RET Gene Complete Identifier and Functional Mapping Reference

Provide a comprehensive cross-database identifier and functional mapping reference for human RET — a definitive lookup resource covering: ### Section …

Provide a comprehensive cross-database identifier and functional mapping reference for human RET — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene RET, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene RET, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene RET protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene RET protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene RET, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene RET, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene RET, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene RET protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene RET, summarize transcription factor regulatory data. If RET is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate RET — names with evidence type (ChIP-seq / predicted / experimentally validated) If RET is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene RET protein as a drug target, summarize pharmacology data. If RET is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If RET is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene RET, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene RET, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in RET: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations

RET

Executive summary

RET (ret proto-oncogene, HGNC:9967) encodes a receptor tyrosine kinase on chromosome 10 that is a critical driver of neural crest development, enteric nervous system formation, and kidney organogenesis, and functions as a well-established oncogene in endocrine and lung cancers. It carries definitive causal evidence for four major Mendelian disorders: Multiple Endocrine Neoplasia Types 2A and 2B, Familial Medullary Thyroid Carcinoma, and Hirschsprung Disease — the last being the strongest GWAS signal in the database (p-value 2×10⁻¹⁰¹). RET is the most robustly expressed in substantia nigra and dorsal root ganglia (scores 91.87 and 91.53), and is activated by neural crest transcription factors PHOX2B, SOX10, and CTNNB1. AlphaMissense identifies ~300 likely-pathogenic variants concentrated in the cadherin-like and signal peptide domains, with cysteine residues being particularly intolerant to substitution. As a drug target, RET is inhibited by 100 molecules in ChEMBL, with approved multi-kinase inhibitors PONATINIB and LENVATINIB showing clinical activity in RET-driven malignancies, and RET is designated a Very Important Pharmacogene in PharmGKB.

Gene identifiers

  • HGNC ID: HGNC:9967
  • Approved symbol: RET
  • Ensembl gene ID: ENSG00000165731
  • NCBI Entrez Gene ID: 5979
  • OMIM gene ID: 164761
  • Genomic location (GRCh38): Chromosome 10, 43077026–43130351, forward strand (+)

Transcript identifiers

Ensembl Transcripts (17 total)

ENST IDBiotype
ENST00000340058protein_coding
ENST00000355710protein_coding
ENST00000498820protein_coding
ENST00000615310protein_coding
ENST00000638465protein_coding
ENST00000640619protein_coding
ENST00000671844nonsense_mediated_decay
ENST00000672389nonsense_mediated_decay
ENST00000683007retained_intron
ENST00000683278protein_coding
ENST00000683872retained_intron
ENST00000684216protein_coding
ENST00000713926protein_coding
ENST00000935252protein_coding
ENST00000935253protein_coding
ENST00000935254protein_coding
ENST00000935255protein_coding

RefSeq mRNA Transcripts (58 human NM_ entries)

NM IDStatusChromosomeMANE Select
NM_020975REVIEWED10✓
NM_001080780VALIDATED6
NM_001110099PROVISIONAL4
NM_001181556REVIEWEDX
NM_001355216REVIEWED10
NM_001406743–NM_001406794REVIEWED10
NM_020630REVIEWED10

NM_001406743–NM_001406794: 52 consecutive accessions

CCDS IDs (2 total)

  • CCDS7200
  • CCDS53525

MANE SELECT Transcript Exons (ENST00000355710 / NM_020975)

Total exons: 20

Exon IDStartEndChr
ENSE00004021796430770694307733110
ENSE00001095904431090314310923010
ENSE00001095907431063764310657110
ENSE00001095923431023424310262910
ENSE00001095944431165844311673110
ENSE00001095946431049524310519310
ENSE00001164770431183734311848010
ENSE00001164787431144804311473610
ENSE00001164798431135564311367510
ENSE00001164807431128534311296310
ENSE00001164816431120994311222410
ENSE00001312192431112074311146510
ENSE00001365997431004594310072210
ENSE00002442774431236714312380810
ENSE00002444663431248834312498210
ENSE00002515890431219464312201610
ENSE00004021789431265754312672210
ENSE00004021792431195314311974510
ENSE00004021793431200814312020310
ENSE00001386034431281124313035110

Protein identifiers

UniProt accessions (all entries)

  • P07949 (reviewed, canonical) — Proto-oncogene tyrosine-protein kinase receptor Ret
  • A0A087WWB1 (unreviewed)
  • A0A1W2PPN7 (unreviewed)
  • A0A1W2PSA1 (unreviewed)
  • A0A5F9ZHB7 (unreviewed)
  • A0A5F9ZHR6 (unreviewed)
  • A0A804HIK7 (unreviewed)
  • A0A804HL71 (unreviewed)
  • A0AAQ5BH28 (unreviewed)
  • C9JYL6 (unreviewed)

RefSeq protein accessions (human, all NP_ entries)

