and nerve growth factor (NGF) induce cell migration in melanoma, with a stronger effect on metastatic cell lines. (PMID:18305571)
• Data show that reduced expression levels of NT-3 mRNAs are found in patients with major depressive disorder in a current depressive state, but not in a remissive state. (PMID:18313696)
• protein levels of translational, splicing, processing, chaperone, protein handling, and metabolism machineries were shown to depend on neurotrophin-3-induced TrkC activation in the medulloblastoma cell line DAOY (PMID:18336001)
• The polymorphism within the exon of NTF3 showed significant association with ADHD symptoms. (PMID:18428117)
• The findings suggest interactive and sequential roles for FGF2 and NT3 on cochlear ganglion development (PMID:18438927)
• Present study in transgenic Alzheimer disease (AD) mice does not support the idea of substantial correlation of NT-3 with AD pathology. (PMID:18438945)
• 6-A resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75(NTR). (PMID:18596692)
• The data of this study provided the first quantitative measure of brain NT-3 and show its increase in the autistic brain. Altered levels of brain NT-3 are likely to contribute to autistic pathology. (PMID:19357934)
• The specificity of sensorimotor connections is regulated independently of the muscle spindle, indicating spindle-derived factors other than NT3 regulate strength of the connections in the first postnatal week in mice with abnormal spindle development. (PMID:19369542)
• Co-culture of human neurotrophin-3 (NT-3) gene-modified Schwann cells (SCs) and human NT-3 receptor tyrosine protein kinase C (TrkC) gene-modified MSCs increase differentiation of neuron-like cells from mesenchymal stem cells. (PMID:19680743)
• The results of this study suggested that increased serum NT-3 levels in BD are likely to be associated with the pathophysiology of manic and depressive symptoms. (PMID:20060128)
• TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. (PMID:20160348)
• Report the proangiogenic capacity of NT-3 and propose NT-3 as a novel potential agent for the treatment of ischemic disease. (PMID:20360537)
• preliminary evidence of an association between NTF3 and the intelligence and selective attention deficit in the Korean population. (PMID:20576502)
• Collagen-binding neurotrophin-3 promotes axonal regeneration after spinal cord transection. (PMID:20597688)
• Data show that serum NT-3 levels were similar in SSc and in the control group. (PMID:21085492)
• Results suggest that proneurotrophin-3 and proBDNF may play important roles in the response to noise-induced injuries or ototoxic damage via the Sortilin:p75(NTR) death-signalling complex. (PMID:21261755)
• NT3 may be involved in early folliculogenesis, particularly in the activation of primordial follicles. (PMID:21392742)
• findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively (PMID:21698095)
• both apoptotic cell death and neuronal differentiation of tumor cells were the mechanisms of growth-inhibitory effect of NT-3-secreting human adipose tissue-derived mesenchymal stem cells (PMID:21720807)
• Mice carrying one or two platelet-derived growth factor beta-NT3 transgenes on a background null for wildtype NT-3 are generated by crossing with an NT-3 null strain; although still ataxic, mice from this cross could survive for periods longer than a year. (PMID:21787840)
• Implantation of NT-3 gene-modified mesenchymal stem cells via a recombinant adenoviral vector into a demyelinated region of rat spinal cord results in significant improvement of locomotor function and electrophysiological restoration in rats. (PMID:21996274)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ntf3	ENSDARG00000059043
mus_musculus	Ntf3	ENSMUSG00000049107
rattus_norvegicus	Ntf3	ENSRNOG00000019716

Paralogs (3): NGF (ENSG00000134259), BDNF (ENSG00000176697), NTF4 (ENSG00000225950)

Protein

Protein identifiers

Neurotrophin-3 — P20783 (reviewed: P20783)

Alternative names: HDNF, Nerve growth factor 2, Neurotrophic factor

All UniProt accessions (1): P20783

UniProt curated annotations — full annotation on UniProt →

Function. Seems to promote the survival of visceral and proprioceptive sensory neurons.

Subcellular location. Secreted.

Tissue specificity. Brain and peripheral tissues.

