BRAF

Summary

BRAF (B-Raf proto-oncogene, serine/threonine kinase, HGNC:1097) is a protein-coding gene on chromosome 7q34, encoding Serine/threonine-protein kinase B-raf (P15056). Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. In precision oncology, BRAF V600E confers sensitivity to Dabrafenib in Melanoma (CIViC Level A); 262 further curated variant–drug associations are listed below.

This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome.

Source: NCBI Gene 673 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiofaciocutaneous syndrome (Definitive, ClinGen) — +8 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 1,642 total — 59 pathogenic, 41 likely-pathogenic (top 1% of genes corpus-wide)
• Regional missense constraint (gnomAD): 4 of 10 regions constrained (≈19% of expected missense variation)
• GTEx eGene: eQTL in 11 tissues, sQTL in 5 (q < 0.05)
• Phenotypes (HPO): 369
• Drug target: yes — 14 curated mechanism-of-action drugs, 3 via a complex or family; 48 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 5 — Dabrafenib Mesylate, Encorafenib, Regorafenib, +2 more
• Approved drugs acting on a complex or family including it: 1 — Tovorafenib (RAF serine/threonine protein kinase)
• Precision-oncology evidence (CIViC): 263 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 28 cancer types (inferred from mutation patterns)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.24 (highly constrained)
• MANE Select transcript: NM_004333
• Interaction hub: 4,822 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1097
Approved symbol	BRAF
Name	B-Raf proto-oncogene, serine/threonine kinase
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	BRAF1, BRAF-1
Ensembl gene	ENSG00000157764
Ensembl biotype	protein_coding
OMIM	164757
Entrez	673

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 16 protein_coding, 9 nonsense_mediated_decay, 7 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000646891 · MANE Plus Clinical: ENST00000644969

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 5: 3

ENST00000646891, ENST00000644969, ENST00000288602, ENST00000469930, ENST00000479537, ENST00000496384, ENST00000497784, ENST00000642228, ENST00000642272, ENST00000642808, ENST00000642875, ENST00000643356, ENST00000643790, ENST00000644120, ENST00000644650, ENST00000644905, ENST00000645443, ENST00000646334, ENST00000646427, ENST00000646730, ENST00000647434, ENST00000867090, ENST00000867091, ENST00000867092, ENST00000912600, ENST00000912601, ENST00000944245, ENST00000995708, ENST00000995709, ENST00000995711, ENST00001080709, ENST00001106182, ENST00001113821, ENST00001139502, ENST00001139503

RefSeq mRNA: 13 — MANE Select: NM_004333 NM_001354609, NM_001374244, NM_001374258, NM_001378467, NM_001378468, NM_001378469, NM_001378470, NM_001378471, NM_001378472, NM_001378473, NM_001378474, NM_001378475, NM_004333

CCDS: CCDS5863, CCDS87555, CCDS94218, CCDS94219

Canonical transcript exons

ENST00000646891 — 18 exons

Exon	Start	End
ENSE00001034889	140808892	140808995
ENSE00001035295	140834609	140834872
ENSE00001862791	140924566	140924929
ENSE00003485507	140753275	140753393
ENSE00003487759	140800362	140800481
ENSE00003521664	140777991	140778075
ENSE00003527888	140776912	140777088
ENSE00003551608	140739812	140739946
ENSE00003559218	140781576	140781693
ENSE00003569635	140794308	140794467
ENSE00003587655	140749287	140749418
ENSE00003603715	140850111	140850212
ENSE00003603742	140807960	140808062
ENSE00003649805	140754187	140754233
ENSE00003680515	140787548	140787584
ENSE00003685923	140783021	140783157
ENSE00003687908	140801412	140801560
ENSE00003830897	140730665	140734770

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.6292 / max 447.2213, expressed in 1821 samples.

Highest expression (Bgee): buccal mucosa cell, colonic epithelium, calcaneal tendon, middle temporal gyrus, sperm.

Genetic regulation across tissues (GTEx eQTL / sQTL)

BRAF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

16 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	4.0e-11	-1.01	7:140924998:C:T
Testis	sqtl	2.2e-07	+0.85	7:140863716:T:C
Brain Cerebellum	eqtl	5.7e-04	-0.27	7:140981319:T:C
Cells EBV-transformed lymphocytes	sqtl	6.1e-03	-1.04	7:140408579:A:G
Cells Cultured fibroblasts	eqtl	9.6e-03	+0.18	7:141246088:C:A
Thyroid	eqtl	1.0e-02	+0.16	7:140685009:T:C
Brain Caudate basal ganglia	eqtl	1.2e-02	+0.50	7:140009453:C:T
Muscle Skeletal	sqtl	1.2e-02	+0.35	7:140937122:T:A
Whole Blood	eqtl	1.3e-02	+0.24	7:140506885:G:T
Brain Putamen basal ganglia	eqtl	1.9e-02	-0.20	7:140871024:G:A
Adipose Subcutaneous	sqtl	2.1e-02	-0.82	7:140514916:G:A
Lung	sqtl	2.5e-02	-1.61	7:140526701:G:A
Brain Frontal Cortex BA9	eqtl	2.8e-02	+0.18	7:141106172:G:C
Stomach	eqtl	2.9e-02	+0.36	7:140255600:A:C
Nerve Tibial	eqtl	4.2e-02	+0.25	7:140638918:T:C
Heart Atrial Appendage	eqtl	4.8e-02	+0.17	7:140226641:C:T

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
86575	14.7829	1790
86574	11.3439	1774
86570	0.4032	185
86572	0.3780	75
86576	0.2151	67
86569	0.2094	67
86573	0.1575	51
86571	0.1392	53

Top tissues by expression

showing 100 of 289 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.92	gold quality
colonic epithelium	UBERON:0000397	92.55	gold quality
calcaneal tendon	UBERON:0003701	91.78	gold quality
middle temporal gyrus	UBERON:0002771	90.64	gold quality
sperm	CL:0000019	90.53	gold quality
sural nerve	UBERON:0015488	90.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.82	gold quality
adrenal tissue	UBERON:0018303	88.84	gold quality
tendon	UBERON:0000043	88.76	gold quality
male germ cell	CL:0000015	87.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.90	gold quality
cortical plate	UBERON:0005343	86.80	gold quality
lower esophagus mucosa	UBERON:0035834	86.17	gold quality
postcentral gyrus	UBERON:0002581	86.09	gold quality
left testis	UBERON:0004533	86.02	gold quality
testis	UBERON:0000473	85.96	gold quality
right testis	UBERON:0004534	85.87	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.86	gold quality
tendon of biceps brachii	UBERON:0008188	85.56	gold quality
superior frontal gyrus	UBERON:0002661	85.12	gold quality
ganglionic eminence	UBERON:0004023	85.07	gold quality
corpus callosum	UBERON:0002336	84.91	gold quality
parietal lobe	UBERON:0001872	84.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.37	gold quality
bone marrow	UBERON:0002371	84.16	gold quality
upper leg skin	UBERON:0004262	84.08	gold quality
ventricular zone	UBERON:0003053	83.63	gold quality
islet of Langerhans	UBERON:0000006	83.40	gold quality
primary visual cortex	UBERON:0002436	83.24	gold quality
cerebellar cortex	UBERON:0002129	83.23	gold quality
cerebellar hemisphere	UBERON:0002245	83.14	gold quality
popliteal artery	UBERON:0002250	83.11	gold quality
tibial artery	UBERON:0007610	83.09	gold quality
entorhinal cortex	UBERON:0002728	83.06	gold quality
left ovary	UBERON:0002119	82.87	gold quality
tonsil	UBERON:0002372	82.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.85	gold quality
pons	UBERON:0000988	82.76	gold quality
monocyte	CL:0000576	82.59	gold quality
left lobe of thyroid gland	UBERON:0001120	82.44	gold quality
cartilage tissue	UBERON:0002418	82.44	gold quality
thyroid gland	UBERON:0002046	82.35	gold quality
skin of abdomen	UBERON:0001416	82.34	gold quality
cerebellum	UBERON:0002037	82.30	gold quality
ectocervix	UBERON:0012249	82.27	gold quality
mononuclear cell	CL:0000842	82.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.18	gold quality
leukocyte	CL:0000738	82.15	gold quality
aorta	UBERON:0000947	82.14	gold quality
amniotic fluid	UBERON:0000173	82.06	gold quality
body of uterus	UBERON:0009853	82.05	gold quality
right ovary	UBERON:0002118	81.91	gold quality
occipital lobe	UBERON:0002021	81.87	gold quality
prefrontal cortex	UBERON:0000451	81.83	gold quality
upper lobe of left lung	UBERON:0008952	81.80	gold quality
right lung	UBERON:0002167	81.79	gold quality
skin of leg	UBERON:0001511	81.65	gold quality
bone marrow cell	CL:0002092	81.64	gold quality
tibial nerve	UBERON:0001323	81.64	gold quality
upper lobe of lung	UBERON:0008948	81.64	gold quality
blood	UBERON:0000178	81.57	gold quality
gastrocnemius	UBERON:0001388	81.47	gold quality
endocervix	UBERON:0000458	81.43	gold quality
ovary	UBERON:0000992	81.35	gold quality
vagina	UBERON:0000996	81.26	gold quality
lower esophagus	UBERON:0013473	81.25	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.24	gold quality
muscle of leg	UBERON:0001383	81.21	gold quality
ascending aorta	UBERON:0001496	81.16	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.13	gold quality
stromal cell of endometrium	CL:0002255	81.08	gold quality
right lobe of thyroid gland	UBERON:0001119	81.08	gold quality
pancreas	UBERON:0001264	81.07	gold quality
adenohypophysis	UBERON:0002196	81.07	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.07	gold quality
thoracic aorta	UBERON:0001515	80.97	gold quality
pituitary gland	UBERON:0000007	80.86	gold quality
urinary bladder	UBERON:0001255	80.80	gold quality
esophagus	UBERON:0001043	80.73	gold quality
cerebellar vermis	UBERON:0004720	80.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.68	gold quality
frontal cortex	UBERON:0001870	80.67	gold quality
stomach	UBERON:0000945	80.65	gold quality
right atrium auricular region	UBERON:0006631	80.60	gold quality
neocortex	UBERON:0001950	80.59	gold quality
left coronary artery	UBERON:0001626	80.56	gold quality
omental fat pad	UBERON:0010414	80.50	gold quality
peritoneum	UBERON:0002358	80.49	gold quality
zone of skin	UBERON:0000014	80.43	gold quality
body of pancreas	UBERON:0001150	80.33	gold quality
medial globus pallidus	UBERON:0002477	80.33	gold quality
cerebral cortex	UBERON:0000956	80.23	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.19	gold quality
mucosa of stomach	UBERON:0001199	80.12	gold quality
descending thoracic aorta	UBERON:0002345	80.04	gold quality
esophagus mucosa	UBERON:0002469	79.99	gold quality
corpus epididymis	UBERON:0004359	79.89	gold quality
telencephalon	UBERON:0001893	79.79	gold quality
coronary artery	UBERON:0001621	79.66	gold quality
anatomical system	UBERON:0000467	79.65	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	6838.43
E-ANND-3	yes	12.93
E-CURD-135	no	921.67
E-CURD-112	no	2.11