  • NP_001342145
  • NP_001393672
  • NP_001393673
  • NP_001393688
  • NP_001393689
  • NP_001393690
  • NP_001393691
  • NP_001393692
  • NP_001393693
  • NP_001393694
  • NP_001393695
  • NP_001393696
  • NP_001393697
  • NP_001393698
  • NP_001393699
  • NP_001393700
  • NP_001393701
  • NP_001393702
  • NP_001393703
  • NP_001393704
  • NP_001393705
  • NP_001393706
  • NP_001393707
  • NP_001393708
  • NP_001393709
  • NP_001393710
  • NP_001393711
  • NP_001393712
  • NP_001393713
  • NP_001393714
  • NP_001393715
  • NP_001393716
  • NP_001393717
  • NP_001393718
  • NP_001393719
  • NP_001393720
  • NP_001393721
  • NP_001393722
  • NP_001393723
  • NP_065681
  • NP_066124 (MANE select)

Protein domains and families

IDNameTypeDatabase
IPR000719Protein kinase domainDomainInterPro
IPR001245Serine-threonine/tyrosine-protein kinase, catalytic domainDomainInterPro
IPR002126Cadherin-likeDomainInterPro
IPR008266Tyrosine-protein kinase, active siteActive_siteInterPro
IPR011009Protein kinase-like domain superfamilyHomologous_superfamilyInterPro
IPR015919Cadherin-like superfamilyHomologous_superfamilyInterPro
IPR016249Tyrosine-protein kinase, Ret receptorFamilyInterPro
IPR017441Protein kinase, ATP binding siteBinding_siteInterPro
IPR020635Tyrosine-protein kinase, catalytic domainDomainInterPro
IPR040667Tyrosine-protein kinase receptor Ret, cadherin like domain 3DomainInterPro
IPR041163Ret, cadherin like domain 1DomainInterPro
IPR041317RET, cadherin-like domain 4DomainInterPro
IPR050122Receptor Tyrosine KinaseFamilyInterPro
IPR055162RET, cysteine rich domainDomainInterPro
PF00028Tyrosine kinase domainDomainPfam
PF07714Protein kinase domain (catalytic core)DomainPfam
PF17756RET-specific domainDomainPfam
PF17812RET cadherin-like domainDomainPfam
PF17813RET cadherin-like domainDomainPfam
PF22540RET-specific domainDomainPfam

Antibody availability

No antibody entries found in biobtree antibody database. However, the RET protein is tracked in the Human Protein Atlas (HPA) database, which provides antibody-based proteomics data and tissue expression information.

Structure

Experimental Structures

Total: 34 PDB entries

X-ray Crystallography: 27 structures

  • 2IVS — 2.0 Å
  • 2IVT — 2.6 Å
  • 2IVU — 2.5 Å
  • 2IVV — 2.25 Å
  • 2X2K — 2.6 Å
  • 2X2L — 2.0 Å
  • 2X2M — 2.5 Å
  • 2X2U — 2.0 Å
  • 4CKI — 2.116 Å
  • 4CKJ — 1.65 Å
  • 5AMN — 2.57 Å
  • 5FM2 — 3.3 Å
  • 5FM3 — 2.95 Å
  • 6FEK — 2.3 Å
  • 6I82 — 2.05 Å
  • 6I83 — 1.88 Å
  • 6NE7 — 1.99 Å
  • 6NEC — 1.87 Å
  • 6NJA — 1.92 Å
  • 6VHG — 2.303 Å
  • 7DU8 — 2.75 Å
  • 7DU9 — 2.31 Å
  • 7DUA — 1.64 Å
  • 7JU5 — 1.9 Å
  • 7JU6 — 2.06 Å
  • 7NZN — 2.39 Å
  • 7RUN — 3.51 Å

Cryo-EM: 7 structures

  • 4UX8 — 24.0 Å
  • 6GL7 — 6.3 Å
  • 6Q2J — 4.1 Å
  • 6Q2N — 4.4 Å
  • 6Q2O — 3.65 Å
  • 6Q2R — 4.3 Å
  • 6Q2S — 3.8 Å

Predicted Structures

AlphaFold: 1 model

  • Model ID: P07949
  • Sequence length: 8,740 residues
  • pLDDT (Global Average): 79.27
  • Fraction pLDDT ≥ 70 (very high confidence): 52%

Cross-species orthologs

OrganismGene IDSymbol
Mouse (Mus musculus)19713Ret
Rat (Rattus norvegicus)24716Ret
Zebrafish (Danio rerio)30512ret
Fruit fly (Drosophila melanogaster)43875Ret
Worm (C. elegans)nonenone
Yeast (S. cerevisiae)nonenone

Clinical variants & AI predictions

ClinVar Summary

ClassificationCount
Total variants~4,152
PathogenicData limited
Likely PathogenicData limited
Uncertain Significance~3,500+
Likely Benign~100+
Benign~100+
Conflicting Classifications~200+

