BRAF Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human BRAF — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene BRAF, 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 BRAF, 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 BRAF 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 BRAF 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 BRAF, 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 BRAF, 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 BRAF, 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 BRAF 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 BRAF, summarize transcription factor regulatory data. If BRAF 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 BRAF — names with evidence type (ChIP-seq / predicted / experimentally validated) If BRAF is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene BRAF protein as a drug target, summarize pharmacology data. If BRAF 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 BRAF is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene BRAF, 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 BRAF, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in BRAF: 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
Executive summary
BRAF (chromosome 7, HGNC:1097) encodes a 766-amino-acid serine/threonine-protein kinase (UniProt P15056, 84.4 kDa) that functions as a central effector in the RAS–RAF–MEK–ERK MAPK cascade, directly phosphorylating MEK1/2 downstream of RAS GTPases. It is one of the most clinically important oncogenes: germline mutations cause autosomal dominant Mendelian disorders including cardiofaciocutaneous syndrome 1, Noonan syndrome 7, and LEOPARD syndrome 3, while somatic mutations drive multiple cancers. BRAF is a well-established drug target with over 100 molecules documented in ChEMBL; vemurafenib (targeting V600E) is FDA-approved for melanoma and papillary thyroid cancer, with BRAF V600 mutation status serving as the primary pharmacogenomic predictor of response. The protein has 103 experimental PDB structures and is expressed ubiquitously across 265 of 289 surveyed tissues (average score 77.73), with particularly high expression in buccal mucosa, colonic epithelium, and nervous system. Approximately 1,473 ClinVar variants are catalogued, and GWAS data link the locus to type 2 diabetes and bipolar disorder.
BRAF — Reference
Cross-database identifier and functional mapping reference for BRAF.
Gene identifiers
- HGNC: HGNC:1097 (approved symbol: BRAF)
- Ensembl: ENSG00000157764
- NCBI Entrez Gene: 673
- OMIM: 164757
- Genomic location (GRCh38): Chromosome 7, 140,719,327–140,924,976 (−strand)
Transcript identifiers
Ensembl Transcripts (ENST)
Total: 27 transcripts
| ENST ID | Biotype |
|---|---|
| ENST00000288602 | protein_coding |
| ENST00000469930 | protein_coding |
| ENST00000479537 | nonsense_mediated_decay |
| ENST00000496384 | protein_coding |
| ENST00000497784 | nonsense_mediated_decay |
| ENST00000642228 | nonsense_mediated_decay |
| ENST00000642272 | retained_intron |
| ENST00000642808 | protein_coding_CDS_not_defined |
| ENST00000642875 | retained_intron |
| ENST00000643356 | retained_intron |
| ENST00000643790 | protein_coding_CDS_not_defined |
| ENST00000644120 | protein_coding_CDS_not_defined |
| ENST00000644650 | nonsense_mediated_decay |
| ENST00000644905 | retained_intron |
| ENST00000644969 | protein_coding |
| ENST00000645443 | retained_intron |
| ENST00000646334 | retained_intron |
| ENST00000646427 | retained_intron |
| ENST00000646730 | nonsense_mediated_decay |
| ENST00000646891 | protein_coding |
| ENST00000647434 | nonsense_mediated_decay |
| ENST00000867090 | protein_coding |
| ENST00000867091 | protein_coding |
| ENST00000867092 | protein_coding |
| ENST00000912600 | protein_coding |
| ENST00000912601 | protein_coding |
| ENST00000944245 | protein_coding |
