Gene Name
essential gene (from dbNSFP)
UniProt accession
Ensembl protein identifier
Long Name
ret proto-oncogene
This gene, a member of the cadherin superfamily, encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentiation. This gene plays a crucial role in neural crest development, and it can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement. Mutations in this gene are associated with the disorders multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, Hirschsprung disease, and medullary thyroid carcinoma. Two transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their biological validity has not been confirmed.
Kinase Group
Tyr: tyrosine protein kinase. (Log odds ratio: 0.628591)
FDA approved inhibitors
Drug Sponsor Indications Target
Cabozantinib Exelixis Metastatic thyroid cancer RET, Met, VEGFR, Kit, TrkB, FLT3, AXL, TIE2
Ponatinib ARIAD Pharmaceuticals T315I-positive Chronic myelogenous leukaemia and T315I-positive-Acute lymphoblastic leukaemia Bcr-Abl, VEGFR, PDGFR, FGFR, EPH, SRC, c-KIT, RET, TIE2, FLT3
Regorafenib Bayer Advanced colorectal cancer, gastrointestinal stromal tumours RET, VEGFR, PDGFR, Bcr-Abl, BRAF, KIT, FGFR, TIE2, EPH2A
Sunitinib Pfizer Renal cell carcinoma, GI stromal tumour, pancreatic neuroendocrine tumour VEGFR, PDGFR, KIT, FLT3, RET, CSF-1R
Vandetanib AstraZeneca Advanced medullary thyroid cancer VEGFR, EGFR, RET, BRK, TIE2, SRC, EPHR

GO terms

Gene Ontology - Biological Process Log-odds ratio
GO:0097021 lymphocyte migration into lymphoid organs 5.036
GO:0072300 positive regulation of metanephric glomerulus development 5.036
GO:0061146 Peyer's patch morphogenesis 5.036
GO:0048484 enteric nervous system development 5.036
GO:0035799 ureter maturation 5.036
GO:0014042 positive regulation of neuron maturation 5.036
GO:0007497 posterior midgut development 5.036
GO:0007158 neuron cell-cell adhesion 5.036
GO:0007156 homophilic cell adhesion via plasma membrane adhesion molecules 5.036
GO:0001657 ureteric bud development 5.0205
GO:0033630 positive regulation of cell adhesion mediated by integrin 4.884
GO:0045793 positive regulation of cell size 4.7843
GO:0001755 neural crest cell migration 4.7433
GO:0033619 membrane protein proteolysis 4.621
GO:0060384 innervation 4.5433
GO:0048265 response to pain 4.5433
GO:0042551 neuron maturation 4.3986
GO:0001838 embryonic epithelial tube formation 4.3986
GO:2001241 positive regulation of extrinsic apoptotic signaling pathway in absence of ligand 4.206
GO:0060041 retina development in camera-type eye 3.4226
GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process 3.3019
GO:0071300 cellular response to retinoic acid 2.621
GO:0050770 regulation of axonogenesis 2.5843
GO:0010976 positive regulation of neuron projection development 2.5763
GO:0042493 response to drug 2.3761
GO:0010628 positive regulation of gene expression 1.8415
GO:0045893 positive regulation of transcription, DNA-templated 1.8156
GO:0030335 positive regulation of cell migration 1.752
GO:0000165 MAPK cascade 1.6588
GO:0030155 regulation of cell adhesion 1.639
GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway 1.2244
GO:0018108 peptidyl-tyrosine phosphorylation 1.2044
GO:0030182 neuron differentiation 0.8833
GO:0007165 signal transduction 0.6552
GO:0006468 protein phosphorylation 0.4403
GO:0007399 nervous system development -0.2581
Gene Ontology - Molecular Function Log-odds ratio
GO:0004872 receptor activity 1.7071
GO:0004714 transmembrane receptor protein tyrosine kinase activity 1.4307
GO:0005509 calcium ion binding 0.7387
GO:0004713 protein tyrosine kinase activity 0.592
GO:0005515 protein binding 0.2913
GO:0004672 protein kinase activity 0.0196
GO:0005524 ATP binding 0.0021
GO:0016772 transferase activity, transferring phosphorus-containing groups 0.0
Gene Ontology - Cellular Component Log-odds ratio
GO:0045121 membrane raft 2.6931
GO:0043235 receptor complex 2.1348
GO:0010008 endosome membrane 1.9666
GO:0043025 neuronal cell body 1.7546
GO:0005887 integral component of plasma membrane 1.7364
GO:0030425 dendrite 1.6951
GO:0005886 plasma membrane 1.403
GO:0016020 membrane 1.2128
GO:0043231 intracellular membrane-bounded organelle 0.2935
GO:0030424 axon 0.1476
GO:0005769 early endosome -0.0202
GO:0005737 cytoplasm -0.355

The JMOL viwer can load structure PDB files associated to that UniProt protein, as well as models provided by Interactome3D. The SVG image and the sequence scroller bellow correspond to the Ensembl protein associated with that UniProt: ENSP00000347942

In order to adress all inconsistencies between the sequences in UniProt, Ensembl, and UniProt, coordinate maps are built using Smith-Waterman pairwise alignment.