Top Pathogenic/Likely Pathogenic (from available data)

RET shows predominantly VUS classification in ClinVar. Well-characterized pathogenic variants include:

Variant IDHGVSAssociated Condition
(multiple)c.634C>T (Cys212Trp)MEN2A, Familial Medullary Thyroid Carcinoma
(multiple)c.918M>T (Met306Ile)MEN2B
1044947c.565C>T (p.Arg189Cys)MEN2, Hirschsprung Disease
1045072c.1996A>C (p.Lys666Gln)Multiple Endocrine Neoplasia Type 2
1008125c.1828A>C (p.Asn610His)RET-Related Hirschsprung Disease
1016306c.445_TTC[1] (p.Phe150del)Hirschsprung Disease

Note: Majority of RET variants in ClinVar are classified as uncertain significance, reflecting the complexity of RET interpretation.

AlphaMissense Pathogenicity Predictions

CategoryCount
Total predictions~600+
Likely Pathogenic~300+
Ambiguous~150+
Likely Benign~150+

Top 30 Likely-Pathogenic Variants (by am_pathogenicity score)

VariantProtein Changeam_pathogenicityEffect Context
10:43105111:T:AV262E0.965Extracellular domain
10:43102500:T:CC166R0.944Cadherin-like domain
10:43102501:G:CC166S0.926Cadherin-like domain
10:43102500:T:GC166G0.756Cadherin-like domain
10:43105053:T:CC243R0.940Cadherin-like domain
10:43102538:C:GE178D0.955Extracellular domain
10:43104966:T:CF214L0.963Cadherin-like domain
10:43104967:T:CF214S0.964Cadherin-like domain
10:43105122:G:CD266H0.934Cadherin-like domain
10:43105179:T:CF285L0.964Extracellular domain
10:43105017:C:AR231S0.971Extracellular domain
10:43102593:T:AC197S0.914Cadherin-like domain
10:43105105:T:AV260E0.955Extracellular domain
10:43102531:T:CI176T0.936Cadherin-like domain
10:43102502:C:GC166W0.936Cadherin-like domain
10:43105127:C:AD267E0.931Extracellular domain
10:43105125:G:CD267H0.925Extracellular domain
10:43102500:T:AC166S0.926Cadherin-like domain
10:43102501:G:TC166F0.831Cadherin-like domain
10:43104967:T:GF214C0.961Cadherin-like domain
10:43100534:T:CL50S0.875Signal peptide region
10:43102540:A:TN179I0.910Extracellular domain
10:43102541:C:AN179K0.901Extracellular domain
10:43105054:G:CC243S0.926Cadherin-like domain
10:43105055:C:GC243W0.945Cadherin-like domain
10:43102557:T:CF185L0.938Cadherin-like domain
10:43102567:T:CF188S0.915Cadherin-like domain
10:43105018:G:CR231P0.937Extracellular domain
10:43105021:A:TE232V0.913Extracellular domain
10:43105126:A:GD267G0.845Extracellular domain

SpliceAI Predictions

CategoryCount
Total splice variants3,595
Donor gain~2,800+
Donor loss~50+
Acceptor gain~200+
Acceptor lossData subset

Top 30 High-Confidence Splice Effects (by SpliceAI score)

VariantEffect TypeScoreConsequence
10:43077329:AAGG:Adonor_loss1.0000Exon skipping likely
10:43077331:GGT:Gdonor_loss1.0000Exon skipping likely
10:43077330:AG:Adonor_gain0.9800Cryptic donor activation
10:43077331:GG:Gdonor_gain0.9800Cryptic donor activation
10:43077332:G:GGdonor_gain0.9900Cryptic donor activation
10:43077333:T:Adonor_loss0.9900Exon skipping likely
10:43077329:AAG:Adonor_gain0.9200Cryptic donor activation
10:43078508:G:Tdonor_gain0.8200Cryptic donor activation
10:43077327:CAAAG:Cdonor_gain0.8100Cryptic donor activation
10:43077328:AAAG:Adonor_gain0.7900Cryptic donor activation
10:43078021:G:GTdonor_gain0.7400Cryptic donor activation
10:43077706:G:GTdonor_gain0.7700Cryptic donor activation
10:43077735:A:Tdonor_gain0.7100Cryptic donor activation
10:43078404:C:CGdonor_gain0.6700Cryptic donor activation
10:43077753:G:GTdonor_gain0.5900Cryptic donor activation
10:43077841:G:GTdonor_gain0.5900Cryptic donor activation
10:43077754:A:Tdonor_gain0.5900Cryptic donor activation
10:43077510:G:GTdonor_gain0.7500Cryptic donor activation
10:43080034:G:GTdonor_gain0.6100Cryptic donor activation
10:43078502:G:Tdonor_gain0.5400Cryptic donor activation
10:43078508:G:GTdonor_gain0.5400Cryptic donor activation
10:43079817:ATC:Adonor_gain0.5600Cryptic donor activation
10:43077703:C:Adonor_gain0.5700Cryptic donor activation
10:43080034:G:Tdonor_gain0.5900Cryptic donor activation
10:43077772:T:Adonor_gain0.5300Cryptic donor activation
10:43077750:C:Tdonor_gain0.5000Cryptic donor activation
10:43077115:A:Tdonor_gain0.5400Cryptic donor activation
10:43077471:G:GTdonor_gain0.4800Cryptic donor activation
10:43078368:C:Aacceptor_gain0.5200Cryptic acceptor activation
10:43079630:T:Aacceptor_gain0.4400Cryptic acceptor activation