Polymorphism. Variant Glu-76 (frequently reported as Glu-63) was thought to be associated with severe forms of schizophrenia. This does not seem to be the case.

Similarity. Belongs to the NGF-beta family.

Isoforms (2)

UniProt ID	Names	Canonical?
P20783-1	1	yes
P20783-2	2

RefSeq proteins (2): NP_001096124, NP_002518 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002072	Nerve_growth_factor-rel	Domain
IPR015578	Neurotrophin-3	Family
IPR019846	Nerve_growth_factor_CS	Conserved_site
IPR020408	Nerve_growth_factor-like	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily
IPR045815	NTF3_N	Domain

Pfam: PF00243, PF19338

UniProt features (22 total): strand 9, disulfide bond 3, turn 2, signal peptide 1, propeptide 1, sequence variant 1, chain 1, region of interest 1, compositionally biased region 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9FIK	X-RAY DIFFRACTION	1.86
1B8K	X-RAY DIFFRACTION	2.15
1BND	X-RAY DIFFRACTION	2.3
1NT3	X-RAY DIFFRACTION	2.4
3BUK	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20783-F1	73.94	0.37

Antibody-complex structures (SAbDab): 1 — 9FIK

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 (3): 152–217, 195–246, 205–248

Glycosylation sites (1): 131

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9025046	NTF3 activates NTRK2 (TRKB) signaling
R-HSA-9034013	NTF3 activates NTRK3 signaling
R-HSA-9034015	Signaling by NTRK3 (TRKC)
R-HSA-9034793	Activated NTRK3 signals through PLCG1
R-HSA-9034864	Activated NTRK3 signals through RAS
R-HSA-9603381	Activated NTRK3 signals through PI3K

MSigDB gene sets: 257 (showing top): PID_SHP2_PATHWAY, RRAGTTGT_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, RORA1_01, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, TATTATA_MIR374, GOBP_INDUCTION_OF_POSITIVE_CHEMOTAXIS, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, TAL1ALPHAE47_01

GO Biological Process (17): positive regulation of receptor internalization (GO:0002092), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), cell-cell signaling (GO:0007267), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), nerve development (GO:0021675), positive regulation of cell migration (GO:0030335), nerve growth factor signaling pathway (GO:0038180), regulation of apoptotic process (GO:0042981), positive regulation of MAPK cascade (GO:0043410), negative regulation of neuron apoptotic process (GO:0043524), neuron projection morphogenesis (GO:0048812), modulation of chemical synaptic transmission (GO:0050804), induction of positive chemotaxis (GO:0050930), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive chemotaxis (GO:0050918)

GO Molecular Function (6): signaling receptor binding (GO:0005102), nerve growth factor receptor binding (GO:0005163), growth factor activity (GO:0008083), chemoattractant activity (GO:0042056), neurotrophin receptor binding (GO:0005165), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), synaptic vesicle (GO:0008021), axon (GO:0030424), dendrite (GO:0030425)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by NTRK3 (TRKC)	4
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
Negative regulation of the PI3K/AKT network	1
Signaling by NTRK2 (TRKB)	1
Signaling by NTRKs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
positive regulation of intracellular signal transduction	2
receptor ligand activity	2
neuron projection	2
regulation of receptor internalization	1
receptor internalization	1
positive regulation of receptor-mediated endocytosis	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
nervous system development	1
anatomical structure development	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
neurotrophin signaling pathway	1
cellular response to nerve growth factor stimulus	1
apoptotic process	1
regulation of programmed cell death	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
positive regulation of positive chemotaxis	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
chemotaxis	1
protein binding	1
death receptor binding	1

Protein interactions and networks

STRING

1374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NTF3	NTRK2	Q16620	999
NTF3	NTRK3	Q16288	999
NTF3	NTRK1	P04629	999
NTF3	NGFR	P08138	998
NTF3	GDNF	P39905	936
NTF3	SORT1	Q99523	851
NTF3	CNTF	P26441	808
NTF3	NGF	P01138	806
NTF3	BDNF	P23560	775
NTF3	IGF1	P01343	730
NTF3	NRN1	Q9NPD7	713
NTF3	GFRA3	O60609	683
NTF3	FGF2	P09038	672
NTF3	GFRA2	O00451	669
NTF3	DPYSL2	Q16555	669