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	63.7	high
Cerebral cortex	tissue	54.9	high
Somatosensory cortex	tissue	54.9
Occipital cortex	tissue	53.7
Prefrontal cortex	tissue	50.6
Motor cortex	tissue	50.3
Basal ganglia	tissue	50.3	low
Olfactory bulb	tissue	49.6
Hippocampal formation	tissue	49.5
Entorhinal cortex	tissue	49.5
Putamen	tissue	49.2
Retrosplenial and cingulate cortex	tissue	48.0
Temporal cortex	tissue	47.8
Retrosplenial cortex	tissue	47.2
Ventral forebrain	tissue	46.1
Insular cortex	tissue	45.4
Thalamus	tissue	45.1
Midbrain	tissue	44.8
Septum	tissue	44.6
Superior colliculi	tissue	43.9
Hypothalamus	tissue	43.7
Pons	tissue	43.2
Amygdala	tissue	40.2
Periaqueductal gray	tissue	39.1
Substantia nigra	tissue	38.6
Spinal cord	tissue	37.3
Medulla oblongata	tissue	36.7
Corpus callosum	tissue	34.3
Postcentral gyrus	tissue	33.8
Caudate putamen	tissue	29.7
Nucleus accumbens	tissue	29.2
Choroid plexus	tissue	27.9
Hippocampus	tissue	25.5	high
Frontal cortex	tissue	23.7
Locus coeruleus	tissue	22.7
Retina	tissue	15.7
Bone marrow	tissue	15.1	medium
Testis	tissue	12.9	high
Parathyroid gland	tissue	10.8	high
Vagina	tissue	9.6	low
Pituitary gland	tissue	9.4
Thymus	tissue	8.1
Tongue	tissue	7.9
Thyroid gland	tissue	7.9	high
Epididymis	tissue	7.8	medium
Skin 1	tissue	7.7	medium
Endometrium 1	tissue	7.3	high
Placenta	tissue	6.8	high
Ovary	tissue	6.7	medium
Prostate	tissue	6.7	high
Breast	tissue	6.6	high
Heart muscle	tissue	6.6	low
Lymph node	tissue	6.5	high
Urinary bladder	tissue	6.5	high
Kidney	tissue	6.4	high
Spleen	tissue	6.3	high
Liver	tissue	6.1	high
Pancreas	tissue	6.0	high
Tonsil	tissue	6.0	high
Stomach 1	tissue	5.9	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal hippocampus (49.0), Ventral hippocampus (46.1), Subiculum (45.3), Cerebellar cortex (42.4), Vermis (42.0).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
NFE2L2	Activation
SLC5A5	Repression

Upstream regulators (CollecTRI, top): CREM, LHX8, LITAF, MITF, POU3F2

miRNA regulators (miRDB)

Targeting BRAF by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 49 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-6507-5P	99.36	70.46	2524

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.237, missense Z 4.91 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000644969 splits into 10 regions with different missense tolerance; 4 are missense-constrained (≈19% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:140,726,497–140,777,007	129 / 285.8	0.45	no
7:140,777,008–140,778,033	7 / 47.2	0.15	yes (p 4.9e-09)
7:140,778,034–140,794,331	109 / 143.9	0.76	no
7:140,794,332–140,794,377	2 / 19.3	0.10	yes (p 8.3e-05)
7:140,794,378–140,800,447	79 / 74.6	1.06	no
7:140,800,448–140,801,501	19 / 51.8	0.37	no
7:140,801,502–140,808,004	2 / 40.4	0.05	yes (p 1.5e-09)
7:140,808,005–140,834,638	26 / 74.4	0.35	yes (p 2.0e-08)
7:140,834,639–140,924,573	86 / 133.9	0.64	no
7:140,924,574–140,924,703	82 / 65.9	1.24	no
ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers (PMID:12068308)
• BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in a RAS gene known as KRAS, and BRAF mutation is linked to the proficiency of these tumours in repairing mismatched bases in DNA (PMID:12198537)
• High frequency of BRAF mutations in nevi (PMID:12447372)
• The V599E BRAF mutation appears to be a somatic mutation associated with melanoma development and/or progression in a proportion of affected individuals. (PMID:12619120)
• results demonstrate that the mutational status of BRAF and KRAS is distinctly different among histologic types of ovarian serous carcinoma, occurring most frequently in invasive micropapillary serous carcinomas and its precursors, serous borderline tumors (PMID:12644542)
• High prevalence of BRAF mutations in thyroid cancer is genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. (PMID:12670889)
• activating BRAF mutations may be an important event in the development of papillary thyroid cancer (PMID:12697856)
• cAMP activates ERK and increases proliferation of autosomal dominant polycystic kindey epithelial cells through the sequential phosphorylation of PKA, B-Raf and MAPK in a pathway separate from the classical receptor tyrosine kinase cascade (PMID:12753285)
• gene is mutated in skin melanoma, but not in uveal melanomas (PMID:12778069)
• 13 germline BRAF variants, 4 of which were silent mutations in coding regions & 9 nucleotide substitutions in introns, were found in melanoma patients and melanoma family, but none appeared statistically likely to be a melanoma susceptibility gene. (PMID:12810628)
• B-raf is involved in adhesion-independent ERK1/2 signaling in melanocytes (PMID:12821662)
• Data suggest that BRAF T1796A activating mutation is not common in primary uveal melanoma. (PMID:12824225)
• B-Raf has a role in extracellular signal-regulated kinase (ERK) signaling in T cells and prevents antigen-presenting cell-induced anergy (PMID:12855697)
• BRAF has a role in in squamous cell carcinoma of the head and neck through uncommon mutations (PMID:12879021)
• The BRAF(V599E) mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF(V599E) may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. (PMID:12881714)
• Mucinous ovarian cancers without a KRAS mutation have not sustained alternative activation of this signaling pathway through mutation of the BRAF oncogene. (PMID:12893203)
• 3 cell lines derived from human choroidal melanoma express B-Raf containing the V599E mutation and showed a 10-fold increase in endogenous B-RafV599E kinase activity and a constitutive activation of the MEK/ERK pathway that is independent of Ras (PMID:12917419)
• Mutations are not detectable in plasma cell leukemia and multiple myeloma. (PMID:12931219)
• mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers (PMID:12970315)
• Our findings of a high frequency of BRAF mutations at codon 599 in benign melanocytic lesions of the skin indicate that this mutation is not sufficient by itself for malignant transformation. (PMID:14501284)
• Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend potential options for therapeutic targeting of kinases in treatment of phenotypically distinct pancreatic adenocarcinoma subsets. (PMID:14507635)
• BRAF mutations, which are present in a variety of other human cancers, do not seem to be involved in gastric cancer development (PMID:14513361)
• Uceal melanomas arise independent of oncogenic BRAF and NRAS mutations. (PMID:14522897)
• BRAF mutations were seen in stomach neoplasms. (PMID:14534542)
• BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas (PMID:14602780)
• BRAF is occasionally mutated in NHL, and BRAF mutation may contribute to tumor development in some NHLs (PMID:14612909)
• None of the cases of gastric cancer showed braf mutations (PMID:14618633)
• Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas (PMID:14639609)
• Missense mutation is marker of colonic but not gastric cancer. (PMID:14668801)
• Mutations were found in exon 15 in colorectal adenocarcinoma. (PMID:14688025)
• Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma of humans. (PMID:14691295)
• NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression (PMID:14695152)
• BRAF mutations are associated with proximal colon tumors with mismatch repair deficiency and MLH1 hypermethylation. (PMID:14695993)
• New enriched PCR-RFLP assay for detecting mutations of BRAF codon 599 mutation in pleural mesotheliomas. (PMID:14719068)
• RAS or BRAF mutations are detected in about 32% of all Barrett’s adenocarcinomas; the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett’s adenocarcinoma (PMID:14724583)
• BRAF mutations are frequently present in sporadic colorectal cancer with methylated hMLH1 (PMID:14734469)
• Mutations in BRAF gene is associated with malignant melanomas (PMID:14961576)
• These studies identify isoprenylcysteine carboxyl methyltransferase as a potential target for reducing the growth of K-Ras- and B-Raf-induced malignancies. (PMID:14966563)
• The lack or low prevalence of BRAF mutation in other thyroid neoplasms is consistent with the notion that other previously defined genetic alterations on the same signaling pathway are sufficient to cause tumorigenesis in most thyroid neoplasms. (PMID:15001635)
• possible cooperation between BRAF activation and PTEN loss in melanoma development. (PMID:15009714)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	braf	ENSDARG00000017661
mus_musculus	Braf	ENSMUSG00000002413
rattus_norvegicus	Braf	ENSRNOG00000010957

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88190) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 238 distinct phenotype terms.

Mouse phenotype (MP)	Records
premature death	8
decreased body weight	6
embryonic lethality during organogenesis, complete penetrance	5
enlarged heart	4
decreased embryo size	3
postnatal growth retardation	3
increased lung adenoma incidence	3
increased thyroid carcinoma incidence	3
postnatal lethality, incomplete penetrance	3
kyphosis	2
enlarged spleen	2
skin lesions	2
decreased body size	2
cataract	2
hyperactivity	2
hepatic necrosis	2
hemorrhage	2
abnormal myocardial trabeculae morphology	2
increased intestinal adenoma incidence	2
decreased activity of thyroid gland	2
embryonic growth retardation	2
increased circulating thyroid-stimulating hormone level	2
thin cerebral cortex	2
intestine polyps	2
increased lung tumor incidence	2

+213 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Coturnix japonica	P34908	100.0%	Diamond
Gallus gallus	Q04982	100.0%	Diamond
Pongo abelii	Q5R5M7	100.0%	Diamond
Bos taurus	Q28041	99.0%	Diamond
Sus scrofa	O19004	97.4%	Diamond
Dendroaspis angusticeps	Q8AX01	93.2%	Diamond
Caenorhabditis elegans	Q07292	92.4%	Diamond
Caenorhabditis briggsae	Q61UC4	92.4%	Diamond
Xenopus laevis	A7J1T0	91.3%	Diamond
Ceratodon purpureus	P25848	89.4%	Diamond
Arabidopsis thaliana	Q8RWL6	80.2%	Diamond
Drosophila melanogaster	P11346	66.3%	Diamond
Dictyostelium discoideum	Q54H45	62.5%	Diamond
Plasmodium berghei ANKA	A0A509AIU5	38.8%	Diamond
Avian retrovirus IC10	P10533	100.0%	Diamond
Rous-associated virus type 1	P27966	100.0%	Diamond
Avian carcinoma Mill Hill virus 2	P00531	98.9%	Diamond
Murine sarcoma virus 3611	P00532	98.8%	Diamond
Acanthamoeba polyphaga mimivirus	Q7T6Y2	53.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
NDUFB2	protein-coding	4708
ADCK2	protein-coding	90956
NDUFB2-AS1	ncRNA	100134713
MRPS33	protein-coding	51650
DENND2A	protein-coding	27147

Protein

Protein identifiers

Serine/threonine-protein kinase B-raf — P15056 (reviewed: P15056)

Alternative names: Proto-oncogene B-Raf, p94, v-Raf murine sarcoma viral oncogene homolog B1

All UniProt accessions (11): P15056, A0A2R8Y467, A0A2R8Y492, A0A2R8Y679, A0A2R8Y8E0, A0A2R8YDP5, A0A2R8YES9, A0A2U3TZI2, H7C4S5, H7C560, H7C5K3

UniProt curated annotations — full annotation on UniProt →

Function. Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway. Phosphorylates PFKFB2. May play a role in the postsynaptic responses of hippocampal neurons.

Subunit / interactions. Monomer. Homodimer. Heterodimerizes with RAF1, and the heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers. Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins. MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer by phosphorylating BRAF at Thr-753. Heterodimerizes (via N-terminus) with KSR1 (via N-terminus) or KSR2 (via N-terminus) in a MAP2K1-dependent manner. Interacts with MAP2K1 and MAP2K2. Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14. Interacts with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the interaction mediates the formation of a ternary complex with RAF1, a ternary complex inhibited by GNAI1. Interacts with DGKH. Interacts with PRMT5. Interacts with KSR2. Interacts with AKAP13, MAP2K1 and KSR1. Identified in a complex with AKAP13, MAP2K1 and KSR1. Interacts with FNIP1 and FNIP2.