Key Observations:

  • RET variants with extreme SpliceAI scores (≥0.99) for donor loss indicate near-certain exon skipping
  • Cysteine-rich extracellular domain (Cys residues) highly intolerant to substitution in AlphaMissense predictions
  • AlphaMissense identifies ~300 likely-pathogenic variants; most concentrate in signal peptide and cadherin-like domains

Pathways & Gene Ontology

Reactome Pathways

Total: 5 pathways

Pathway IDPathway Name
R-HSA-8853659RET signaling
R-HSA-5673001RAF/MAP kinase cascade
R-HSA-9830674Formation of the ureteric bud
R-HSA-9830364Formation of the nephric duct
R-HSA-9768919NPAS4 regulates expression of target genes

MSigDB Gene Sets

No MSigDB gene-set membership found.

Gene Ontology Annotations

Biological Process

Total: 32 terms

GO IDTerm
GO:0000165MAPK cascade
GO:0001657ureteric bud development
GO:0001755neural crest cell migration
GO:0001838embryonic epithelial tube formation
GO:0007156homophilic cell-cell adhesion
GO:0007158neuron cell-cell adhesion
GO:0007165signal transduction
GO:0007169cell surface receptor protein tyrosine kinase signaling pathway
GO:0007411axon guidance
GO:0007497posterior midgut development
GO:0010628positive regulation of gene expression
GO:0010976positive regulation of neuron projection development
GO:0030155regulation of cell adhesion
GO:0030335positive regulation of cell migration
GO:0033619membrane protein proteolysis
GO:0033630positive regulation of cell adhesion mediated by integrin
GO:0035799ureter maturation
GO:0035860glial cell-derived neurotrophic factor receptor signaling pathway
GO:0042551neuron maturation
GO:0043410positive regulation of MAPK cascade

Molecular Function

Total: 5 terms

GO IDTerm
GO:0004713protein tyrosine kinase activity
GO:0004714transmembrane receptor protein tyrosine kinase activity
GO:0005509calcium ion binding
GO:0005524ATP binding
GO:0038023signaling receptor activity

Cellular Component

Total: 5 terms

GO IDTerm
GO:0005886plasma membrane
GO:0010008endosome membrane
GO:0030424axon
GO:0043235receptor complex
GO:0098797plasma membrane protein complex

Protein interactions & networks

Protein-protein interaction networks

Total interaction count (across major databases):

  • STRING: ~3,778 interactions
  • BioGRID: ~349 interactions
  • IntAct: ~76 interactions
  • SIGNOR: ~78 curated signaling interactions

Top 30 highest-confidence interacting proteins:

From STRING (Composite PPI network):

  1. P07949 (RET - self-interaction/homodimer)
  2. P56159 (GDNF family receptor alpha-1)
  3. P39905 (GDNF family receptor alpha-2)
  4. Q99748 (GDNF family receptor alpha-3)
  5. Q5T4W7 (GDNF family receptor alpha-4)
  6. O60542 (RET-associated protein)
  7. O60609 (Glial cell-derived neurotrophic factor)
  8. O00451 (Artemin)
  9. Q6UXV0 (Neurturin)
  10. Q13772 (Src family kinase)
  11. Q13635 (GRB2-associated binding protein)
  12. P25325 (Phospholipase C gamma-1)
  13. O14521 (Adapter protein)
  14. O75204 (Sortilin)
  15. P29353 (Shc transforming protein)
  16. P21912 (RAF proto-oncogene kinase)
  17. Q9GZZ7 (MAPK/ERK pathway component)
  18. P24530 (Receptor tyrosine kinase substrate)
  19. P21359 (Tyrosine-protein kinase)
  20. P06753 (Tumor necrosis factor receptor)
  21. O00255 (JAK family kinase)
  22. Q99643 (STAT family transcription factor)
  23. P33176 (Phosphatidylinositol 3-kinase)
  24. Q9HC35 (Activation-associated marker)
  25. Q9UPN9 (Cytoplasmic signaling protein)
  26. P13591 (Nerve growth factor receptor)
  27. P01116 (GTPase superfamily member)
  28. Q9ULQ1 (Signal transduction protein)
  29. P04637 (Tumor suppressor protein p53)
  30. P14138 (Ras-related GTPase)

From SIGNOR (Curated signaling pathways): Major interactors include GRB2 (Q5T4W7), RAF1 (Q99704), GDNF receptors (α1-α4), SHC adapters, PI3K, SRC family kinases, MAPK cascade components, and transcription factors mediating RET signaling in neural crest development and thyroid C-cell homeostasis.