RefSeq mRNA Transcripts (NM_)
Total: 17 NM_ accessions
| Accession | Status | MANE Select |
|---|---|---|
| NM_001324516 | VALIDATED | |
| NM_001354609 | REVIEWED | |
| NM_001374244 | REVIEWED | |
| NM_001374258 | REVIEWED | |
| NM_001378467 | REVIEWED | |
| NM_001378468 | REVIEWED | |
| NM_001378469 | REVIEWED | |
| NM_001378470 | REVIEWED | |
| NM_001378471 | REVIEWED | |
| NM_001378472 | REVIEWED | |
| NM_001378473 | REVIEWED | |
| NM_001378474 | REVIEWED | |
| NM_001378475 | REVIEWED | |
| NM_001427466 | VALIDATED | |
| NM_004333 | REVIEWED | ✓ |
| NM_139294 | VALIDATED | |
| NM_205744 | VALIDATED |
CCDS IDs
Total: 4
- CCDS5863
- CCDS87555
- CCDS94218
- CCDS94219
Exons of MANE Select Transcript (ENST00000646891 / NM_004333)
Total exons: 18
| Exon ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00003830897 | 140730665 | 140734770 | − | 7 |
| ENSE00003649805 | 140754187 | 140754233 | − | 7 |
| ENSE00003587655 | 140749287 | 140749418 | − | 7 |
| ENSE00003551608 | 140739812 | 140739946 | − | 7 |
| ENSE00003485507 | 140753275 | 140753393 | − | 7 |
| ENSE00003680515 | 140787548 | 140787584 | − | 7 |
| ENSE00003685923 | 140783021 | 140783157 | − | 7 |
| ENSE00003559218 | 140781576 | 140781693 | − | 7 |
| ENSE00003521664 | 140777991 | 140778075 | − | 7 |
| ENSE00003527888 | 140776912 | 140777088 | − | 7 |
| ENSE00003569635 | 140794308 | 140794467 | − | 7 |
| ENSE00003687908 | 140801412 | 140801560 | − | 7 |
| ENSE00003603742 | 140807960 | 140808062 | − | 7 |
| ENSE00001034889 | 140808892 | 140808995 | − | 7 |
| ENSE00003487759 | 140800362 | 140800481 | − | 7 |
| ENSE00003603715 | 140850111 | 140850212 | − | 7 |
| ENSE00001035295 | 140834609 | 140834872 | − | 7 |
| ENSE00001862791 | 140924566 | 140924929 | − | 7 |
Protein identifiers
UniProt accessions
Reviewed (canonical):
- P15056 — Serine/threonine-protein kinase B-raf (766 aa, 84.4 kDa)
Unreviewed isoforms/variants:
- A0A2R8Y467
- A0A2R8Y492
- A0A2R8Y679
- A0A2R8Y8E0
- A0A2R8YDP5
- A0A2R8YES9
- A0A2U3TZI2
- H7C4S5
- H7C560
- H7C5K3
RefSeq protein accessions (NP_)
- NP_004324 — canonical (corresponds to P15056)
- NP_001311445
- NP_001341538
- NP_001361173
- NP_001361187
- NP_001365396
- NP_001365397
- NP_001365398
- NP_001365399
- NP_001365400
- NP_001365401
- NP_001365402
- NP_001365403
- NP_001414395
- NP_991307
Protein domains and families
InterPro domains:
| ID | Name | Type |
|---|---|---|
| IPR000719 | Protein kinase domain | Domain |
| IPR001245 | Serine-threonine/tyrosine-protein kinase, catalytic domain | Domain |
| IPR002219 | Protein kinase C-like, phorbol ester/diacylglycerol-binding domain | Domain |
| IPR003116 | Raf-like Ras-binding | Domain |
| IPR008271 | Serine/threonine-protein kinase, active site | Active_site |
| IPR017441 | Protein kinase, ATP binding site | Binding_site |
| IPR020454 | Diacylglycerol/phorbol-ester binding | Domain |
| IPR011009 | Protein kinase-like domain superfamily | Homologous_superfamily |
| IPR029071 | Ubiquitin-like domain superfamily | Homologous_superfamily |
| IPR046349 | C1-like domain superfamily | Homologous_superfamily |
| IPR051681 | Serine/Threonine Kinases and Pseudokinases | Family |
Pfam families:
| ID | Name | Type |
|---|---|---|
| PF00130 | Protein kinase domain | Domain |
| PF02196 | C1 domain | Domain |
| PF07714 | Ubiquitin domain | Domain |
Antibody availability
No curated antibody resources found in current biobtree annotation for BRAF. Manual review of commercial resources (Abcam, Santa Cruz, Cell Signaling) or PubMed queries recommended for current antibody availability.
Structure
Experimental Structures
X-ray Diffraction: 86 PDB entries (resolution in Ångströms)
- 1UWH (2.95 Å) · 1UWJ (3.5 Å) · 2FB8 (2.9 Å) · 3C4C (2.57 Å) · 3D4Q (2.8 Å) · 3IDP (2.7 Å) · 3II5 (2.79 Å) · 3NY5 (1.993 Å) · 3OG7 (2.45 Å) · 3PPJ (3.7 Å)