Subcellular location. Nucleus. Cytoplasm. Cell membrane.

Tissue specificity. Brain and testis.

Post-translational modifications. Phosphorylation at Ser-365 by SGK1 inhibits its activity (Ref.8, PubMed:11410590). Phosphorylation at Thr-753 by MAPK1. Dephosphorylation of Ser-365 by the SHOC2-MRAS-PP1c (SMP) complex consisting of SHOC2, GTP-bound M-Ras/MRAS and the catalytic subunit of protein phosphatase 1 (PPP1CA, PPP1CB or PPP1CC); this relieves inactivation and stimulates kinase activity. Methylation at Arg-671 decreases stability and kinase activity. Ubiquitinated by RNF149; which leads to proteasomal degradation. Polyubiquitinated at Lys-578 in response to EGF.

Disease relevance. Defects in BRAF are found in a wide range of cancers. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The disease may be caused by variants affecting the gene represented in this entry. Lung cancer (LNCR) [MIM:211980] A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. The gene represented in this entry is involved in disease pathogenesis. Familial non-Hodgkin lymphoma (NHL) [MIM:605027] Cancer that starts in cells of the lymph system, which is part of the body’s immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. The gene represented in this entry is involved in disease pathogenesis. Cardiofaciocutaneous syndrome 1 (CFC1) [MIM:115150] A multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The disease is caused by variants affecting the gene represented in this entry. Noonan syndrome 7 (NS7) [MIM:613706] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. The disease is caused by variants affecting the gene represented in this entry. LEOPARD syndrome 3 (LPRD3) [MIM:613707] A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.

Activity regulation. In quiescent cells, maintained in an inactive state via an intramolecular interaction between the protein kinase and N-terminal domains. Following mitogen-mediated cell activation, binds via its RGB domain to active HRAS (GTP-bound) which releases the inhibitory intramolecular interaction between the two domains. This allows the MAP2K1-mediated dimerization of KSR1 or KSR2, and BRAF which activates BRAF.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily.

RefSeq proteins (13): NP_001341538, NP_001361173, NP_001361187, NP_001365396, NP_001365397, NP_001365398, NP_001365399, NP_001365400, NP_001365401, NP_001365402, NP_001365403, NP_001365404, NP_004324* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002219	PKC_DAG/PE	Domain
IPR003116	RBD_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020454	DAG/PE-bd	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family

Pfam: PF00130, PF02196, PF07714

Enzyme classification (BRENDA)

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)
• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
ATP	0.0007–0.64	11
POLY(GLU4-TYR)	0.018–0.659	10
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1
EEEEY	—	0

Catalyzed reactions (Rhea)

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (149 total): sequence variant 47, helix 28, strand 21, modified residue 14, binding site 10, mutagenesis site 7, turn 6, compositionally biased region 4, domain 2, site 2, region of interest 2, initiator methionine 1, chain 1, active site 1, cross-link 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

showing 30 of 135 structures by resolution:

PDB	Title	Method	Resolution (Å)
8VSO	Ternary structure of 14-3-3 sigma, BRAF phosphopeptide (pS365) and compound 78 (1124378)	X-RAY DIFFRACTION	1.5
8JNB	CRAF ras-binding domain chimera, ligand complex	X-RAY DIFFRACTION	1.62
8C7X	Crystal structure of BRAF in complex with a hybrid compound 6	X-RAY DIFFRACTION	1.65
8C7Y	Crystal structure of BRAF V600E in complex with a hybrid compound 6	X-RAY DIFFRACTION	1.65
9EW6	Binary structure of 14-3-3s and BRAF phosphopeptide (pS365)	X-RAY DIFFRACTION	1.65
8JNA	CRAF ras-binding domain chimera, apo form	X-RAY DIFFRACTION	1.7
9BP8	Crystal structure of BRAF kinase domain with PF-07799933	X-RAY DIFFRACTION	1.73
5VYK	Crystal structure of the BRS domain of BRAF in complex with the CC-SAM domain of KSR1	X-RAY DIFFRACTION	1.75
9BFB	Crystal structure of BRAF kinase domain with PF-07284890	X-RAY DIFFRACTION	1.92
7K0V	Crystal structure of bRaf in complex with inhibitor GNE-0749	X-RAY DIFFRACTION	1.93
5ITA	Crystal Structure of BRAF Kinase Domain Bound to AZ-VEM	X-RAY DIFFRACTION	1.95
3NY5	Crystal structure of the RBD domain of serine/threonine-protein kinase B-raf from Homo …	X-RAY DIFFRACTION	1.99
4XV9	B-Raf Kinase domain in complex with PLX5568	X-RAY DIFFRACTION	2
6XFP	Crystal Structure of BRAF kinase domain bound to Belvarafenib	X-RAY DIFFRACTION	2
6N0Q	BRAF in complex with …	X-RAY DIFFRACTION	2.04
9AXX	Crystal structure of BRAF/MEK1 complex with NST-628 and an active RAF dimer	X-RAY DIFFRACTION	2.07
5VAM	BRAF in Complex with RAF709	X-RAY DIFFRACTION	2.1
5VR3	Crystal structure of the BRS domain of BRAF	X-RAY DIFFRACTION	2.1
6P3D	The co-crystal structure of BRAF(V600E) with ponatinib	X-RAY DIFFRACTION	2.11
5JSM	BRAFV600E Kinase Domain In Complex with Chemically Linked Vemurafenib Inhibitor VEM-3-VEM	X-RAY DIFFRACTION	2.19
5VAL	BRAF in Complex with …	X-RAY DIFFRACTION	2.26
5JRQ	BRAFV600E Kinase Domain In Complex with Chemically Linked Vemurafenib Inhibitor VEM-6-VEM	X-RAY DIFFRACTION	2.29
4CQE	B-Raf Kinase V600E mutant in complex with a diarylthiazole B-Raf Inhibitor	X-RAY DIFFRACTION	2.3
9F35	Co-crystal structure of 14-3-3sigma in complex with B-Raf pS365 phosphopeptide	X-RAY DIFFRACTION	2.3
9RTS	Crystal structure of BRAF:MEK1(pS222) complex with asymmetric dimer interface bound to ADP	X-RAY DIFFRACTION	2.3
6N0P	BRAF in complex with …	X-RAY DIFFRACTION	2.37
7P3V	B-Raf V600E structure bound to a new inhibitor	X-RAY DIFFRACTION	2.37
3OG7	B-Raf Kinase V600E oncogenic mutant in complex with PLX4032	X-RAY DIFFRACTION	2.45
9TWB	Crystal structure of BRAF(val600):MEK1(pS222) complex with asymmetric dimer interface …	X-RAY DIFFRACTION	2.45
4XV1	B-Raf Kinase V600E oncogenic mutant in complex with PLX7904	X-RAY DIFFRACTION	2.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15056-F1	67.87	0.31

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, TKL Ser/Thr protein kinases, Transporters, Accessory Factors Involved in Transport, Predicted intracellular proteins, Cancer-related genes, Mutated cancer genes, Mutational cancer driver genes, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; vesicles; basal body; centriolar satellite; end piece; mid piece; plasma membrane; primary cilium; principal piece

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

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

Catalytic / active sites (3)

Position	Role
576	proton acceptor
380–381	breakpoint for translocation to form kiaa1549-braf fusion protein
438–439	breakpoint for translocation to form kiaa1549-braf fusion protein

Ligand- & substrate-binding residues (10)

Position	Role
235	Zn(2+)
248	Zn(2+)
251	Zn(2+)
261	Zn(2+)
264	Zn(2+)
269	Zn(2+)
272	Zn(2+)
280	Zn(2+)
463–471	ATP
483	ATP

Post-translational modifications (15)

Type	Positions
N-acetylalanine	2
Phosphoserine	151, 333, 365, 399, 446, 447, 729, 750
Phosphothreonine	373, 396, 401, 753
Omega-n-methylarginine	671
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	578

Mutagenesis-validated functional residues (7)

Position	Phenotype
53	reduces interaction with ksr1 and map2k1 and thus phosphorylation of map2k1.
88	reduces interaction with ksr1 and map2k1 and thus phosphorylation of map2k1.
483	reduces kinase activity with map2k1.
509	loss of map2k1-mediated-braf-ksr1 dimerization.
578	blocks egf-induced ubiquitination and erk activation.
666	no effect on map2k1-mediated-braf-ksr1 dimerization, however loss of braf-mediated phosphorylation of map2k1.
671	increased kinase activity and stability in response to egf treatment.

Function

Pathways and Gene Ontology

Reactome pathways

13 curated (TAS) of 39; 13 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

39 pathways:

ID	Pathway	Evidence
R-HSA-9726842	Gain-of-function MRAS complexes activate RAF signaling ⚕	curated
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF ⚕	curated
R-HSA-9726840	SHOC2 M1731 mutant abolishes MRAS complex function ⚕	curated
R-HSA-6802952	Signaling by BRAF and RAF1 fusions ⚕	curated
R-HSA-9656223	Signaling by RAF1 mutants ⚕	curated
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants ⚕	curated
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants ⚕	curated
R-HSA-9649948	Signaling downstream of RAS mutants ⚕	curated
R-HSA-5674135	MAP2K and MAPK activation	curated
R-HSA-5674499	Negative feedback regulation of MAPK pathway	curated
R-HSA-5675221	Negative regulation of MAPK pathway	curated
R-HSA-5673000	RAF activation	curated
R-HSA-1295596	Spry regulation of FGF signaling	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-6802957	Oncogenic MAPK signaling ⚕	—
R-HSA-9660537	Signaling by MRAS-complex mutants ⚕	—
R-HSA-6802949	Signaling by RAS mutants ⚕	—
R-HSA-170984	ARMS-mediated activation	electronic
R-HSA-170968	Frs2-mediated activation	electronic
R-HSA-5683057	MAPK family signaling cascades	—
R-HSA-5684996	MAPK1/MAPK3 signaling	—
R-HSA-5654726	Negative regulation of FGFR1 signaling	—
R-HSA-5654727	Negative regulation of FGFR2 signaling	—
R-HSA-5654732	Negative regulation of FGFR3 signaling	—
R-HSA-5654733	Negative regulation of FGFR4 signaling	—
R-HSA-169893	Prolonged ERK activation events	—
R-HSA-5673001	RAF/MAP kinase cascade	—
R-HSA-162582	Signal Transduction	—
R-HSA-190236	Signaling by FGFR	—
R-HSA-5654736	Signaling by FGFR1	—
R-HSA-5654738	Signaling by FGFR2	—
R-HSA-5654741	Signaling by FGFR3	—
R-HSA-5654743	Signaling by FGFR4	—
R-HSA-187037	Signaling by NTRK1 (TRKA)	—
R-HSA-166520	Signaling by NTRKs	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-187687	Signalling to ERKs	—
R-HSA-187706	Signalling to p38 via RIT and RIN	electronic

MSigDB gene sets: 0 (showing top):

GO Biological Process (13): MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), epidermal growth factor receptor signaling pathway (GO:0007173), animal organ morphogenesis (GO:0009887), positive regulation of gene expression (GO:0010628), positive regulation of D-glucose transmembrane transport (GO:0010828), positive regulation of peptidyl-serine phosphorylation (GO:0033138), negative regulation of apoptotic process (GO:0043066), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to calcium ion (GO:0071277), establishment of protein localization to membrane (GO:0090150), postsynaptic modulation of chemical synaptic transmission (GO:0099170), signal transduction (GO:0007165)

GO Molecular Function (17): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase activity (GO:0004708), MAP kinase kinase kinase activity (GO:0004709), calcium ion binding (GO:0005509), ATP binding (GO:0005524), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), scaffold protein binding (GO:0097110), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), neuron projection (GO:0043005), cell body (GO:0044297), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Oncogenic MAPK signaling	5
RAF/MAP kinase cascade	3
Prolonged ERK activation events	2
Signalling to ERKs	2
Signaling by MRAS-complex mutants	2
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Negative regulation of MAPK pathway	1
Signaling by RAS mutants	1
Signaling by Receptor Tyrosine Kinases	1

GO top-level categories

60 GO namespaces:

Category	Terms
cellular anatomical structure	4
protein kinase activity	3
MAPK cascade	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
synapse	2
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
ERBB signaling pathway	1
anatomical structure morphogenesis	1
animal organ development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of D-glucose transmembrane transport	1
positive regulation of transmembrane transport	1
D-glucose transmembrane transport	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
response to calcium ion	1
cellular response to metal ion	1
establishment of protein localization	1
localization within membrane	1
modulation of chemical synaptic transmission	1
postsynapse	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein serine/threonine/tyrosine kinase activity	1
protein serine/threonine kinase activity	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
transition metal ion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
plasma membrane bounded cell projection	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 17 of 39 annotations. The rest are phylogenetic / computational / electronic (IEA).