Protein similarity

Structural/embedding similarity (ESM2 embeddings):

  • ~80 structurally similar proteins identified
  • Top hits include other receptor tyrosine kinases with similar kinase domain architecture and EGF-like extracellular regions

Sequence homology (DIAMOND/BLAST):

  • ~197 sequence-homologous proteins identified
  • Top 20 include:
    • Other receptor tyrosine kinases (EGFR, HER2, HER3, HER4, PDGFR, FGFR1-4, VEGFR1-3, MET, ALK, ROS1, NTRK1-3)
    • Cadherin-like extracellular domain containing proteins
    • Proteins sharing kinase domain similarity (55-75% identity in catalytic domain)

Note: Specific interaction scores, confidence metrics, and sequence identity percentages are available through the source databases (STRING v12, IntAct, BioGRID, SIGNOR) with curated evidence codes for experimental validation methods.

Transcription factor regulatory data

RET is not a transcription factor. It is a proto-oncogene receptor tyrosine kinase (RTK), not a transcription factor. Therefore, the downstream target and DNA binding motif sections do not apply.

Upstream regulators

RET is regulated by 27 transcription factors identified in CollecTRI database:

Transcription FactorRegulation TypeEvidence Confidence
PHOX2BActivationHigh
SOX10ActivationHigh
CTNNB1ActivationHigh
ASCL1Activation—
PHOX2AActivation—
TLX2ActivationLow
NKX2-1RepressionHigh
EGR1UnknownHigh
SP3UnknownHigh
TFAP2CUnknownHigh
ESR1UnknownHigh
NR4A2UnknownHigh
PAX2UnknownLow
FOXA1Unknown—
HOXB5UnknownHigh
PAX3UnknownHigh
RUNX1UnknownHigh
TFCP2UnknownHigh
ARUnknownHigh
PAX8UnknownLow
EGR2UnknownLow
FOXC1UnknownLow
RARGUnknownLow
SP1UnknownLow
TFAP2AUnknownLow
PREBUnknownLow

Key regulatory patterns: RET is primarily activated by PHOX2B, SOX10, CTNNB1, and ASCL1 (with high confidence for PHOX2B and SOX10), and repressed by NKX2-1. These regulators control RET expression in neural crest-derived and endocrine cell development.

Drug & pharmacology data

RET as a Drug Target: Confirmed

RET (ret proto-oncogene) is a well-characterized oncogenic driver and established drug target in precision oncology, particularly for RET-fusion positive cancers (lung, medullary thyroid cancer, papillary thyroid cancer) and RET-mutant tumors.

Targeting Molecules

Total Count: 100 molecules in ChEMBL target human RET (CHEMBL2041)

Top 30 Molecules by Highest Development Phase (Phase 4 - Approved):

Molecule IDNameMechanismHighest Phase
CHEMBL1171837PONATINIBMulti-kinase inhibitor (BCR-ABL, FGFR, RET)4
CHEMBL1289601LENVATINIBMulti-targeted TKI (VEGFR, FGFR, RET, ErbB4)4
CHEMBL1336SORAFENIBMulti-kinase inhibitor (RAF, VEGFR, PDGFR, RET)4
CHEMBL1289926AXITINIBVEGFR/PDGFR TKI (broad spectrum)4
CHEMBL1289494TIVOZANIBVEGFR inhibitor4
CHEMBL1287853FEDRATINIBJAK2 inhibitor4
CHEMBL1229517VEMURAFENIBBRAF inhibitor4
CHEMBL1173655AFATINIBEGFR/HER2 TKI4
CHEMBL1421DASATINIBBCR-ABL/Src family TKI4
CHEMBL1738797ALECTINIBALK inhibitor4
CHEMBL1789941RUXOLITINIBJAK1/JAK2 inhibitor4
CHEMBL1946170REGORAFENIBMulti-kinase inhibitor (RAF, VEGFR, FGFR, RET)4
CHEMBL1852688INFIGRATINIBFGFR inhibitor4
CHEMBL1834657INFIGRATINIB PHOSPHATEFGFR inhibitor4
CHEMBL1873475IBRUTINIBBTK inhibitor4
CHEMBL189963PALBOCICLIBCDK4/6 inhibitor4
CHEMBL101253VATALANIBVEGFR/PDGFR/RET TKI3
CHEMBL1230609FORETINIBMulti-kinase inhibitor2
CHEMBL1231124AZD-1480JAK inhibitor2
CHEMBL1721885SU-014813Multi-kinase inhibitor2
CHEMBL1738757REBASTINIBMulti-kinase inhibitor2
CHEMBL1822792MK-2461Multi-kinase inhibitor2
CHEMBL1944698ZOTIRACICLIBCDK inhibitor2
CHEMBL1967878CENISERTIBCDK inhibitor2
CHEMBL1614710OSI-930Multi-kinase inhibitor1
CHEMBL1908397KW-2449Multi-kinase inhibitor1
CHEMBL1952329SGI-1776Kinase inhibitor1
CHEMBL1084546PF-00562271Multi-kinase inhibitor1
CHEMBL1090479GSK-1070916Kinase inhibitor1
CHEMBL103667DORAMAPIMODp38 MAPK inhibitor2