- 3PPK (3.0 Å) · 3PRF (2.9 Å) · 3PRI (3.5 Å) · 3PSB (3.4 Å) · 3PSD (3.6 Å) · 3Q4C (3.2 Å) · 3Q96 (3.1 Å) · 3SKC (3.2 Å) · 3TV4 (3.4 Å) · 3TV6 (3.3 Å)
- 4CQE (2.3 Å) · 4DBN (3.15 Å) · 4E26 (2.55 Å) · 4E4X (3.6 Å) · 4EHE (3.3 Å) · 4EHG (3.5 Å) · 4FC0 (2.95 Å) · 4FK3 (2.65 Å) · 4G9C (3.5 Å) · 4G9R (3.2 Å)
- 4H58 (3.1 Å) · 4JVG (3.09 Å) · 4KSP (2.93 Å) · 4KSQ (3.3 Å) · 4MBJ (3.6 Å) · 4MNE (2.8483 Å) · 4MNF (2.802 Å) · 4PP7 (3.4 Å) · 4R5Y (3.5 Å) · 4RZV (2.994 Å)
- 4RZW (3.493 Å) · 4WO5 (2.83 Å) · 4XV1 (2.47 Å) · 4XV2 (2.5 Å) · 4XV3 (2.8 Å) · 4XV9 (2.0 Å) · 4YHT (3.05 Å) · 5C9C (2.7 Å) · 5CSW (2.66 Å) · 5CSX (2.51 Å)
- 5CT7 (3.17 Å) · 5FD2 (2.89 Å) · 5HI2 (2.512 Å) · 5HID (2.5 Å) · 5HIE (3.0 Å) · 5ITA (1.95 Å) · 5JRQ (2.287 Å) · 5JSM (2.19 Å) · 5JT2 (2.702 Å) · 5VAL (2.26 Å)
- 5VAM (2.1 Å) · 5VR3 (2.102 Å) · 5VYK (1.749 Å) · 6B8U (2.68 Å) · 6CAD (2.55 Å) · 6N0P (2.37 Å) · 6N0Q (2.04 Å) · 6NSQ (3.05 Å) · 6P3D (2.11 Å) · 6P7G (2.65 Å)
- 6PP9 (2.59 Å) · 6U2G (2.886 Å) · 6U2H (2.5 Å) · 6UUO (3.288 Å) · 6V2U (3.78 Å) · 6V2W (3.12 Å) · 6V34 (3.15 Å) · 6XAG (3.3 Å) · 6XFP (2.0 Å) · 6XLO (2.493 Å)
- 7K0V (1.93 Å) · 7M0T (3.19 Å) · 7M0U (3.09 Å) · 7M0V (3.16 Å) · 7M0W (3.09 Å) · 7M0X (2.47 Å) · 7M0Y (3.45 Å) · 7M0Z (3.12 Å) · 7P3V (2.37 Å) · 7SHV (2.88 Å)
- 8C7X (1.65 Å) · 8C7Y (1.65 Å) · 8F7O (3.54 Å) · 8F7P (2.74 Å) · 8QQG (2.979 Å) · 8VSO (1.5 Å) · 9AXX (2.07 Å) · 9AXY (3.6 Å) · 9BFB (1.92 Å) · 9BP8 (1.73 Å)
- 9EW6 (1.65 Å) · 9F35 (2.3 Å)
Cryo-Electron Microscopy: 13 PDB entries (resolution in Ångströms)
- 6NYB (4.1 Å) · 6Q0J (4.9 Å) · 6Q0K (6.8 Å) · 6Q0T (5.7 Å) · 6UAN (3.9 Å) · 7MFD (3.66 Å) · 7MFE (4.07 Å) · 7MFF (3.89 Å) · 7ZR0 (3.4 Å) · 7ZR5 (3.9 Å) · 7ZR6 (4.2 Å) · 8DGS (4.3 Å) · 8DGT (3.9 Å)
Solution NMR: 4 PDB entries (no resolution reported)
- 2L05 · 5J17 · 5J18 · 5J2R
Total experimental structures: 103 PDB entries
Predicted Structures
AlphaFold: AF-P15056-F1
- Global pLDDT: 67.87
- Fraction very high confidence (pLDDT ≥90): 31.1%
- Fraction confident (pLDDT 70–90): 26.7%
- Fraction low confidence (pLDDT 50–70): 5.9%
- Fraction very low confidence (pLDDT <50): 36.3%
- Mean PAE: 24.7 Å
- Version: AlphaFold v4
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000002413 | Braf |
| Rat (Rattus norvegicus) | ENSRNOG00000010957 | Braf |
| Zebrafish (Danio rerio) | ENSDARG00000017661 | braf |
| Fruit fly (Drosophila melanogaster) | FBGN0003079 | Raf |
| Worm (C. elegans) | WBGENE00003030 | lin-45 |
| Yeast (S. cerevisiae) | YLR362W | STE11 |
Clinical variants & AI predictions
ClinVar Summary
| Classification | Count |
|---|---|
| Total variants | ~1,473 |
| Pathogenic | 1 |
| Likely Pathogenic | 3+ |
| Uncertain Significance (VUS) | ~300 |
| Likely Benign | ~400 |
| Benign | ~400 |
| Conflicting classifications | 5+ |
Top Pathogenic/Likely Pathogenic ClinVar Variants
| ClinVar ID | HGVS Notation | Protein Change | Classification |
|---|---|---|---|
| 1210729 | c.2125C>G | p.Gln709Glu | Pathogenic |
| 1163474 | c.1402T>C | p.Phe468Leu | Likely Pathogenic |
| 1198003 | c.1448A>T | p.Lys483Ile | Likely Pathogenic |
| 1050230 | c.1789C>T | p.Leu597= | Conflicting |
| 1065152 | c.858T>G | p.Leu286= | Conflicting |
| 1091347 | c.915G>A | p.Ala305= | Conflicting |
| 1130636 | c.1797A>G | p.Thr599= | Conflicting |
| 1188158 | c.901C>T | p.Pro301Ser | Conflicting |
SpliceAI Predictions
| Metric | Count |
|---|---|
| Total splice predictions | 3,893 |
| Shown (sample) | 100 |
Top SpliceAI variants by effect score (high-confidence splice impact):
| Position | Effect Type | Score |
|---|---|---|
| 7:140720900:A:G | Acceptor gain | 0.91 |
| 7:140720923:T:G | Acceptor gain | 0.88 |
| 7:140720885:C:CA | Acceptor gain | 0.79 |
| 7:140720899:A:AG | Acceptor gain | 0.76 |
| 7:140719812:T:A | Acceptor gain | 0.74 |
| 7:140720925:T:G | Acceptor gain | 0.94 |
| 7:140719977:G:GT | Donor gain | 0.72 |
AlphaMissense Missense Pathogenicity Predictions
| Metric | Count |
|---|---|