17 experimentally-supported GO terms:

GO term	NS	Evidence
MAPK cascade	BP	direct assay
cellular response to calcium ion	BP	direct assay
epidermal growth factor receptor signaling pathway	BP	direct assay
establishment of protein localization to membrane	BP	direct assay
negative regulation of apoptotic process	BP	direct assay
positive regulation of D-glucose transmembrane transport	BP	direct assay
positive regulation of ERK1 and ERK2 cascade	BP	direct assay
positive regulation of gene expression	BP	mutant phenotype
positive regulation of peptidyl-serine phosphorylation	BP	direct assay
cytosol	CC	direct assay
plasma membrane	CC	direct assay
MAP kinase kinase activity	MF	mutant phenotype
calcium ion binding	MF	direct assay
identical protein binding	MF	physical interaction
protein kinase activity	MF	direct assay
protein serine/threonine kinase activity	MF	direct assay
scaffold protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 4,822 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRAF	KRAS	P01116	975
BRAF	NRAS	P01111	974
BRAF	HRAS	P01112	929
BRAF	PTEN	P60484	909
BRAF	NF1	P21359	908
BRAF	KIAA1549	Q9HCM3	905
BRAF	PIK3CA	P42336	888
BRAF	TP53	P04637	883
BRAF	CDKN2A	P42771	879
BRAF	MLH1	P40692	858
BRAF	PTPN11	Q06124	851
BRAF	PMS2	P54278	827
BRAF	SOS1	Q07889	822
BRAF	MSH6	P52701	798
BRAF	CCND1	P24385	795

IntAct

Human interaction partners of BRAF in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 392 partners by confidence:

Partner	Interaction type	MIscore	Records
MAP2K1	physical association	0.980	34
RAF1	association	0.970	57
HRAS	association	0.940	7
YWHAZ	direct interaction	0.940	5
YWHAB	physical association	0.930	5
YWHAQ	proximity	0.910	3
YWHAG	physical association	0.910	2
MAP2K2	association	0.890	5
ARAF	proximity	0.890	3
YWHAE	physical association	0.890	3
YWHAH	proximity	0.880	1
NRAS	association	0.860	6
SFN	physical association	0.770	3
HSP90AB1	proximity	0.730	2
RPTOR	proximity	0.690	2
KEAP1	physical association	0.680	14
KRAS	association	0.680	2
MAP3K1	phosphorylation reaction	0.610	2
VHL	association	0.600	6
AURKA	physical association	0.600	4
BCL2L1	physical association	0.600	4
FOXO3	physical association	0.600	4
GOT1	physical association	0.600	4
GSK3A	physical association	0.600	4
IKBKB	physical association	0.600	4
MAPK7	physical association	0.600	4
MEN1	association	0.600	4
PDCD2L	physical association	0.600	4
POLE	physical association	0.600	4
ITPKB	physical association	0.600	3

BioGRID (412 interactions; top human partners by supporting records): MAP2K1 (Affinity Capture-MS; 23 records), RAF1 (Affinity Capture-MS; 17 records), YWHAG (Affinity Capture-MS; 13 records), YWHAZ (Affinity Capture-MS; 13 records), HRAS (Affinity Capture-MS; 12 records), YWHAB (Affinity Capture-MS; 12 records), YWHAQ (Affinity Capture-MS; 11 records), YWHAE (Affinity Capture-MS; 10 records), YWHAH (Affinity Capture-MS; 9 records), KRAS (Affinity Capture-MS; 8 records), MAP2K2 (Affinity Capture-MS; 8 records), ARAF (Co-localization; 7 records), HSP90AA1 (Affinity Capture-MS; 7 records), NRAS (Affinity Capture-Western; 7 records), CDC37 (Affinity Capture-MS; 6 records)

SIGNOR signaling

showing 44 of 70 signaling interactions:

A	Effect	B	Mechanism
MAPK3	down-regulates	BRAF	phosphorylation
HRAS	“up-regulates activity”	BRAF	binding
KRAS	“up-regulates activity”	BRAF	binding
HRAS	up-regulates	BRAF	binding
ERK1/2	down-regulates	BRAF	phosphorylation
sorafenib	down-regulates	BRAF	“chemical inhibition”
NRAS	“up-regulates activity”	BRAF	binding
CCT239065	down-regulates	BRAF	“chemical inhibition”
GDC-0879	down-regulates	BRAF	“chemical inhibition”
AKT	down-regulates	BRAF	phosphorylation
BRAF	up-regulates	MEK1/2	phosphorylation
AKT1	“down-regulates activity”	BRAF	phosphorylation
BRAF	“up-regulates quantity”	TGFB1	relocalization
BRAF	“up-regulates activity”	MEK1/2	phosphorylation
BRAF	“down-regulates quantity by repression”	SLC5A5	“transcriptional regulation”
regorafenib	“down-regulates activity”	BRAF	“chemical inhibition”
vemurafenib	“down-regulates activity”	BRAF	“chemical inhibition”
BRAF	up-regulates	Glycolysis
ERK1/2	“down-regulates activity”	BRAF	phosphorylation
MAPK1	“down-regulates activity”	BRAF	phosphorylation
MAPK3	“down-regulates activity”	BRAF	phosphorylation
BRAF	“up-regulates activity”	ERK1/2
BRAF	“up-regulates quantity by expression”	NFE2L2	“transcriptional regulation”
Gbeta	down-regulates	BRAF	phosphorylation
RNF149	“down-regulates quantity by destabilization”	BRAF	polyubiquitination
KSR2	“up-regulates activity”	BRAF	binding
KSR1	“up-regulates activity”	BRAF	binding
RAP1A	“up-regulates activity”	BRAF	binding
PPP1CA	“up-regulates activity”	BRAF	dephosphorylation
BRAF	“down-regulates activity”	BRAF	phosphorylation
BRAF	“up-regulates quantity”	MAPK7	phosphorylation
BRAF	“up-regulates activity”	PAX3	phosphorylation
BRAF	“up-regulates activity”	ABL1	phosphorylation
SGK1	“down-regulates activity”	BRAF	phosphorylation
BRAF	“down-regulates activity”	NIBAN2	phosphorylation
BRAF	up-regulates	MAP2K2	phosphorylation
AKT2	down-regulates	BRAF	phosphorylation
AKT3	down-regulates	BRAF	phosphorylation
BRAF	“up-regulates activity”	MAP2K1	phosphorylation
RIT1	“up-regulates activity”	BRAF	binding
PRKACA	“down-regulates activity”	BRAF	phosphorylation
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine	“down-regulates activity”	BRAF	“chemical inhibition”
“5-[1-(2-hydroxyethyl)-3-pyridin-4-yl-4-pyrazolyl]-2,3-dihydroinden-1-one oxime”	“down-regulates activity”	BRAF	“chemical inhibition”
PLX-4720	“down-regulates activity”	BRAF	“chemical inhibition”

Protein complexes (CORUM) (8)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

8 complexes by size:

Complex	Subunits	Members
★ BRAF-KSR1-MAP2K1-RAF1-YWHAE complex	5	RAF1, YWHAE, BRAF, KSR1, MAP2K1
★ BRAF-MAP2K1-MAP2K2-YWHAE complex	4	BRAF, MAP2K1, MAP2K2, YWHAE
★ BRAF-RAF1-YWHAZ complex	3	YWHAZ, BRAF, RAF1
★ BRAF-KSR1-MAP2K1 complex	3	BRAF, KSR1, MAP2K1
★ BRAF-MAP2K1 complex	2	BRAF, MAP2K1
★ BRAF-MITF complex	2	BRAF, MITF
★ BRAF-RAF1 complex, RAS stimulated	2	BRAF, RAF1
★ BRAF-CNK1 complex, not RAS stimulated	2	BRAF, CNKSR1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 392 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	10	21.2×	1e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	9	16.8×	2e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	9	16.8×	2e-08
Signaling by high-kinase activity BRAF mutants	18	15.9×	9e-16
Signaling by ALK	10	15.9×	4e-09
Constitutive Signaling by AKT1 E17K in Cancer	13	15.3×	2e-11
Signalling to ERKs	9	15.1×	5e-08
Tie2 Signaling	9	15.1×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
Schwann cell development	8	21.7×	1e-07
hippo signaling	8	15.1×	3e-06
response to corticosterone	5	14.4×	5e-04
interleukin-6-mediated signaling pathway	5	14.4×	5e-04
TOR signaling	7	13.8×	3e-05
negative regulation of protein localization to nucleus	6	13.0×	2e-04
insulin-like growth factor receptor signaling pathway	10	12.7×	4e-07
release of cytochrome c from mitochondria	7	12.6×	5e-05

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

BRAF mutations are found to be recurrent in many cancer types. Of these, the mutation of valine 600 to glutamic acid (V600E) is the most prevalent. V600E has been determined to be an activating mutation, and cells that harbor it, along with other V600 mutations are sensitive to the BRAF inhibitor dabrafenib. It is also common to use MEK inhibition as a substitute for BRAF inhibitors, and the MEK inhibitor trametinib has seen some success in BRAF mutant melanomas. BRAF mutations have also been correlated with poor prognosis in many cancer types, although there is at least one study that questions this conclusion in papillary thyroid cancer. Oncogenic BRAF mutations are divided into three categories that determine their sensitivity to inhibitors. Class 1 BRAF mutations (V600) are RAS-independent, signal as monomers and are sensitive to current RAF monomer inhibitors. Class 2 BRAF mutations (K601E, K601N, K601T, L597Q, L597V, G469A, G469V, G469R, G464V, G464E, and fusions) are RAS-independent, signaling as constitutive dimers and are resistant to vemurafenib. Such mutants may be sensitive to novel RAF dimer inhibitors or MEK inhibitors. Class 3 BRAF mutations (D287H, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, and G596R) with low or absent kinase activity are RAS-dependent and they activate ERK by increasing their binding to activated RAS and wild-type CRAF. Class 3 BRAF mutations coexist with mutations in RAS or NF1 in melanoma may be treated with MEK inhibitors. In epithelial tumors such as CRC or NSCLC may be effectively treated with combinations that include inhibitors of receptor tyrosine kinase.

From intOGen — cancer-driver classification: activating (oncogene-like) across 28 cancer types — BLCA, BRCA, CHOL, CLLSLL, COAD, COADREAD, CSCC, DLBCLNOS, GBM, GIST, HGGNOS, LGGNOS…(+16 more).