IntAct

18 interactions, top by confidence:

A	B	Type	Score
NTF3	Ngfr	psi-mi:“MI:0407”(direct interaction)	0.650
NTF3	BDNF	psi-mi:“MI:0407”(direct interaction)	0.590
NTF3	BDNF	psi-mi:“MI:0914”(association)	0.590
NTF3	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	NTF3	psi-mi:“MI:0915”(physical association)	0.560
DOK6	NTF3	psi-mi:“MI:0914”(association)	0.460
NTF3	NTF3	psi-mi:“MI:0407”(direct interaction)	0.440
SORCS2	NTF3	psi-mi:“MI:0407”(direct interaction)	0.440
Dok6	NTF3	psi-mi:“MI:0914”(association)	0.350
NTF3	PYGL	psi-mi:“MI:0914”(association)	0.350
NTF3	HSPA5	psi-mi:“MI:0914”(association)	0.350
NTF3	CA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): NTF3 (Two-hybrid), LAMB1 (Affinity Capture-MS), PYGB (Affinity Capture-MS), PYGL (Affinity Capture-MS), ITIH3 (Affinity Capture-MS), MAD2L1BP (Affinity Capture-MS), MAD2L1BP (Affinity Capture-MS), PYGL (Affinity Capture-MS), PYGB (Affinity Capture-MS), NTF3 (Affinity Capture-RNA), NTRK1 (Reconstituted Complex), NTRK2 (Reconstituted Complex), NTRK3 (Reconstituted Complex), NTF3 (Affinity Capture-MS), NTF3 (Reconstituted Complex)

ESM2 similar proteins: A0A2R8Y4Y8, A0A2R8YFL7, A0A2R8YFM6, A0A8J1K1A4, A5D791, E7FKV8, O77726, O88393, P20239, P20783, P26342, P35054, P40200, P47984, Q03167, Q05996, Q08DT3, Q17R60, Q2Q0J1, Q3MHP9, Q3U0X8, Q3V1M1, Q4FZG8, Q4V7E2, Q5BK49, Q5SY80, Q5XI99, Q6DFV8, Q6WRH9, Q6WRI0, Q6X784, Q7TST5, Q80VH0, Q86WS3, Q8JIR8, Q8R1W8, Q925U0, Q95KG7, Q9D9J7, Q9ET62

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

3 interactions.

A	Effect	B	Mechanism
NTF3	up-regulates	NTRK3	binding
hsa-miR-21-5p	“down-regulates quantity by destabilization”	NTF3	“post transcriptional regulation”
OPTN	“up-regulates quantity by expression”	NTF3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

190 predictions. Top by Δscore:

Variant	Effect	Δscore
12:5494883:C:G	acceptor_gain	0.5500
12:5494831:GGG:G	donor_gain	0.5300
12:5494832:GGG:G	donor_gain	0.5300
12:5494623:AAACG:A	donor_loss	0.4900
12:5494624:AACG:A	donor_loss	0.4900
12:5494625:ACG:A	donor_loss	0.4900
12:5494626:CG:C	donor_loss	0.4900
12:5494627:GGT:G	donor_loss	0.4900
12:5494628:GTA:G	donor_loss	0.4900
12:5494629:TACG:T	donor_loss	0.4900
12:5494204:TGAAC:T	donor_gain	0.4800
12:5494630:A:C	donor_loss	0.4800
12:5494812:C:T	donor_gain	0.4800
12:5494832:G:A	donor_gain	0.4800
12:5494978:G:T	donor_gain	0.4800
12:5494411:C:G	donor_gain	0.4700
12:5494803:G:GT	donor_gain	0.4700
12:5494631:C:CC	donor_loss	0.4600
12:5494826:T:TA	donor_gain	0.4600
12:5494830:AGG:A	donor_gain	0.4600
12:5494215:AT:A	donor_gain	0.4500
12:5494837:T:TG	donor_gain	0.4400
12:5494471:T:G	donor_gain	0.4300
12:5494861:A:AG	acceptor_gain	0.4200
12:5494862:G:GG	acceptor_gain	0.4200
12:5494470:A:AG	donor_gain	0.4100
12:5494668:T:A	donor_loss	0.4100
12:5494795:GAT:G	donor_gain	0.4100
12:5494798:G:GG	donor_gain	0.4100
12:5494954:T:A	donor_gain	0.4100