| Total missense predictions | 1,000+ |
| Likely Pathogenic | 100+ (shown) |
Top 30 AlphaMissense likely-pathogenic variants:
| Protein Variant | am_pathogenicity Score | Genomic Position |
|---|---|---|
| P754L | 0.977 | 7:140734637:G:A |
| P754R | 0.978 | 7:140734637:G:C |
| P754H | 0.989 | 7:140734637:G:T |
| P754S | 0.977 | 7:140734638:G:A |
| P754A | 0.897 | 7:140734638:G:C |
| P754T | 0.974 | 7:140734638:G:T |
| T753I | 0.986 | 7:140734640:G:A |
| T753R | 0.963 | 7:140734640:G:C |
| T753K | 0.961 | 7:140734640:G:T |
| T753S | 0.828 | 7:140734641:T:A |
| T753A | 0.905 | 7:140734641:T:C |
| T753P | 0.874 | 7:140734641:T:G |
| K752N | 0.955 | 7:140734642:T:A |
| K752I | 0.968 | 7:140734643:T:A |
| K752T | 0.901 | 7:140734643:T:G |
| K752E | 0.936 | 7:140734644:T:C |
| K752Q | 0.720 | 7:140734644:T:G |
| P751L | 0.974 | 7:140734646:G:A |
| P751R | 0.978 | 7:140734646:G:C |
| P751Q | 0.984 | 7:140734646:G:T |
| P751S | 0.981 | 7:140734647:G:A |
| P751A | 0.910 | 7:140734647:G:C |
| P751T | 0.972 | 7:140734647:G:T |
| S750F | 0.973 | 7:140734649:G:A |
| S750C | 0.854 | 7:140734649:G:C |
| S750Y | 0.968 | 7:140734649:G:T |
| S750P | 0.886 | 7:140734650:A:G |
| A749D | 0.948 | 7:140734652:G:T |
| C748W | 0.972 | 7:140734654:A:C |
| C748F | 0.759 | 7:140734655:C:A |
Pathways & Gene Ontology
Reactome Pathways
Total: 16 pathways
| ID | Pathway Name | Disease |
|---|---|---|
| R-HSA-5673000 | RAF activation | No |
| R-HSA-5674135 | MAP2K and MAPK activation | No |
| R-HSA-5674499 | Negative feedback regulation of MAPK pathway | No |
| R-HSA-5675221 | Negative regulation of MAPK pathway | No |
| R-HSA-1295596 | Spry regulation of FGF signaling | No |
| R-HSA-170968 | Frs2-mediated activation | No |
| R-HSA-170984 | ARMS-mediated activation | No |
| R-HSA-187706 | Signalling to p38 via RIT and RIN | No |
| R-HSA-6802946 | Signaling by moderate kinase activity BRAF mutants | Yes |
| R-HSA-6802948 | Signaling by high-kinase activity BRAF mutants | Yes |
| R-HSA-6802952 | Signaling by BRAF and RAF1 fusions | Yes |
| R-HSA-6802955 | Paradoxical activation of RAF signaling by kinase inactive BRAF | Yes |
| R-HSA-9649948 | Signaling downstream of RAS mutants | Yes |
| R-HSA-9656223 | Signaling by RAF1 mutants | Yes |
| R-HSA-9726840 | SHOC2 M1731 mutant abolishes MRAS complex function | Yes |
| R-HSA-9726842 | Gain-of-function MRAS complexes activate RAF signaling | Yes |
Note: MSigDB data not available for BRAF in biobtree.
Gene Ontology Annotations
Biological Process (40 total)
| GO ID | Term |
|---|---|
| GO:0000165 | MAPK cascade |
| GO:0002318 | myeloid progenitor cell differentiation |
| GO:0006468 | protein phosphorylation |
| GO:0007173 | epidermal growth factor receptor signaling pathway |
| GO:0008542 | visual learning |
| GO:0009887 | animal organ morphogenesis |
| GO:0010628 | positive regulation of gene expression |
| GO:0010764 | negative regulation of fibroblast migration |
| GO:0010828 | positive regulation of D-glucose transmembrane transport |
| GO:0016079 | synaptic vesicle exocytosis |
| GO:0030878 | thyroid gland development |
| GO:0033077 | T cell differentiation in thymus |
| GO:0033138 | positive regulation of peptidyl-serine phosphorylation |
| GO:0034446 | substrate adhesion-dependent cell spreading |
| GO:0035019 | somatic stem cell population maintenance |
| GO:0042127 | regulation of cell population proliferation |
| GO:0043066 | negative regulation of apoptotic process |
| GO:0043149 | stress fiber assembly |
| GO:0043367 | CD4-positive, alpha-beta T cell differentiation |
| GO:0043369 | CD4-positive or CD8-positive, alpha-beta T cell lineage commitment |
Molecular Function (10 total)
| GO ID | Term |
|---|---|
| GO:0004672 | protein kinase activity |
| GO:0004674 | protein serine/threonine kinase activity |
| GO:0004708 | MAP kinase kinase activity |
| GO:0004709 | MAP kinase kinase kinase activity |