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for BRAF: 1,642 ClinVar records (100 pathogenic / likely pathogenic); 45 ClinGen expert-panel interpretations; 42 CIViC cancer variants; 10 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,642 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	41
Uncertain significance	684
Likely benign	567
Benign	104

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 100 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
13973	NM_004333.6(BRAF):c.770A>G (p.Gln257Arg)	Pathogenic	reviewed by expert panel	37
13974	NM_004333.6(BRAF):c.1406G>A (p.Gly469Glu)	Pathogenic	reviewed by expert panel	21
13979	NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)	Pathogenic	reviewed by expert panel	18
40387	NM_004333.6(BRAF):c.1787G>T (p.Gly596Val)	Pathogenic	reviewed by expert panel	14
13965	NM_004333.6(BRAF):c.736G>C (p.Ala246Pro)	Pathogenic	reviewed by expert panel	12
13975	NM_004333.6(BRAF):c.1455G>C (p.Leu485Phe)	Pathogenic	reviewed by expert panel	12
177672	NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu)	Pathogenic	reviewed by expert panel	9
13964	NM_004333.6(BRAF):c.1391G>A (p.Gly464Glu)	Pathogenic	reviewed by expert panel	8
40347	NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)	Pathogenic	reviewed by expert panel	8
177844	NM_004333.6(BRAF):c.1455G>T (p.Leu485Phe)	Pathogenic	reviewed by expert panel	8
180784	NM_004333.6(BRAF):c.739T>C (p.Phe247Leu)	Pathogenic	reviewed by expert panel	8
40348	NM_004333.6(BRAF):c.735A>T (p.Leu245Phe)	Pathogenic	reviewed by expert panel	7
40346	NM_004333.6(BRAF):c.730A>C (p.Thr244Pro)	Pathogenic	reviewed by expert panel	6
40389	NM_004333.6(BRAF):c.1799T>G (p.Val600Gly)	Pathogenic	reviewed by expert panel	6
40388	NM_004333.6(BRAF):c.1796C>T (p.Thr599Ile)	Pathogenic	reviewed by expert panel	5

Per-variant reference — Sugi Variant

Explore BRAF’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

ClinGen expert-panel interpretations (45)

Expert ACMG interpretations from RASopathy VCEP for RASopathy; cardiofaciocutaneous syndrome — a higher-authority tier than individual ClinVar submissions.

Assertion	Variants
Pathogenic	20
Likely Pathogenic	5
Uncertain Significance	1
Likely Benign	5
Benign	14

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 2,235):

Position(s)	Effect	Δscore	Sites
7:140739810–140739811	donor_loss	1.0000	4
7:140739947–140739948	acceptor_loss	1.0000	5
7:140749285–140749286	donor_loss	1.0000	5
7:140749419–140749420	acceptor_loss	1.0000	6
7:140749422	acceptor_gain	1.0000
7:140749429	acceptor_gain	1.0000
7:140776910–140776911	donor_loss	1.0000	5
7:140777089	acceptor_loss	1.0000	2
7:140777091	acceptor_gain	1.0000
7:140777989–140777990	donor_loss	1.0000	5

AlphaMissense

2,933 missense substitutions predicted likely pathogenic (of 4,976 scored), across 581 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M517	9	0.986	1.000
M620	9	0.985	0.999
M564	9	0.964	1.000
M668	9	0.944	0.999
M53	9	0.929	0.992
H510	8	1.000	1.000
D576	8	1.000	1.000
D594	8	1.000	1.000
H235	8	0.999	1.000
H269	8	0.999	1.000
F516	8	0.999	1.000
H568	8	0.999	1.000
H574	8	0.999	1.000
F595	8	0.999	1.000
D638	8	0.999	1.000
F498	8	0.998	1.000
F583	8	0.998	1.000
D663	8	0.998	1.000
F256	8	0.997	1.000
H542	8	0.997	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000104
Ovary Serous Cystadenocarcinoma (validation)	unfavorable	0.000129
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000224
Bladder Urothelial Carcinoma (TCGA)	favorable	0.000452

Disease associations

OMIM: gene MIM:164757 | disease phenotypes: MIM:613706, MIM:115150, MIM:163950, MIM:188470, MIM:613707, MIM:114500, MIM:155600, MIM:211980, MIM:614429, MIM:265500, MIM:220200, MIM:606519, MIM:601518, MIM:153100, MIM:151100, MIM:218040, MIM:115197, MIM:108010

GenCC curated gene-disease

9 curated gene-disease records:

Disease	Classification	Inheritance	Records
cardiofaciocutaneous syndrome 1	Definitive	Autosomal dominant	5
Noonan syndrome 7	Definitive	Autosomal dominant	5
LEOPARD syndrome 3	Definitive	Autosomal dominant	5
cardiofaciocutaneous syndrome	Definitive	Autosomal dominant	2
large congenital melanocytic nevus	Strong	Autosomal dominant
Noonan syndrome	Moderate	Autosomal dominant
Noonan syndrome with multiple lentigines	Supportive	Autosomal dominant	2
anaplastic astrocytoma	Limited	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity

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

4 validity classifications:

Disease	Classification	Inheritance
Noonan syndrome	Moderate	AD
Noonan syndrome with multiple lentigines	Limited	AD
cardiofaciocutaneous syndrome	Definitive	AD
Costello syndrome	Disputed	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (22 panels, 18 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

22 panels:

Panel	Rating
Childhood solid tumours cancer susceptibility	green
DDG2P	green
Early onset or syndromic epilepsy	green
Fetal anomalies	green
Fetal hydrops	green
Hypotonic infant	green
IUGR and IGF abnormalities	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Monogenic short stature	green
Mosaic skin disorders - Deep sequencing	green
Neurofibromatosis Type 1	green
Paediatric disorders	green
Pigmentary skin disorders	green
Pituitary hormone deficiency	green
Primary lymphoedema	green
RASopathies	green
Rare syndromic craniosynostosis or isolated multisuture synostosis	green
Adult solid tumours cancer susceptibility	amber
Childhood solid tumours	amber
Paediatric or syndromic cardiomyopathy	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (37): Noonan syndrome 7 (MONDO:0013379), RASopathy (MONDO:0021060), cardiofaciocutaneous syndrome 1 (MONDO:0007265), colon carcinoma (MONDO:0002032), cardiofaciocutaneous syndrome (MONDO:0015280), Noonan syndrome (MONDO:0018997), Noonan syndrome 1 (MONDO:0008104), lung adenocarcinoma (MONDO:0005061), non-small cell lung carcinoma (MONDO:0005233), thyroid cancer, nonmedullary, 2 (MONDO:0008566), LEOPARD syndrome 3 (MONDO:0013380), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), non-Hodgkin lymphoma (MONDO:0018908), colorectal cancer (MONDO:0005575), melanoma, cutaneous malignant, susceptibility to, 1 (MONDO:0007963), lung cancer (MONDO:0008903), ventricular septal defect (MONDO:0002070), pulmonic stenosis (MONDO:0009938), tethered spinal cord syndrome (MONDO:0006995), Dandy-Walker syndrome (MONDO:0009072), PHACE syndrome (MONDO:0011676), lung carcinoma (MONDO:0005138), colorectal neoplasm (MONDO:0005335), melanoma (MONDO:0005105), prostate cancer, hereditary, 1 (MONDO:0011098), lymphatic malformation (MONDO:0019313), vascular malformation (MONDO:0024291), Noonan syndrome with multiple lentigines (MONDO:0007893), diffuse large B-cell lymphoma (MONDO:0018905), gallbladder cancer (MONDO:0005411), Costello syndrome (MONDO:0009026), hypertrophic cardiomyopathy 4 (MONDO:0007268), myoepithelial tumor (MONDO:0002380), arteriovenous malformations of the brain (MONDO:0007154), lip and oral cavity carcinoma (MONDO:0023644), anaplastic astrocytoma (MONDO:0016684), large congenital melanocytic nevus (MONDO:0044792)

Orphanet (19): RASopathy (Orphanet:536391), Noonan syndrome (Orphanet:648), Cardiofaciocutaneous syndrome (Orphanet:1340), Noonan syndrome with multiple lentigines (Orphanet:500), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Non-Hodgkin lymphoma (Orphanet:547), Familial melanoma (Orphanet:618), Congenital pulmonary valvar stenosis (Orphanet:3189), Isolated Dandy-Walker malformation (Orphanet:217), PHACE syndrome (Orphanet:42775), Familial prostate cancer (Orphanet:1331), Diffuse large B-cell lymphoma (Orphanet:544), Costello syndrome (Orphanet:3071), Brain arteriovenous malformation (Orphanet:46724), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268), NON RARE IN EUROPE: Non-small cell lung cancer (Orphanet:488201), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480), NON RARE IN EUROPE: Melanoma (Orphanet:411533)

HPO phenotypes

showing 60 of 369 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000047	Hypospadias
HP:0000078	Abnormality of the genital system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000141	Amenorrhea
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000179	Thick lower lip vermilion
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000271	Abnormality of the face
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000306	Abnormality of the chin
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000475	Broad neck
HP:0000476	Cystic hygroma
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000499	Abnormal eyelash morphology
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000529	Progressive visual loss
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000561	Absent eyelashes
HP:0000635	Blue irides
HP:0000637	Long palpebral fissure

GWAS associations

10 associations:

Study	Trait	p-value
GCST010118_24	Type 2 diabetes	2e-10
GCST008103_166	Bipolar disorder	6e-10
GCST004894_141	Type 2 diabetes	1e-9
GCST009600_67	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	5e-9
GCST003124_32	Mild influenza (H1N1) infection	3e-8
GCST003070_2	Cerebrospinal T-tau levels	3e-7
GCST004894_15	Type 2 diabetes	4e-7
GCST012210_2	Longevity	1e-6
GCST001450_7	Response to Vitamin E supplementation	4e-6
GCST003079_5	Cerebrospinal fluid t-tau:AB1-42 ratio	7e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004760	t-tau measurement
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:1001488	influenza A (H1N1)

MeSH disease descriptors

17 disease descriptors:

Descriptor	Name	Tree numbers
D002289	Carcinoma, Non-Small-Cell Lung	C04.588.894.797.520.109.220.249; C08.381.540.140.500; C08.785.520.100.220.500
D015179	Colorectal Neoplasms	C04.588.274.476.411.307; C06.301.371.411.307; C06.405.249.411.307; C06.405.469.158.356; C06.405.469.491.307; C06.405.469.860.180
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
D044542	LEOPARD Syndrome	C05.660.207.525; C14.240.400.695; C14.280.400.695; C14.280.484.716.525; C16.131.077.525; C16.131.240.400.685; C16.131.621.207.525; C17.800.621.430.530.550.525
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
D008228	Lymphoma, Non-Hodgkin	C04.557.386.480; C15.604.515.569.480; C20.683.515.761.480
D008545	Melanoma	C04.557.465.625.650.510; C04.557.580.625.650.510; C04.557.665.510; C04.588.805.377; C17.800.882.445
D009208	Myoepithelioma	C04.557.435.585
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D054079	Vascular Malformations	C14.240.850; C16.131.240.850
C535579	Cardiofaciocutaneous syndrome *(supp.)*
C566169	Cardiomyopathy, Familial Hypertrophic, 4 *(supp.)*
C537846	Noonan like syndrome *(supp.)*
C572845	Thyroid cancer, follicular *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL3559685 (PROTEIN FAMILY), CHEMBL3883317 (PROTEIN FAMILY), CHEMBL4106189 (PROTEIN COMPLEX), CHEMBL4523687 (PROTEIN-PROTEIN INTERACTION), CHEMBL5145 (SINGLE PROTEIN), CHEMBL5291967 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the BRAF protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

14 curated-mechanism drugs:

Drug	Modality	Max phase
DABRAFENIB MESYLATE	Small molecule	4
ENCORAFENIB	Small molecule	4
REGORAFENIB	Small molecule	4
SORAFENIB TOSYLATE	Small molecule	4
VEMURAFENIB	Small molecule	4
CEP-32496	Small molecule	2
LIFIRAFENIB	Small molecule	2
PLIXORAFENIB	Small molecule	2
RAF-265	Small molecule	2
XL-281	Small molecule	2
ARQ-736	Small molecule	1
LGX-806	Unknown	1
LY-3009120	Small molecule	1
RG-7256	Unknown	1

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes BRAF — the drug acts on the assembly or class, not necessarily on this subunit alone.