ENSP00000347942 Transmembrane ... Low complexity (... Cleavage site (Si... Cadherin-like Kinase-like_dom Superfamily dom... Tyr_kinase_cat_dom Ser/Thr_dual-sp_kinase_dom SMART domains Ser-Thr/Tyr_kinase_cat_dom Prints domain Ser-Thr/Tyr_kinase_cat_dom Cadherin Prot_kinase_dom Pfam domain Cadherin Prot_kinase_dom PROSITE profiles Tyr_kinase_Ret_rcpt PIRSF domain Sequence variant... COSMIC somatic ... 0 100 200 300 400 500 600 700 800 900 1000 0 1114 Scale bar Stop gained Frameshift variant Inframe insertion Missense variant Splice region variant Synonymous variant Coding sequence variant Insert Delete Variation Legend
MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAPEEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLTVYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENRPPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELVAVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFDADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNRNLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFAQIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAELHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGRCEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPRGIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCYHKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS* _________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________|_________| ________10________20________30________40________50________60________70________80________90_______100_______110_______120_______130_______140_______150_______160_______170_______180_______190_______200_______210_______220_______230_______240_______250_______260_______270_______280_______290_______300_______310_______320_______330_______340_______350_______360_______370_______380_______390_______400_______410_______420_______430_______440_______450_______460_______470_______480_______490_______500_______510_______520_______530_______540_______550_______560_______570_______580_______590_______600_______610_______620_______630_______640_______650_______660_______670_______680_______690_______700_______710_______720_______730_______740_______750_______760_______770_______780_______790_______800_______810_______820_______830_______840_______850_______860_______870_______880_______890_______900_______910_______920_______930_______940_______950_______960_______970_______980_______990______1000______1010______1020______1030______1040______1050______1060______1070______1080______1090______1100______1110

Scroll horizontaly across the sequence

The following information is extracted from Structure-PPi, a workflow for the annotation of protein residues. It finds features overlapping the variant or overlapping any residue that is in close physical proximity to the variant: 5 angstroms spatial distance or adjacent in the sequence if no PDB covers that area.

It may also report protein protein interfaces that might be affected by the variant, i.e. when they are at a distance of 8 angstroms from residues from a partner protein.

The structure PDB files used for these calculations are all those associated with the UniProt protein in UniProt and Interactome3D, which extends this set with models of single proteins and protein-protein interaction complexes. Pairwise alignment is used to resolve any sequence discrepancies.

The databases examined are UniProt, InterPro, COSMIC and Appris. The COSMIC database reports variants affecting that residue, not necessarily the same amino-acid change. Appris agglutinates features from FireDB, which are catalytic sites, and ligand-binding sites, and others such as trans-membrane domains, signal peptides, and ligand binding sites.

Structure-PPi A module for the annotation of cancer-related single-nucleotide variants at protein-protein interfaces. Miguel Vazquez, Alfonso Valencia, Tirso Pons. 2015. Bioinformatics. DOI: 10.1093/bioinformatics/btv142

KinMut Random Forest is a method specific for prediction of the pathogenicity of variants affecting the protein kinase superfamily. It characterizes the variants at the gene, domain and residue level with a combination of general and kinase-specific features. The pathogenicity of variants is evaluated by a random forest algorithm. Predictions are accompanied with a reliability score. Our approach outperforms available methods in a cross-validation experiment on the 3689 kinase variants in Uniprot. (Accuracy: 88.45%, Precision: 81.62%, recall: 75.22%, f-score: 78.29% and MCC: 0.68)

KinMut Random Forest
disease if score >0, neutral if score <0

Group log-odds ratio
Kyte-Doolittle Hydrophobicity
GO log-odds ratio
C-beta branching
Formal charge
FireDB residue
PhosphoELM residue
Uniprot residue
Active site
Modified residue
NP Binding
Zinc finger
Affected protein domains
Domain Log odds ratio
Protein_kinase 0.950917
Other predictors (dbNSFP)

Precomputed prediction not found on dbNSFP for ENSP00000347942:A883F

CADD Kircher (2014) Nature Genetics 46(3):310-5
FATHMM Shihab (2013) Human Mutation 34(1):57-65
VEST3 Carter (2013) BMC Genomics 14(3):1-16
Mutation Assessor Reva (2011) Nucleic Acids Research 1-14
Mutation Taster Schwarz (2014) Nature Methods 11, 361-362
Polyphen2 Adzhubei (2010) Nature Methods 7(4), 248-249
SIFT Ng (2001) Genome Research 11(45), 863-874
These literature co-mentions have been extracted automatically from the literature with iHop. Although it has proved to be a powerful guide to gather contextual information, manual inspection of these results might be required. Refer to Hoffmann and Valencia, 2004 for further details.

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