| GO:0005509 | calcium ion binding |
| GO:0005524 | ATP binding |
| GO:0008270 | zinc ion binding |
| GO:0042802 | identical protein binding |
| GO:0097110 | scaffold protein binding |
| GO:0106310 | protein serine kinase activity |
Cellular Component (16 total)
| GO ID | Term |
|---|---|
| GO:0005634 | nucleus |
| GO:0005737 | cytoplasm |
| GO:0005739 | mitochondrion |
| GO:0005829 | cytosol |
| GO:0005886 | plasma membrane |
| GO:0005929 | cilium |
| GO:0034451 | centriolar satellite |
| GO:0036064 | ciliary basal body |
| GO:0043005 | neuron projection |
| GO:0044297 | cell body |
| GO:0097225 | sperm midpiece |
| GO:0097228 | sperm principal piece |
| GO:0097229 | sperm end piece |
| GO:0098793 | presynapse |
| GO:0098794 | postsynapse |
| GO:0098978 | glutamatergic synapse |
Protein interactions & networks
Protein-Protein Interactions
Total interaction count: ~7,380 interactions (approximate)
- STRING: 6,138 interactions
- IntAct: 846 interactions
- BioGRID: 396 interactions
TOP 30 highest-confidence interacting proteins (STRING scores normalized 0-1000):
| Rank | Gene | Protein | Score | Key Role |
|---|---|---|---|---|
| 1 | RAF1 | P04049 | 983 | Serine/threonine kinase, RAF family member |
| 2 | MAP2K1 | Q02750 | 983 | MAPK/ERK kinase 1 (MEK1) - direct substrate |
| 3 | KRAS | P01116 | 974 | Small GTPase, upstream activator |
| 4 | NRAS | P01111 | 973 | Small GTPase, upstream activator |
| 5 | HRAS | P01112 | 953 | Small GTPase, upstream activator |
| 6 | HSP90AA1 | P07900 | 933 | Heat shock protein 90, chaperone |
| 7 | HSP90AB1 | P08238 | 931 | Heat shock protein 90 beta, chaperone |
| 8 | PIK3CA | P42336 | 931 | Phosphatidylinositol 3-kinase catalytic subunit |
| 9 | PTEN | P60484 | 928 | Phosphatase and tensin homolog, PI3K antagonist |
| 10 | IQGAP1 | P46940 | 919 | Ras GTPase-activating-like protein |
| 11 | KIAA1549 | Q9HCM3 | 908 | UPF0606 protein, fusion partner in NF1 pathway |
| 12 | NF1 | P21359 | 895 | Neurofibromin, RAS GAP |
| 13 | CDKN2A | P42771 | 886 | Cyclin-dependent kinase inhibitor 2A (p16) |
| 14 | TP53 | P04637 | 883 | Tumor suppressor p53, transcription factor |
| 15 | SOS1 | Q07889 | 881 | Son of sevenless homolog 1, RAS GEF |
| 16 | MLH1 | P40692 | 876 | DNA mismatch repair protein |
| 17 | CCND1 | P24385 | 864 | Cyclin D1, cell cycle regulator |
| 18 | ARAF | P07557 | 861 | A-Raf serine/threonine kinase |
| 19 | PTPN11 | Q06124 | 853 | Protein tyrosine phosphatase SHP2 |
| 20 | MAP2K2 | P36507 | 836 | MAPK/ERK kinase 2 (MEK2) - direct substrate |
| 21 | PMS2 | P54278 | 834 | Mismatch repair endonuclease |
| 22 | TSC2 | P49815 | 832 | Tuberin, mTOR pathway regulator |
| 23 | RPS6KB2 | Q9UBS0 | 826 | Ribosomal S6 kinase beta-2 |
| 24 | MSH6 | P52701 | 805 | Mismatch repair protein |
| 25 | GNA11 | P29992 | 797 | G protein subunit alpha-11 |
| 26 | CD274 | Q9NZQ7 | 792 | Programmed death ligand 1 (PD-L1) |
| 27 | IDH2 | O75874 | 789 | Isocitrate dehydrogenase 2 (cytoplasmic) |
| 28 | KSR1 | Q8IVT5 | 780 | Kinase suppressor of Ras 1, MAPK scaffolder |
| 29 | ATM | Q13315 | 779 | Serine/protein kinase ATM, DNA damage response |
| 30 | TERT | O14746 | 777 | Telomerase reverse transcriptase |
Protein Similarity
Structural/embedding similarity (ESM2 embeddings) - TOP 20 similar proteins:
| Rank | UniProt | Top Similarity | Avg Similarity | Description |
|---|---|---|---|---|
| 1 | P04049 | 1.0000 | 0.9853 | RAF1 (RAF proto-oncogene kinase) |
| 2 | P11345 | 1.0000 | 0.9855 | Protein kinase C alpha |
| 3 | P27037 | 1.0000 | 0.9704 | Activin receptor type-2A |
| 4 | P27038 | 1.0000 | 0.9707 | Activin receptor type-2B |
| 5 | Q5RCK6 | 1.0000 | 0.9733 | Serine/threonine kinase (mammalian ortholog) |
| 6 | Q6XYQ8 | 1.0000 | 0.9734 | Serine/threonine kinase (mammalian ortholog) |
| 7 | Q28043 | 0.9999 | 0.9707 | Avian RAF kinase ortholog |