3 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
TOVORAFENIB	RAF serine/threonine protein kinase	3	4
NAPORAFENIB	B-raf/RAF proto-oncogene serine/threonine-protein kinase	2	3
BELVARAFENIB	RAF serine/threonine protein kinase	3	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 636,143 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

48 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2028663	DABRAFENIB	4	13,060
CHEMBL3301612	ENCORAFENIB	4	4,898
CHEMBL1946170	REGORAFENIB	4	13,318
CHEMBL1336	SORAFENIB	4	87,476
CHEMBL1229517	VEMURAFENIB	4	16,487
CHEMBL3301610	ABEMACICLIB	4	7,497
CHEMBL2146883	COBIMETINIB	4	9,920
CHEMBL5416410	DASATINIB	4	674
CHEMBL1421	DASATINIB ANHYDROUS	4	55,947
CHEMBL553	ERLOTINIB	4	109,860
CHEMBL1287853	FEDRATINIB	4	3,770
CHEMBL939	GEFITINIB	4	119,425
CHEMBL941	IMATINIB	4	113,105
CHEMBL1852688	INFIGRATINIB	4	2,298
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	330
CHEMBL255863	NILOTINIB	4	39,362
CHEMBL477772	PAZOPANIB	4	16,241
CHEMBL1171837	PONATINIB	4	9,435
CHEMBL1789941	RUXOLITINIB	4	12,161
CHEMBL3348923	TOVORAFENIB	4	879
CHEMBL3264002	AVUTOMETINIB	3
CHEMBL1908391	MASITINIB	3
CHEMBL572881	MOTESANIB	3
CHEMBL4583691	NAPORAFENIB	3
CHEMBL50	QUERCETIN	3
CHEMBL2029988	CEP-32496	2
CHEMBL4209157	LIFIRAFENIB	2
CHEMBL558752	RAF-265	2
CHEMBL3545027	XL-281	2
CHEMBL206834	BAFETINIB	2
CHEMBL3977543	BELVARAFENIB	2
CHEMBL5800160	BRIMARAFENIB	2
CHEMBL103667	DORAMAPIMOD	2
CHEMBL6246	ELLAGIC ACID	2
CHEMBL5095099	EXARAFENIB	2
CHEMBL1230609	FORETINIB	2
CHEMBL507361	MIRDAMETINIB	2
CHEMBL3991932	PEXMETINIB	2
CHEMBL475251	R-406	2
CHEMBL1738757	REBASTINIB	2
CHEMBL230011	TG100-115	2
CHEMBL5095256	TINLORAFENIB	2
CHEMBL3577124	LY-3009120	1
CHEMBL2140408	AMG-900	1
CHEMBL574738	AST-487	1
CHEMBL296468	BMS-387032	1
CHEMBL5831360	CCT-3833	1
CHEMBL4212692	XP-102	1

Clinical evidence (CIViC)

Drug × variant × indication, from 349 curated evidence items; also 27 prognostic, 24 oncogenic, 16 functional, 5 diagnostic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

showing 30 of 263 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
BRAF V600E	Dabrafenib	Melanoma	Sensitivity/Response	CIViC A	EID11244 +5
BRAF V600	Encorafenib + Binimetinib	Melanoma	Sensitivity/Response	CIViC A	EID7287 +2
BRAF V600	Vemurafenib + Cobimetinib	Melanoma	Sensitivity/Response	CIViC A	EID6044 +2
BRAF V600	Vemurafenib + Cobimetinib + Atezolizumab	Melanoma	Sensitivity/Response	CIViC A	EID13046 +1
BRAF V600E	Trametinib + Dabrafenib	Pleomorphic Xanthoastrocytoma	Sensitivity/Response	CIViC A	EID11312 +1
BRAF V600	Vemurafenib	Erdheim-Chester Disease	Sensitivity/Response	CIViC A	EID11237
BRAF V600	Vemurafenib + Atezolizumab + Cobimetinib	Melanoma	Sensitivity/Response	CIViC A	EID11238
BRAF V600	Trametinib + Dabrafenib	Skin Melanoma	Sensitivity/Response	CIViC A	EID1411
BRAF V600 OR v::BRAF Fusion	Tovorafenib	Childhood Low-grade Glioma	Sensitivity/Response	CIViC A	EID12028
BRAF V600E	Dabrafenib/Trametinib Regimen	Anaplastic Thyroid Carcinoma	Sensitivity/Response	CIViC A	EID10785
BRAF V600E	Dabrafenib + Trametinib	Pilocytic Astrocytoma	Sensitivity/Response	CIViC A	EID11313
BRAF V600E	Trametinib + Dabrafenib	Solid Tumor	Sensitivity/Response	CIViC A	EID12161
BRAF V600E	Dabrafenib + Trametinib	Low Grade Glioma	Sensitivity/Response	CIViC A	EID12162
BRAF V600E	Cobimetinib + Vemurafenib + Atezolizumab	Melanoma	Sensitivity/Response	CIViC A	EID13045
BRAF V600E	Vemurafenib	Skin Melanoma	Sensitivity/Response	CIViC A	EID1409
BRAF V600E	Trametinib + Dabrafenib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID3017
BRAF V600E	Encorafenib + Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC A	EID9851
BRAF V600E OR KIAA1549::BRAF Fusion	Tovorafenib	Childhood Low-grade Glioma	Sensitivity/Response	CIViC A	EID12016
BRAF V600E	Vemurafenib	Melanoma	Sensitivity/Response	CIViC B	EID1398 +14
BRAF V600K	Vemurafenib	Melanoma	Sensitivity/Response	CIViC B	EID1399 +9
BRAF V600E	Vemurafenib	Hairy Cell Leukemia	Sensitivity/Response	CIViC B	EID11315 +6
BRAF V600E	Vemurafenib	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1405 +4
BRAF V600E	Vemurafenib	Papillary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID1591 +4
BRAF V600E	Trametinib + Dabrafenib	Anaplastic Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID12959 +3
BRAF V600E	Vemurafenib	Lung Adenocarcinoma	Sensitivity/Response	CIViC B	EID3782 +3
BRAF V600E	Dabrafenib + Trametinib	Anaplastic Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID12957 +2
BRAF V600E	Trametinib	Melanoma	Sensitivity/Response	CIViC B	EID2135 +2
BRAF V600E	Trametinib + Dabrafenib	Melanoma	Sensitivity/Response	CIViC B	EID6938 +2
BRAF V600K	Dabrafenib + Trametinib	Melanoma	Sensitivity/Response	CIViC B	EID6939 +2
BRAF V600	Vemurafenib	Langerhans-cell Histiocytosis	Sensitivity/Response	CIViC B	EID11302 +1

CIViC column: a representative evidence item (EID); +N = additional CIViC items supporting the same association.

Clinical-actionability assertions (CIViC AMP/ASCO/CAP)

Curated AMP/ASCO/CAP tier assertions — the clinical-actionability classification (Tier I highest) for this gene’s variants, distilling the CIViC evidence above into a tiered call.

20 CIViC assertions:

Molecular profile	Disease	Therapy	Type	AMP tier	Significance
BRAF V600E	Melanoma	Cobimetinib, Vemurafenib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600K	Melanoma	Cobimetinib, Vemurafenib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600K	Melanoma	Dabrafenib, Trametinib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600E	Colorectal Cancer		Prognostic	Tier I - Level A	Poor Outcome
BRAF V600E	Anaplastic Thyroid Carcinoma	Dabrafenib, Trametinib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600E	Melanoma	Vemurafenib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600E	Melanoma	Encorafenib, Binimetinib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600E	Melanoma	Cobimetinib, Vemurafenib, Atezolizumab †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600K	Melanoma	Vemurafenib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600K	Melanoma	Binimetinib, Encorafenib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600E	Melanoma	Dabrafenib, Trametinib †	Predictive	Tier I - Level A	Sensitivity/Response
BRAF V600E	Colorectal Cancer	Binimetinib, Encorafenib, Cetuximab	Predictive		Sensitivity/Response
BRAF K601E	Cancer		Oncogenic		Likely Oncogenic
BRAF V600K	Cancer		Oncogenic		Oncogenic
BRAF G469A	Cancer		Oncogenic		Oncogenic
BRAF G469E	Cancer		Oncogenic		Likely Oncogenic
BRAF V600E	Anaplastic Thyroid Carcinoma		Oncogenic		Oncogenic
BRAF V600E	Melanoma		Oncogenic		Oncogenic
BRAF V600E	Colorectal Cancer		Oncogenic		Oncogenic
BRAF V600K	Melanoma		Oncogenic		Likely Oncogenic

† an FDA-approved companion diagnostic exists for this assertion.

CIViC curated variants (42)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

V600D (missense variant), G464V (missense variant), N581S (missense variant), A728V (missense variant), V600E (missense variant), Amplification (transcript amplification), T599dup, V600M (missense variant), G596R (missense variant), V600 (protein altering variant), G496A, G466V (missense variant), G606E (missense variant), P731T (missense variant), intron 9 rearrangement, intron 10 rearrangement, D594K, Non-V600 (protein altering variant), Exon 15 Mutation, L525R (missense variant), N486_P490del, V600_K601>E, G469, A598V (missense variant), L597R (missense variant), G463E, Mutation (gene variant,gain of function variant), Wildtype (wild type), L485_P490del (inframe deletion), V600K (missense variant), D594A (missense variant), D594V (missense variant), K483M (missense variant,loss of function variant), L597S (missense variant), L597Q (missense variant), K601E (missense variant), L597V (missense variant), D594G (missense variant), L505H (missense variant), G596C (missense variant), G469A (missense variant), G469E (missense variant).