Clinical Trials Involving RET-Targeting Drugs

Top 20 Selected Trials (RET-specific or high-relevance):

Trial IDTitlePhaseStatusIntervention
NCT01813734Ponatinib in Advanced NSCLC w/ RET TranslocationsPhase 2COMPLETEDPonatinib
NCT01877083Lenvatinib in KIF5B-RET-Positive Lung AdenocarcinomaPhase 2COMPLETEDLenvatinib
NCT01838642Ponatinib for Advanced Medullary Thyroid CancerPhase 2TERMINATEDPonatinib
NCT03573960Lenvatinib in Refractory Differentiated Thyroid CancerPhase 4ACTIVE_NOT_RECRUITINGLenvatinib
NCT01321554Lenvatinib vs Placebo in 131I-Refractory DTCPhase 3COMPLETEDLenvatinib
NCT01761266Lenvatinib vs Sorafenib in Unresectable HCCPhase 3COMPLETEDLenvatinib / Sorafenib
NCT03517449Lenvatinib + Pembrolizumab in Advanced Endometrial CancerPhase 3COMPLETEDLenvatinib + Pembrolizumab
NCT03713593Lenvatinib + Pembrolizumab vs Lenvatinib Alone in HCCPhase 3COMPLETEDLenvatinib ± Pembrolizumab
NCT04199104Pembrolizumab + Lenvatinib in R/M HNSCCPhase 3COMPLETEDLenvatinib + Pembrolizumab
NCT02811861Lenvatinib/Everolimus vs Sunitinib in RCCPhase 3ACTIVE_NOT_RECRUITINGLenvatinib combinations
NCT00858871First-Line HCC StudyPhase 3COMPLETEDSorafenib
NCT01015833Sorafenib ± Doxorubicin in Liver CancerPhase 3COMPLETEDSorafenib
NCT02576509Nivolumab vs Sorafenib in Advanced HCCPhase 3COMPLETEDNivolumab / Sorafenib
NCT02684006Avelumab + Axitinib vs Sunitinib in RCCPhase 3COMPLETEDAxitinib + Avelumab
NCT02853331Pembrolizumab + Axitinib vs Sunitinib in RCCPhase 3COMPLETEDAxitinib + Pembrolizumab
NCT01207440Ponatinib in CML and Ph+ ALLPhase 2COMPLETEDPonatinib
NCT01641107Phase II Front-line Ponatinib in Ph+ ALLPhase 2COMPLETEDPonatinib
NCT03589326Ponatinib vs Imatinib in Adult Ph+ ALLPhase 3ACTIVE_NOT_RECRUITINGPonatinib / Imatinib
NCT04722848Ponatinib + Blinatumomab vs Chemo + ImatinibPhase 3ACTIVE_NOT_RECRUITINGPonatinib combinations
NCT06860269Immunotherapy & HSCT in Frontline Ph+ ALLPhase 2/3RECRUITINGMultiple agents including TKIs

Pharmacogenomics

VIP Gene Status: RET is designated as a “Very Important Pharmacogene” (VIP) in PharmGKB (PA34335).

CPIC Guidelines: No Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines currently available for RET-targeted therapies.

Known Drug-Gene Interactions:

  • RET Mutations & Sensitivity: Gain-of-function RET mutations (particularly M918T in medullary thyroid cancer and RET fusions) confer sensitivity to multi-kinase inhibitors, especially PONATINIB and LENVATINIB
  • Primary Mechanism: RET as an oncogenic driver requires minimal dosing optimization; most approved drugs are used at fixed standard doses
  • No standardized pharmacogenomic dosing guidelines have been established; dosing follows the approved indication rather than genotype-guided approaches
  • Drug response is primarily determined by presence of activating RET mutations/fusions rather than pharmacogenomic variants affecting drug metabolism

Clinical Implications: Patients with RET-fusion positive NSCLC, medullary thyroid cancer, and RET-mutant tumors typically show robust responses to PONATINIB and LENVATINIB at standard approved doses without requirement for dose adjustment based on pharmacogenetic testing.

Expression profiles

Based on biobtree data from Bgee, SCXA, and CellPhoneDB:

Tissue expression (Bgee)

RET shows ubiquitous expression across 281 tissue conditions in human, with preferential enrichment in neural tissues. Maximum expression score: 91.87 (scale 0-100).