| 8 | Q6P3S6 | 0.9999 | 0.9729 | Mammalian BRAF ortholog |
| 9 | Q8CGF6 | 0.9997 | 0.9786 | Kinase domain similar protein |
| 10 | O19004 | 0.9997 | 0.9793 | Plant BRAF ortholog |
| 11 | O94967 | 0.9997 | 0.9784 | Serine/threonine kinase ortholog |
| 12 | O94806 | 0.9996 | 0.9762 | Mammalian BRAF ortholog |
| 13 | Q925T6 | 0.9996 | 0.9767 | BRAF family kinase |
| 14 | Q8K1Y2 | 0.9996 | 0.9759 | Kinase ortholog |
| 15 | P04627 | 0.9999 | 0.9788 | RAF2 serine/threonine kinase |
| 16 | P14056 | 0.9999 | 0.9788 | RAF2 (RAF proto-oncogene kinase) |
| 17 | P05625 | 0.9995 | 0.9847 | Protein kinase C delta |
| 18 | P09560 | 0.9989 | 0.9848 | Protein kinase C beta |
| 19 | P34908 | 0.9993 | 0.9833 | Serine/threonine kinase ortholog |
| 20 | Q04982 | 0.9993 | 0.9820 | Mammalian serine/threonine kinase |
Sequence homology (DIAMOND BLAST) - TOP 20 homologous proteins:
| Rank | UniProt | Identity | Bitscore | Organism/Description |
|---|---|---|---|---|
| 1 | P04049 | 100.00% | 1303 | RAF1 (human) |
| 2 | Q5S006 | 86.10% | 4259 | Mammalian BRAF ortholog |
| 3 | Q5S007 | 86.10% | 4260 | Mammalian BRAF ortholog |
| 4 | Q3UH66 | 78.70% | 2726 | Mammalian BRAF-like kinase |
| 5 | Q9Y3S1 | 86.30% | 2712 | BRAF structural homolog |
| 6 | Q60700 | 98.40% | 1699 | Mouse BRAF ortholog |
| 7 | A7MBB4 | 93.80% | 1731 | Mammalian BRAF ortholog |
| 8 | A7J1T2 | 91.30% | 1712 | Mammalian BRAF ortholog |
| 9 | A7J1T0 | 91.30% | 1710 | Mammalian BRAF ortholog |
| 10 | O43283 | 97.10% | 1813 | MAP3K13 (Raf family kinase) |
| 11 | Q5R8X7 | 97.10% | 1812 | Mammalian RAF family protein |
| 12 | Q61271 | 99.40% | 1028 | Mouse BRAF ortholog |
| 13 | P36898 | 98.20% | 1022 | Serine/threonine kinase ortholog |
| 14 | P80204 | 98.80% | 999 | Mammalian kinase ortholog |
| 15 | Q80U40 | 99.10% | 776 | Mouse BRAF ortholog |
| 16 | P63796 | 98.40% | 1695 | Mammalian BRAF ortholog |
| 17 | P36897 | 97.30% | 966 | Serine/threonine kinase homolog |
| 18 | P36896 | 98.80% | 1023 | RAF family kinase ortholog |
| 19 | P36895 | 98.90% | 1087 | Mammalian kinase ortholog |
| 20 | P37172 | 98.40% | 1036 | Serine/threonine kinase ortholog |
Key interaction network features:
- Direct upstream regulators: RAS proteins (KRAS, NRAS, HRAS) bind and activate BRAF
- Direct substrates: MAP2K1/MEK1 and MAP2K2/MEK2 are phosphorylated by BRAF downstream in MAPK cascade
- Scaffolding/modulators: HSP90, KSR1, and 14-3-3 proteins (YWHAB/YWHAQ/YWHAG/YWHAE/YWHAH/YWHAZ) stabilize or regulate BRAF
- Pathway cross-talk: PIK3CA, PTEN interact for PI3K/AKT pathway coordination
- Tumor suppressors: NF1, TP53, CDKN2A regulate BRAF-driven proliferation
Transcription factor regulatory data
BRAF is a transcription factor (B-Raf proto-oncogene, serine/threonine kinase) with dual roles: it encodes a kinase enzyme but also functions as a transcriptional regulator.
Downstream targets
Total: 2 documented targets (CollecTRI database)
| Target | Regulation | Evidence Source |
|---|---|---|
| SLC5A5 | Repression | SIGNOR |
| NFE2L2 | Activation | SIGNOR |
Note: Only 2 BRAF target genes are documented in available curated databases. This limited set likely reflects selective curation of high-confidence interactions rather than exhaustive target discovery.
DNA binding motifs (JASPAR)
No JASPAR motifs are available for BRAF in the curated databases.
Upstream regulators
5 transcription factors regulate BRAF:
| Regulator | Confidence | Evidence Type |
|---|---|---|
| MITF | High | Experimentally validated (ExTRI) |
| LITAF | Low | Experimentally validated (ExTRI) |
| POU3F2 | Low | Experimentally validated (ExTRI) |
| LHX8 | Low | Experimentally validated (ExTRI) |
| CREM | Low | Experimentally validated (ExTRI) |
Drug & pharmacology data
BRAF is a well-established drug target. Over 100 molecules target BRAF (CHEMBL5145) in ChEMBL, with multiple FDA-approved drugs and numerous compounds in development.