AlphaMissense

1746 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:5494668:T:A	C152S	1.000
12:5494668:T:C	C152R	1.000
12:5494669:G:A	C152Y	1.000
12:5494669:G:C	C152S	1.000
12:5494669:G:T	C152F	1.000
12:5494670:T:G	C152W	1.000
12:5494686:T:A	W158R	1.000
12:5494686:T:C	W158R	1.000
12:5494688:G:C	W158C	1.000
12:5494688:G:T	W158C	1.000
12:5494782:T:C	F190L	1.000
12:5494783:T:C	F190S	1.000
12:5494783:T:G	F190C	1.000
12:5494784:T:A	F190L	1.000
12:5494784:T:G	F190L	1.000
12:5494797:T:A	C195S	1.000
12:5494797:T:C	C195R	1.000
12:5494798:G:C	C195S	1.000
12:5494827:T:A	C205S	1.000
12:5494827:T:C	C205R	1.000
12:5494828:G:A	C205Y	1.000
12:5494828:G:C	C205S	1.000
12:5494829:C:G	C205W	1.000
12:5494833:G:C	G207R	1.000
12:5494833:G:T	G207C	1.000
12:5494851:T:A	W213R	1.000
12:5494851:T:C	W213R	1.000
12:5494853:G:C	W213C	1.000
12:5494853:G:T	W213C	1.000
12:5494863:T:A	C217S	1.000

dbSNP variants (sampled 300 via entrez): RS1000021071 (12:5453330 T>A), RS1000075380 (12:5460408 G>A), RS1000114211 (12:5474007 T>G), RS1000135888 (12:5469381 C>G,T), RS1000222594 (12:5484814 T>A), RS1000388300 (12:5456546 GGAGA>G), RS1000470797 (12:5471013 C>G), RS1000492936 (12:5443616 T>C), RS1000561453 (12:5486211 G>A,C), RS1000565152 (12:5443837 T>C), RS1000723167 (12:5457661 C>T), RS1000729389 (12:5449866 G>A), RS1000757523 (12:5491957 A>G), RS1000824685 (12:5462159 C>T), RS1000830263 (12:5473443 C>T)

Disease associations

OMIM: gene MIM:162660 | disease phenotypes: MIM:142623

GenCC curated gene-disease

Mondo (2): Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), Hirschsprung disease (MONDO:0018309)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005566_21	Insomnia	2.000000e-08
GCST006585_669	Blood protein levels	9.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	3
trichostatin A	decreases expression	2
sodium arsenite	affects methylation, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Hydrogen Peroxide	affects expression, decreases expression	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
bisphenol A	decreases expression	1
trimellitic anhydride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, decreases reaction, increases abundance, decreases phosphorylation, increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
1-(2-chlorobenzyl)-5’-phenyl-3’H-spiro(indoline-3,2’-(1,3,4)thiadiazol)-2-one	increases expression, affects response to substance	1
Decitabine	affects expression	1
Acetaminophen	decreases expression	1
Acetylcysteine	decreases expression, decreases reaction	1
Arsenic	affects expression	1
Bleomycin	decreases expression	1
Cisplatin	affects expression	1
Manganese	decreases phosphorylation, increases expression, decreases expression, decreases reaction, increases abundance	1
Methapyrilene	increases methylation	1
Mustard Gas	affects expression, affects reaction, decreases expression	1
Silicon Dioxide	increases expression	1
Vanadates	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, decreases reaction	1
Vitamin K 3	affects expression	1
Magnetite Nanoparticles	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06197061	Not specified	UNKNOWN	Comparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)