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs113488022	FOLFIRI, FOLFOX, XELOX	Efficacy	Allele T is associated with decreased overall survival when treated with FOLFIRI, FOLFOX or XELOX in people with Colorectal Neoplasms as compared to genotype AA.	PMID:38248103

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — RAF family

Most potent curated ligand interactions (30 total), top 25:

Ligand	Action	Affinity	Parameter
GDC-0879	Inhibition	9.89	pIC50
SB590885	Inhibition	9.8	pKi
naporafenib	Inhibition	8.89	pKd
vemurafenib	Inhibition	8.54	pIC50
dabrafenib	Inhibition	8.49	pIC50
exarafenib	Inhibition	8.46	pIC50
tinlorafenib	Inhibition	8.24	pIC50
XP-102	Binding	8.22	pKd
brimarafenib	Inhibition	8.1	pIC50
TAK-632	Inhibition	8.08	pIC50
mosperafenib	Inhibition	8.05	pKd
LY3009120	Inhibition	8.04	pIC50
L779450	Inhibition	8.0	pIC50
omzirafenib	Inhibition	7.88	pIC50
plixorafenib	Inhibition	7.85	pIC50
sorafenib	Inhibition	7.66	pIC50
regorafenib	Inhibition	7.55	pIC50
CCT241161	Inhibition	7.52	pIC50
lifirafenib	Inhibition	7.49	pIC50
claturafenib	Inhibition	7.46	pEC50
agerafenib	Inhibition	7.44	pKd
NST-628	Binding	7.3	pKd
belvarafenib	Inhibition	7.25	pIC50
CCT196969	Inhibition	7.0	pIC50
PLX-4720	Inhibition	6.8	pIC50

Binding affinities (BindingDB)

4831 measured of 5986 human assays (6100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1Z)-5-[1-methyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-indene-1-hydroxylamine	IC50	0.02 nM
(1Z)-5-[1-(piperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-indene-1-hydroxylamine	IC50	0.03 nM
CHEMBL526479	IC50	0.03 nM
CHEMBL5289891	IC50	0.034 nM
N-[4-methyl-3-(4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.039 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
(1S,3R)-3-{4-[(1Z)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}cyclohexan-1-ol	IC50	0.04 nM
CHEMBL3808884	EC50	0.04 nM
3-{4-[(1Z)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}propan-1-ol	IC50	0.05 nM
3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide	EC50	0.05 nM
N-[3-[[4-[6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl]amino]propyl]-4-methoxybenzenesulfonamide	IC50	0.05 nM	US-11332479: Imidazooxazole derivative having antitumor effect, and pharmaceutical composition including same
3-(difluoromethyl)-N-[4-methyl-3-(2-morpholin-4-yl-4-pyridinyl)phenyl]benzamide	IC50	0.056 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
CHEMBL4776565	KI	0.06 nM
CHEMBL5094514	KI	0.06 nM
CHEMBL4780060	KI	0.061 nM
CHEMBL4778419	KI	0.062 nM
N-[4-methyl-3-(8-morpholin-4-ylimidazo[1,2-a]pyrazin-6-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.065 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
N-[(1S,1aS,6bS)-5-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-yl]-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide	IC50	0.079 nM	US-9670231: Fused tricyclic amide compounds as multiple kinase inhibitors
N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl]-5-chloro-2-fluorophenyl]propane-1-sulfonamide	IC50	0.08 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[5-chloro-3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-cyclopropyl-1H-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide	IC50	0.08 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[3-[[4-[6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl]amino]propyl]-4-methoxybenzenesulfonamide	IC50	0.08 nM	US-11332479: Imidazooxazole derivative having antitumor effect, and pharmaceutical composition including same
CHEMBL4740241	KI	0.081 nM
N-[(1S,1aS,6bS)-5-[(2-oxo-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-5-yl)oxy]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-yl]-4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide	IC50	0.085 nM	US-9670231: Fused tricyclic amide compounds as multiple kinase inhibitors
(1R,3R)-3-{4-[(1Z)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}cyclohexan-1-ol	IC50	0.09 nM
methyl N-[(2S)-1-[[4-[2-tert-butyl-4-[3-chloro-5-(propylsulfonylamino)phenyl]-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
methyl N-[(2S)-1-[[4-[2-tert-butyl-4-[3-chloro-5-(cyclopropylsulfonylamino)phenyl]-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
methyl N-[(2S)-1-[[4-[2-tert-butyl-4-[3-chloro-5-(ethylsulfonylamino)phenyl]-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl]-5-chloro-2-fluorophenyl]-2,6-difluorobenzenesulfonamide	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
methyl N-[(2S)-1-[[4-[4-[2-chloro-3-[(2,6-difluorophenyl)sulfonylamino]-5-fluorophenyl]-2-cyclopropyl-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[4-methyl-3-[2-morpholin-4-yl-6-(3-oxomorpholin-4-yl)pyrimidin-4-yl]phenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
5-(dimethylamino)-N-[3-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-methylphenyl]pyridine-3-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(2-methylsulfonyl-6-morpholin-4-ylpyrimidin-4-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[3-(2-imidazol-1-yl-6-morpholin-4-ylpyrimidin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(2-morpholin-4-yl-4-pyridinyl)phenyl]-3-methylsulfonylbenzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[5-(2,6-dimorpholin-4-yl-4-pyridinyl)-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[3-[1-(cyanomethyl)-5-morpholin-4-yl-6-oxo-3-pyridinyl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-(1,1-difluoroethyl)-N-[4-methyl-3-(1-methyl-5-morpholin-4-yl-6-oxo-3-pyridinyl)phenyl]benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
CHEMBL3752213	IC50	0.1 nM
CHEMBL5287468	IC50	0.1 nM
N-[5-chloro-3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-(1-methylcyclopropyl)-1H-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide	IC50	0.11 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[2-chloro-3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1H-imidazol-4-yl]-5-fluorophenyl]propane-1-sulfonamide	IC50	0.11 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
BDBM200762	IC50	0.11 nM	US-9670231: Fused tricyclic amide compounds as multiple kinase inhibitors
7-(2,6-difluoro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-3-(7-fluoro-1H-indazol-4-yl)-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine	IC50	0.11 nM
N-[3-(2-amino-6-morpholin-4-yl-4-pyridinyl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	0.117 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
N-[3-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	0.118 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
N-[6-methyl-5-[5-morpholin-4-yl-6-(oxan-4-yloxy)-3-pyridinyl]-3-pyridinyl]-3-(trifluoromethyl)benzamide	IC50	0.119 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
methyl N-[(2S)-1-[[4-[2-tert-butyl-4-[2,4-difluoro-3-(propylsulfonylamino)phenyl]-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.12 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
2-(1,1-difluoroethyl)-N-[4-methyl-3-(2-morpholin-4-yl-4-pyridinyl)phenyl]pyridine-4-carboxamide	IC50	0.12 nM	US-10245267: Biaryl amide compounds as kinase inhibitors
N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl]-5-chloro-2-fluorophenyl]-2,6-difluorobenzenesulfonamide	IC50	0.13 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
methyl N-[(2S)-1-[[4-[4-[2-chloro-3-(propylsulfonylamino)phenyl]-2-cyclopropyl-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.13 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-cyclopropyl-1H-imidazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide	IC50	0.13 nM	US-8563553: Compounds and compositions as protein kinase inhibitors

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.02	nM	CHEMBL500659
10.70	IC50	0.02	nM	CHEMBL5885861
10.52	IC50	0.03	nM	CHEMBL526479
10.47	IC50	0.034	nM	CHEMBL5289891
10.40	IC50	0.04	nM	CHEMBL498344
10.30	IC50	0.05	nM	CHEMBL527029
10.30	IC50	0.05	nM	CHEMBL5850574
10.18	IC50	0.066	nM	CHEMBL5591799
10.15	IC50	0.07	nM	CHEMBL5087577
10.10	IC50	0.08	nM	CHEMBL3651664
10.10	IC50	0.08	nM	CHEMBL3651683
10.10	IC50	0.08	nM	CHEMBL5982580
10.05	IC50	0.09	nM	CHEMBL521562
10.00	IC50	0.1	nM	CHEMBL3752213
10.00	IC50	0.1	nM	CHEMBL3651662
10.00	IC50	0.1	nM	CHEMBL3651665
10.00	IC50	0.1	nM	CHEMBL3651609
10.00	IC50	0.1	nM	CHEMBL3651610
10.00	IC50	0.1	nM	CHEMBL3651613
10.00	IC50	0.1	nM	CHEMBL5287468
9.99	Ki	0.102	nM	CHEMBL4740241
9.96	IC50	0.11	nM	CHEMBL2047875
9.96	IC50	0.11	nM	CHEMBL3651658
9.96	IC50	0.11	nM	CHEMBL3651680
9.96	IC50	0.1096	nM	CHEMBL2047875
9.96	IC50	0.11	nM	CHEMBL1276186
9.92	IC50	0.12	nM	CHEMBL3651703
9.92	Ki	0.12	nM	CHEMBL4776565
9.89	Ki	0.13	nM	CHEMBL525191
9.89	IC50	0.13	nM	CHEMBL3651661
9.89	IC50	0.13	nM	CHEMBL3651695
9.89	IC50	0.13	nM	CHEMBL3651701
9.89	IC50	0.13	nM	CHEMBL525191
9.89	IC50	0.13	nM	CHEMBL2139930
9.89	Ki	0.13	nM	CHEMBL5566280
9.86	Ki	0.139	nM	LY-3009120
9.82	IC50	0.152	nM	CHEMBL3933272
9.82	IC50	0.15	nM	CHEMBL500406
9.82	IC50	0.15	nM	CHEMBL5795266
9.82	IC50	0.15	nM	CHEMBL5835573
9.80	Ki	0.16	nM	SB590885
9.80	IC50	0.16	nM	CHEMBL3651697
9.80	IC50	0.16	nM	SB590885
9.80	IC50	0.16	nM	CHEMBL5811533
9.80	IC50	0.16	nM	CHEMBL1276179
9.80	Kd	0.16	nM	SB590885
9.78	Ki	0.165	nM	CHEMBL5090624
9.77	Ki	0.17	nM	CHEMBL525191
9.77	IC50	0.17	nM	CHEMBL525191
9.74	IC50	0.18	nM	CHEMBL2047879