Approved & Advanced BRAF Drugs (Phase 4)
| Molecule ID | Name | Mechanism | Indication |
|---|---|---|---|
| CHEMBL1229517 | Vemurafenib (Zelboraf) | BRAF V600E serine/threonine kinase inhibitor | Melanoma, papillary thyroid cancer |
| CHEMBL1336 | Sorafenib (Nexavar) | Multi-kinase inhibitor (BRAF/CRAF/RAF1) | Hepatocellular carcinoma, renal cell carcinoma, thyroid cancer |
| CHEMBL1171837 | Ponatinib (Iclusig) | Pan-RAF/ABL tyrosine kinase inhibitor | CML, ALL, BRAF-mutant cancers |
| CHEMBL1287853 | Fedratinib | JAK2 inhibitor; also targets BRAF | Myelofibrosis |
| CHEMBL1421 | Dasatinib | Multi-kinase inhibitor | Chronic myeloid leukemia |
| CHEMBL1789941 | Ruxolitinib | JAK1/2 inhibitor | Polycythemia vera, myelofibrosis |
Phase 2 Compounds
- CHEMBL103667: Doramapimod (p38 MAP kinase inhibitor)
- CHEMBL1230609: Foretinib (c-MET/VEGFR inhibitor)
- CHEMBL1738757: Rebastinib (Src family/FAK inhibitor)
Clinical Trials (BRAF-targeting drugs)
Major Vemurafenib melanoma trials (n=132 total):
- NCT01006980 (BRIM-3): Phase 3, Vemurafenib vs dacarbazine, metastatic melanoma, COMPLETED
- NCT01307397: Phase 3, Vemurafenib alone, metastatic melanoma, COMPLETED
- NCT01667419: Phase 3, Adjuvant vemurafenib, resected BRAF-mutant melanoma, COMPLETED
- NCT01689519: Phase 3, Vemurafenib ± cobimetinib, metastatic melanoma, COMPLETED
- NCT02908672: Phase 3, Atezolizumab + cobimetinib + vemurafenib, untreated BRAF V600-mutant melanoma, COMPLETED
- NCT05768178 (DETERMINE): Phase 2/3, Vemurafenib + cobimetinib, BRAF-positive cancers, RECRUITING
Trials in non-melanoma BRAF-mutant cancers:
- Papillary thyroid cancer, colorectal cancer, hairy cell leukemia, non-small cell lung cancer, pediatric malignancies
Pharmacogenomics & Dosing
BRAF V600 mutation status is the primary pharmacogenomic predictor:
- BRAF V600E mutations show strongest response to BRAF inhibitors (vemurafenib, dabrafenib)
- Other BRAF V600 variants (V600K, V600D, V600R) show variable responses; some require higher doses or combination therapy
- BRAF wild-type tumors do not respond to selective BRAF inhibitors
Standard dosing:
- Vemurafenib: 960 mg PO twice daily (adjust for tolerability)
- Sorafenib: 400 mg PO twice daily
- Ponatinib: 45 mg PO daily
No formal dosing guidelines based on drug-gene interactions are established; response guided by mutation status and clinical monitoring.
Expression profiles
Tissue expression (Bgee)
BRAF shows ubiquitous expression across 265 of 289 surveyed tissues (average score: 77.73; max: 97.92).
Top 30 tissues with highest expression scores:
| Rank | Tissue/Cell Type | Expression Score | Quality |
|---|---|---|---|
| 1 | Buccal mucosa cell | 97.92 | Gold |
| 2 | Colonic epithelium | 92.55 | Gold |
| 3 | Calcaneal tendon | 91.78 | Gold |
| 4 | Middle temporal gyrus | 90.64 | Gold |
| 5 | Sperm | 90.53 | Gold |
| 6 | Sural nerve | 90.26 | Gold |
| 7 | Male germ line stem cell (testis) | 89.82 | Gold |
| 8 | Adrenal tissue | 88.84 | Gold |
| 9 | Tendon | 88.76 | Gold |
| 10 | Male germ cell | 87.85 | Gold |
| 11 | Lateral nuclear group of thalamus | 86.90 | Gold |
| 12 | Cortical plate | 86.80 | Gold |
| 13 | Lower esophagus mucosa | 86.17 | Gold |
| 14 | Postcentral gyrus | 86.09 | Gold |
| 15 | Testis (combined) | 85.96 | Gold |
| 16 | Brodmann area 23 | 85.86 | Gold |
| 17 | Tendon of biceps brachii | 85.56 | Gold |
| 18 | Superior frontal gyrus | 85.12 | Gold |
| 19 | Ganglionic eminence | 85.07 | Gold |
| 20 | Corpus callosum | 84.91 | Gold |
| 21 | Parietal lobe | 84.79 | Gold |
| 22 | Primordial germ cell in gonad | 84.37 | Gold |
| 23 | Bone marrow | 84.16 | Gold |
| 24 | Upper leg skin | 84.08 | Gold |
| 25 | Ventricular zone | 83.63 | Gold |
| 26 | Islet of Langerhans | 83.40 | Gold |
| 27 | Primary visual cortex | 83.24 | Gold |
| 28 | Cerebellar cortex | 83.23 | Gold |
| 29 | Cerebellar hemisphere | 83.14 | Gold |
| 30 | Popliteal artery | 83.11 | Gold |
Key patterns:
- Germ cell enrichment: Highest expression in sperm, testis, and germ cells (90.53–89.82)
- Epithelial cell enrichment: Very high in buccal mucosa (97.92) and colonic epithelium (92.55)
- Nervous system breadth: Widespread in brain regions (cortex, thalamus, cerebellum), developmentally important tissues (cortical plate, ventricular zone)
- Connective tissue: Strong expression in tendons and skeletal muscle regions
- Epithelial tissues: Consistent high expression in gastrointestinal and respiratory mucosa
Single-cell expression (SCXA)
- Total experiments: 4
- Marker status: BRAF is a marker gene in 4/4 experiments (100%)
- Total cell clusters identified: 389
- Expression range: Mean expression 151.47 (average) with peak of 6,838 in specialized clusters
The marker status across multiple single-cell experiments indicates strong cell-type specificity within tissues, with distinct clusters showing 45-fold variation in expression levels, suggesting roles in specific cell states or lineages.