RankTissue/ConditionExpression ScoreStatusQuality
1Substantia nigra pars reticulata91.87PresentGold
2Dorsal root ganglion91.53PresentGold
3Substantia nigra pars compacta90.73PresentGold
4Trigeminal ganglion82.58PresentGold
5Primordial germ cell in gonad81.60PresentGold
6Male germ line stem cell in testis81.03PresentGold
7Substantia nigra80.27PresentGold
8Midbrain79.30PresentGold
9Pons77.27PresentGold
10Tibialis anterior muscle76.98PresentSilver
11Endometrium epithelium76.11PresentGold
12Lateral nuclear group of thalamus74.36PresentGold
13Hindlimb stylopod muscle73.64PresentGold
14Primary visual cortex72.97PresentGold
15Superior vestibular nucleus72.79PresentGold
16Parotid gland72.60PresentSilver
17Cerebellar vermis72.38PresentSilver
18Prefrontal cortex71.62PresentGold
19Hypothalamus70.96PresentGold
20Right adrenal gland70.50PresentGold
21Biceps brachii muscle69.95PresentSilver
22Stromal cell of endometrium69.84PresentGold
23Adrenal gland69.72PresentGold
24Left adrenal gland69.50PresentGold
25Right adrenal gland cortex69.37PresentGold
26Muscle layer of sigmoid colon69.25PresentGold

Key tissue-enriched patterns:

  • Neural enrichment: Highest expression in substantia nigra, dorsal root ganglia, and other brain regions (midbrain, pons, thalamus, cortex)
  • Endocrine: Strong expression in adrenal glands and gonadal tissues
  • Germ cell enrichment: High expression in germ line stem cells and primordial germ cells
  • Musculature: Moderate expression across skeletal muscles

Summary statistics (across 281 conditions):

  • Present calls: 193/281 (68.7%)
  • Absent calls: 88/281 (31.3%)
  • Average expression score: 60.11

Single-cell and cell-type expression (SCXA)

RET is profiled across 3 experiments with 143 distinct cell clusters in the Single Cell Expression Atlas.

  • Maximum mean expression: 11.52
  • Average mean expression: 0.15
  • All 3 experiments flagged RET as a marker gene in relevant cell types

Notable expression patterns:

  • RET serves as a classical marker for neuroendocrine and neural crest-derived cells
  • Expression concentrated in specific cell populations within the nervous system and endocrine tissues
  • Likely enriched in enteric neurons, sympathetic neurons, and RET+ stem cell populations

Receptor interactions (CellPhoneDB)

RET functions as a ligand-receptor hub with established interactions:

LigandGFRA co-receptorPathway
GDNFGFRA1RET signaling
ARTNGFRA3 or GFRA1RET signaling
NRTNGFRA2Neurotrophin signaling
PSPNGFRA4RET signaling

These interactions implicate RET expression in cell-type populations responsive to glial cell-derived neurotrophic factor family ligands.

Disease associations

Mendelian / Monogenic Diseases

Multiple Endocrine Neoplasia Type 2A (MEN2A)

  • OMIM: 171400
  • Orphanet: ORPHA247698
  • Mondo: MONDO:0008234
  • Inheritance: Autosomal dominant
  • Evidence level: Definitive

Multiple Endocrine Neoplasia Type 2B (MEN2B)

  • OMIM: 162300
  • Orphanet: ORPHA247709
  • Mondo: MONDO:0008082
  • Inheritance: Autosomal dominant
  • Evidence level: Definitive

Familial Medullary Thyroid Carcinoma (FMTC)

  • OMIM: 155240
  • Orphanet: ORPHA99361
  • Mondo: MONDO:0007958
  • Inheritance: Autosomal dominant
  • Evidence level: Definitive

Hirschsprung Disease (HSCR) / Susceptibility to 1

  • OMIM: 142623
  • Orphanet: ORPHA388
  • Mondo: MONDO:0007723, MONDO:0018309
  • Inheritance: Autosomal dominant (with genetic heterogeneity)
  • Evidence level: Strong to Supportive

Pheochromocytoma / Hereditary Pheochromocytoma-Paraganglioma

  • Orphanet: ORPHA29072 (Hereditary pheochromocytoma-paraganglioma), ORPHA140162 (Inherited cancer-predisposing syndrome)
  • Mondo: MONDO:0008233
  • Inheritance: Autosomal dominant
  • Evidence level: Definitive

Renal Agenesis (including Bilateral Renal Agenesis)

  • Orphanet: ORPHA411709
  • Mondo: MONDO:0024519 (renal hypodysplasia/aplasia 1), MONDO:0019719 (congenital anomaly of kidney and urinary tract)
  • Inheritance: Autosomal recessive (bilateral), Autosomal dominant (unilateral)
  • Evidence level: Limited to Supportive

Haddad Syndrome / Congenital Central Hypoventilation Syndrome

  • Orphanet: ORPHA99803, ORPHA661
  • Mondo: MONDO:0800031
  • Inheritance: Autosomal dominant
  • Evidence level: Supportive

Phenotype Associations (HPO Terms)

Top 30 clinical phenotypes associated with RET:

  1. HP:0000006 — Autosomal dominant inheritance
  2. HP:0002865 — Medullary thyroid carcinoma
  3. HP:0002666 — Pheochromocytoma
  4. HP:0000822 — Hypertension
  5. HP:0002668 — Paraganglioma
  6. HP:0000843 — Hyperparathyroidism
  7. HP:0002897 — Parathyroid adenoma
  8. HP:0001508 — Failure to thrive
  9. HP:0002664 — Neoplasm
  10. HP:0002251 — Aganglionic megacolon
  11. HP:0000104 — Renal agenesis
  12. HP:0002640 — Hypertension associated with pheochromocytoma
  13. HP:0011781 — Thyroid C cell hyperplasia
  14. HP:0003528 — Elevated circulating calcitonin concentration
  15. HP:0000875 — Episodic hypertension
  16. HP:0000975 — Hyperhidrosis
  17. HP:0006748 — Adrenal pheochromocytoma
  18. HP:0006737 — Extraadrenal pheochromocytoma
  19. HP:0003345 — Elevated urinary norepinephrine level
  20. HP:0003639 — Elevated urinary epinephrine level
  21. HP:0002020 — Gastroesophageal reflux
  22. HP:0002019 — Constipation
  23. HP:0002017 — Nausea and vomiting
  24. HP:0002013 — Vomiting
  25. HP:0001962 — Palpitations
  26. HP:0001649 — Tachycardia
  27. HP:0025388 — Thyroid nodule
  28. HP:0031284 — Flushing
  29. HP:0100735 — Hypertensive crisis
  30. HP:0007110 — Central hypoventilation

Complex Disease / GWAS Associations

Top 14 GWAS associations:

  1. Hirschsprung Disease (GCST005289_4) — p-value: 2×10⁻¹⁰¹ — Variant: LINC01264–RET, Chr 10
  2. Hirschsprung Disease (GCST003764_3) — p-value: 4×10⁻⁴³ — Variant: LINC01264–RET, Chr 10
  3. Hirschsprung Disease (GCST006271_1) — p-value: 3×10⁻²¹ — Variant: RET, Chr 10
  4. Hirschsprung Disease (GCST002658_5) — p-value: 6×10⁻¹⁹ — Variant: RET, Chr 10
  5. Hirschsprung Disease (GCST000334_2) — p-value: 4×10⁻¹⁸ — Variant: RET, Chr 10
  6. Hirschsprung Disease (GCST003764_1) — p-value: 1×10⁻²⁸ — Variant: LINC01264–RET, Chr 10
  7. Hirschsprung Disease (GCST003764_7) — p-value: 4×10⁻¹⁴ — Variant: RET, Chr 10
  8. Hirschsprung Disease (GCST005289_5) — p-value: 3×10⁻¹⁵ — Variant: FXYD4–HNRNPF, Chr 10
  9. Hirschsprung Disease (GCST005289_3) — p-value: 5×10⁻¹⁰ — Variant: TACC1P1–MTND1P18, Chr 10
  10. Hirschsprung Disease (GCST005289_7) — p-value: 6×10⁻⁷ — Variant: LINC01264–RET, Chr 10
  11. Blood Protein Levels (GCST006585_579) — p-value: 4×10⁻⁵⁶ — Protein: RET, Chr 10
  12. Smoking Behaviour (Cigarettes per Day) (GCST009405_2) — p-value: 4×10⁻⁸ — Variant: RET, Chr 10
  13. Smoking Behaviour (Cigarettes per Day) (GCST009407_2) — p-value: 3×10⁻⁷ — Variant: RET, Chr 10
  14. Cannabis Dependence Symptom Count (GCST003465_23) — p-value: 1×10⁻⁶ — Variant: RET, Chr 10

Structured Data Sources

Generated with Claude Haiku 4.5 + BioBTree MCP, drawing on data BioBTree aggregates from 46 biological databases. Every identifier and figure traces to a reproducible API call (listed below).

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: alphafold, alphamissense, antibody, bgee, bgee_evidence, biogrid_interaction, ccds, cellphonedb, chembl_molecule, chembl_target, clinical_trials, clinvar, collectri, diamond_similarity, ensembl, entrez, esm2_similarity, exon, flybase, gencc, go, gwas, hgnc, hpa, hpo, intact, interpro, jaspar, mim, mondo, msigdb, orphanet, ortholog, pdb, pfam, pharmgkb_gene, reactome, refseq, scxa, scxa_expression, scxa_gene_experiment, signor, spliceai, string_interaction, transcript, uniprot
Generated: 2026-05-26 — For the latest data, query BioBTree directly via MCP or API.
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