Disease associations
Mendelian / Monogenic Diseases
BRAF mutations cause several well-characterized monogenic disorders with autosomal dominant inheritance:
| Disease | Disease ID(s) | Inheritance | Evidence Level |
|---|---|---|---|
| Cardiofaciocutaneous syndrome 1 | OMIM:115150, MONDO:0007265, Orphanet:1340 | Autosomal dominant | Definitive |
| Noonan syndrome 7 | OMIM:613706, MONDO:0013379, Orphanet:648 | Autosomal dominant | Definitive |
| LEOPARD syndrome 3 | OMIM:613707, MONDO:0013380, Orphanet:500 | Autosomal dominant | Definitive |
| Noonan syndrome with multiple lentigines | MONDO:0007893, Orphanet:500 | Autosomal dominant | Supportive |
| Anaplastic astrocytoma | MONDO:0016684 | Autosomal dominant | Limited |
Phenotype Associations (HPO Terms)
Top phenotypes associated with BRAF mutations (selected from 100 total):
| HPO ID | Phenotype | HPO ID | Phenotype |
|---|---|---|---|
| HP:0000006 | Autosomal dominant inheritance | HP:0001003 | Multiple lentigines |
| HP:0000271 | Abnormality of the face | HP:0001004 | Lymphedema |
| HP:0000280 | Coarse facial features | HP:0001249 | Intellectual disability |
| HP:0000316 | Hypertelorism | HP:0001250 | Seizure |
| HP:0000337 | Broad forehead | HP:0001263 | Global developmental delay |
| HP:0000465 | Webbed neck | HP:0001626 | Abnormality of the cardiovascular system |
| HP:0000474 | Thickened nuchal skin fold | HP:0001629 | Ventricular septal defect |
| HP:0000486 | Strabismus | HP:0001638 | Cardiomyopathy |
| HP:0000494 | Downslanted palpebral fissures | HP:0001639 | Hypertrophic cardiomyopathy |
| HP:0000545 | Myopia | HP:0001642 | Pulmonic stenosis |
| HP:0000689 | Dental malocclusion | HP:0002861 | Melanoma |
| HP:0000822 | Hypertension | HP:0003006 | Neuroblastoma |
| HP:0000953 | Hyperpigmentation of the skin | HP:0004322 | Short stature |
| HP:0000957 | Cafe-au-lait spot | HP:0005600 | Congenital giant melanocytic nevus |
| HP:0000995 | Melanocytic nevus | HP:0007565 | Multiple cafe-au-lait spots |
Complex Disease / GWAS Associations
Top 10 GWAS associations for BRAF:
| Trait/Disease | SNP ID | P-value | Mapped Gene |
|---|---|---|---|
| Type 2 diabetes | GCST010118_100 | 2.0e-10 | BRAF |
| Type 2 diabetes | GCST004894_108 | 1.0e-09 | BRAF |
| Bipolar disorder | GCST008103_6 | 6.0e-10 | BRAF |
| Anorexia nervosa, ADHD, autism spectrum disorder, bipolar disorder, major depression, OCD, schizophrenia, or Tourette syndrome | GCST009600_25 | 5.0e-09 | BRAF - CCT4P1 |
| Type 2 diabetes | GCST004894_16 | 4.0e-07 | BRAF |
| Cerebrospinal fluid t-tau:Aβ1-42 ratio | GCST003079_5 | 7.0e-06 | BRAF - CCT4P1 |
| Response to Vitamin E supplementation | GCST001450_7 | 4.0e-06 | BRAF |
| Mild influenza (H1N1) infection | GCST003124_32 | 3.0e-08 | BRAF |
| Cerebrospinal T-tau levels | GCST003070_2 | 3.0e-07 | BRAF - CCT4P1 |
| Longevity | GCST012210_2 | 1.0e-06 | BRAF |