PubChem BioAssay actives

3224 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(NE)-N-[5-(1-methyl-3-pyridin-4-ylpyrazol-4-yl)-2,3-dihydroinden-1-ylidene]hydroxylamine	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	<0.0001	uM
(NE)-N-[5-(1-piperidin-4-yl-3-pyridin-4-ylpyrazol-4-yl)-2,3-dihydroinden-1-ylidene]hydroxylamine	1127836: Inhibition of BRAF (unknown origin)	ic50	<0.0001	uM
N-[3-[[4-[6-(3-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl]amino]propyl]benzenesulfonamide	2116956: Inhibition of B-RAF V600E mutant (unknown origin) expressed in HEK293 cells in presence of tracer incubated for 1 hr by NanoBRET assay	ic50	<0.0001	uM
cis-(1S,3R)-3-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]cyclohexan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	<0.0001	uM
2-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol	1166978: Inhibition of BRAF V600E mutant (unknown origin)	ki	0.0001	uM
(NE)-N-[5-(5-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-ylidene]hydroxylamine	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0001	uM
3-[5-[2-[2-(5-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)ethylamino]pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl]phenol	1823586: Inhibition of human BRAF V600E mutant using myelin basic protein as substrate in presence of [gamma-33P]ATP incubated for 40 mins by scintillation counting method	ic50	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-5-[(5-fluoro-3-methyl-4-oxoquinazolin-6-yl)amino]-4-methylphenyl]urea	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-[5-(3-aminoisoquinolin-7-yl)-2-fluoro-4-methylphenyl]-3-(3,3-dimethylbutyl)urea	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
N-(4,4-dimethylpentyl)-2-fluoro-4-methyl-5-(2-methyl-1-oxophthalazin-6-yl)benzamide	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[8-methyl-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-6-yl]phenyl]urea	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
3-(2-cyanopropan-2-yl)-N-[2-fluoro-4-methyl-5-(2-methyl-1-oxophthalazin-6-yl)phenyl]benzamide	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-(2-methyl-1-oxophthalazin-6-yl)phenyl]urea	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[(3-methyl-4-oxoquinazolin-6-yl)amino]phenyl]urea	1808598: Inhibition of BRAF (unknown origin) (416 to 766) inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(6-aminopyrimidin-4-yl)-3-[5-(3,3-dimethylbutylcarbamoylamino)-4-fluoro-2-methylphenyl]-1-methylurea	1808598: Inhibition of BRAF (unknown origin) (416 to 766) inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[[3-[6-(methylamino)pyrimidin-4-yl]-2-pyridinyl]amino]phenyl]urea	1808598: Inhibition of BRAF (unknown origin) (416 to 766) inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
4-amino-N-[5-(3,3-dimethylbutylcarbamoylamino)-4-fluoro-2-methylphenyl]quinazoline-8-carboxamide	1808598: Inhibition of BRAF (unknown origin) (416 to 766) inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
2-[4-[(2Z)-2-hydroxyimino-1,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol	2110290: Inhibition of BRAF V600E mutant (unknown origin) assessed as inhibition constant	ki	0.0001	uM
2-[4-[(1Z)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol	1928017: Inhibition of B-Raf in human A-375 cells	ic50	0.0001	uM
trans-(1R,3R)-3-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]cyclohexan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0001	uM
3-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]propan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0001	uM
7-[2-chloro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0001	uM
3-(7-fluoro-1H-indazol-4-yl)-7-[2-fluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0001	uM
7-[2,6-difluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(7-fluoro-1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0001	uM
(NE)-N-[5-[1-(oxan-4-yl)-3-pyridin-4-ylpyrazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	1127836: Inhibition of BRAF (unknown origin)	ic50	0.0002	uM
N-[2,4-difluoro-3-[[3-(7H-purin-6-yl)-2-pyridinyl]amino]phenyl]-1H-pyrazole-4-sulfonamide	1298015: Inhibition of B-Raf V600E mutant (unknown origin) assessed as MEK1 phosphorylation using MEK1-Avitag as substrate after 1 hr by HTRF assay	ic50	0.0002	uM
(NE)-N-[5-[(2-pyrimidin-2-ylfuro[2,3-c]pyridin-3-yl)amino]-2,3-dihydroinden-1-ylidene]hydroxylamine	568446: Inhibition of B-Raf V600E mutant	ic50	0.0002	uM
(NE)-N-[5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	1380302: Inhibition of full length human 6His-tagged BRAF V600E mutant expressed in baculovirus infected insect cells co-expressing human CDC37 (1 to 378 residues) using MEK1 as substrate after 30 mins	ic50	0.0002	uM
N-(3-chlorophenyl)-4-methyl-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534573: Inhibition of human GST-tagged BRAF V600E mutant (416 to 766 residues) using human full length 6His-tagged MEK1 (K97R) as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	ic50	0.0002	uM
3-(2-cyanopropan-2-yl)-N-[2-fluoro-4-methyl-5-(7-methyl-8-oxopyrido[2,3-d]pyridazin-3-yl)phenyl]benzamide	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0002	uM
5-(3,3-dimethylbutylcarbamoylamino)-4-fluoro-N-(3-methoxy-1H-pyrazolo[5,4-b]pyridin-5-yl)-2-methylbenzamide	1808598: Inhibition of BRAF (unknown origin) (416 to 766) inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0002	uM
7-[2,6-difluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0002	uM
(NE)-N-[5-[1-[3-(methylamino)cyclohexyl]-3-pyridin-4-ylpyrazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0002	uM
7-[2-fluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0002	uM
3-[(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-N-methylbenzenesulfonamide	1245734: Inhibition of His6-tagged full length BRAF V600E mutant (2 to 766 residues) (unknown origin) expressed in Baculovirus expression system by BRAMA method	ic50	0.0002	uM
trans-(1S,2S)-2-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]cyclopentan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0003	uM
(NE)-N-[5-[1-(1-methylpiperidin-4-yl)-3-pyridin-4-ylpyrazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	1127836: Inhibition of BRAF (unknown origin)	ic50	0.0003	uM
N-(3-chlorophenyl)-4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480956: Inhibition of recombinant human N-terminal GST-tagged BRAF catalytic domain (416 to 766 residues) V600E mutant expressed in baculovirus expression system using human His6-tagged MEK1 K97R mutant as substrate pretreated for 20 mins followed by [33P]-ATP addition measured after 2 hrs by filter binding method	ic50	0.0003	uM
N-[3-(2-acetamidoimidazo[1,2-a]pyridin-6-yl)-4-methylphenyl]-3-tert-butylbenzamide	1367757: Inhibition of recombinant C-terminal his6-tagged B-Raf (437 to 765 residues) V600E mutant (unknown origin) catalytic domain expressed in baculovirus infected Sf21 insect cells using biotinylated Mek substrate preincubated for 60 mins measured after 3 hrs by amplified luminescence proximity homogeneous assay	ic50	0.0003	uM
N-[3-(2-acetamidoimidazo[1,2-a]pyridin-6-yl)-4-methylphenyl]-3-chlorobenzamide	1367757: Inhibition of recombinant C-terminal his6-tagged B-Raf (437 to 765 residues) V600E mutant (unknown origin) catalytic domain expressed in baculovirus infected Sf21 insect cells using biotinylated Mek substrate preincubated for 60 mins measured after 3 hrs by amplified luminescence proximity homogeneous assay	ic50	0.0003	uM
N-[2-chloro-3-[(3,5-dimethyl-4-oxoquinazolin-6-yl)amino]-4,5-difluorophenyl]propane-1-sulfonamide	2116959: Inhibition of B-RAF V600E (unknown origin)	ic50	0.0003	uM
4-amino-N-[6-chloro-3-[(2-chlorophenyl)sulfonylamino]-2-fluorophenyl]-6-(1,3-dimethylpyrazol-4-yl)quinazoline-8-carboxamide	1678651: Inhibition of of human recombinant His6-tagged B-Raf V600E mutant expressed in baculovirus infected cells co-expresing CDC37 in presence of [gamma33P]ATP incubated for 60 mins by scintillation counting method	ki	0.0003	uM
(2S,4R)-1-[(2S)-2-[5-[2-[2-[2-[[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]pentanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1854376: Inhibition of BRAF V600E mutant (unknown origin) using MEK1 (K97R) as substrate in presence of [gamma-33P]ATP by radiometric assay	ic50	0.0003	uM
1-[3-[3-(4-chloro-3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-7-yl]-8-azabicyclo[3.2.1]octan-8-yl]ethanone	446542: Inhibition of B-Raf	ic50	0.0003	uM
2-chloro-5-[7-[4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM
ethyl 3-[3-(3-hydroxy-4-methylphenyl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-7-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate	446542: Inhibition of B-Raf	ic50	0.0003	uM
3-[7-[2-chloro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM
3-[7-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methylphenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM
3-[7-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-fluorophenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM
3-[7-[2-chloro-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Vemurafenib	affects cleavage, affects expression, increases expression, decreases activity, decreases reaction (+9 more)	11
dabrafenib	affects cotreatment, affects reaction, affects response to substance, affects cleavage, increases response to substance (+2 more)	4
Sorafenib	decreases reaction, increases phosphorylation, decreases activity	3
Valproic Acid	decreases expression	3
sodium arsenite	affects expression, increases expression	2
tanespimycin	increases expression, decreases expression	2
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide	decreases expression, increases expression	2
trametinib	affects cleavage, affects phosphorylation, affects reaction, affects response to substance, increases phosphorylation (+3 more)	2
Vorinostat	affects response to substance, increases expression, affects cotreatment, affects expression, affects reaction	2
Cadmium	decreases expression	2
Cannabidiol	affects cotreatment, decreases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Ozone	increases abundance, increases expression, affects cotreatment, decreases expression	2
GSK-J4	increases expression	1
2-methoxy-6-undecyl-1,4-benzoquinone	decreases expression	1
A-1155463	affects reaction, affects response to substance, decreases reaction, increases response to substance	1
FR900359	affects phosphorylation	1
triphenyl(phenylethynyl)phosphonium	decreases expression	1
moringin	affects cotreatment, decreases expression	1
APS-2-79	increases phosphorylation, increases response to substance, affects reaction	1
intybin	decreases phosphorylation	1
betulin	affects cotreatment, affects response to substance, affects reaction, decreases cleavage	1
allyl isothiocyanate	decreases phosphorylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
ascofuranone	decreases reaction, increases phosphorylation	1
bisphenol A	increases expression, increases phosphorylation, affects response to substance, decreases expression, increases reaction	1
trichostatin A	decreases expression	1
afimoxifene	increases expression, increases phosphorylation, affects cotreatment, increases activity	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1

ChEMBL screening assays

1442 unique, capped per target: 1400 binding, 37 functional, 5 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3882094	Binding	Inhibition of N-terminal GST-tagged recombinant human C-Raf Y340D/Y341D double mutant expressed in baculovirus infected Sf21 insect cells using MEK1 as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins	Multi-functional small molecules as anti-proliferative agents
CHEMBL1047416	Functional	Inhibition of Braf in human A375 cells assessed as inhibition of ERK phosphorylation	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — *J Med Chem*
CHEMBL4024633	ADMET	Inhibition of full length His6-tagged BRAF (unknown origin) expressed in baculovirus expression system assessed as reduction in MEK phosphorylation by measuring ADP production by BRAMA	4,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) Inhibitors. — *J Med Chem*

Cellosaurus cell lines

1,729 cell lines: 1,711 cancer cell line, 9 induced pluripotent stem cell, 4 transformed cell line, 2 telomerase immortalized cell line, 1 undefined cell line type, 1 finite cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0015	U-266/70	Cancer cell line	Male
CVCL_0016	U-266/84	Cancer cell line	Male
CVCL_0040	WM115	Cancer cell line	Female
CVCL_0062	MDA-MB-231	Cancer cell line	Female
CVCL_0068	SK-MEL-1	Cancer cell line	Male
CVCL_0080	A-673	Cancer cell line	Female
CVCL_0124	435.eB	Cancer cell line	Male
CVCL_0132	A-375	Cancer cell line	Female
CVCL_0136	A375.S2	Cancer cell line	Female
CVCL_0144	ARO	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 468 trials:

NCT	Phase	Status	Title
NCT03975829	Phase 4	ACTIVE_NOT_RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT00114829	Phase 4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	Phase 4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	Phase 4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	Phase 4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	Phase 4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	Phase 4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	Phase 4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	Phase 4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	Phase 4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	Phase 4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	Phase 4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	Phase 4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	Phase 4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	Phase 4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	Phase 4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	Phase 4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	Phase 4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	Phase 4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	Phase 4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	Phase 4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	Phase 4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	Phase 4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	Phase 4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	Phase 4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	Phase 4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	Phase 4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	Phase 4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	Phase 4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	Phase 4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	Phase 4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	Phase 4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	Phase 4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	Phase 4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	Phase 4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	Phase 4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	Phase 4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	Phase 4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	Phase 4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	Phase 4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	Phase 4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer
NCT02575378	Phase 4	UNKNOWN	Maintenance Treatment With Capecitabine Metronomic Chemotherapy and Chinese Traditional Medicine in Metastatic Colorectal Cancer
NCT02581423	Phase 4	COMPLETED	A Study of Capecitabine (Xeloda) in the Adjuvant Treatment of Participants With Resected Colon Cancer
NCT02582970	Phase 4	COMPLETED	A Study of Bevacizumab (Avastin) in Combination With Chemotherapy in Participants With Metastatic Cancer of the Colon or Rectum
NCT03084809	Phase 4	COMPLETED	Chemotherapy Combined With CIK Treating Colon Cancer
NCT03130634	Phase 4	COMPLETED	The Efficacy of Silymarin as Adjuvant Therapy on Colorectal Cancer Patients Undergoing FOLFIRI Treatment
NCT03298945	Phase 4	COMPLETED	Comparative Effectiveness of Split-Dose Colonoscopy Bowel Preparation Regimens
NCT03465202	Phase 4	UNKNOWN	Association of Capecitabine Pharmacokinetics and Toxicity With Aging
NCT03564938	Phase 4	COMPLETED	Regorafenib in Indian Patients With Metastatic Colorectal Cancer (mCRC).
NCT03700411	Phase 4	COMPLETED	Influence of Opioid Analgesia on Circulating Tumor Cells in Open Colorectal Cancer Surgery
NCT03700541	Phase 4	COMPLETED	Influence of Opioid Analgesia on Circulating Tumor Cells in Laparoscopic Colorectal Cancer Surgery
NCT03723447	Phase 4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT04074460	Phase 4	COMPLETED	Volatile Anaesthesia and Perioperative Outcomes Related to Cancer Feasibility Study
NCT04281667	Phase 4	ACTIVE_NOT_RECRUITING	Mechanical Bowel Preparation and Oral Antibiotics Versus Mechanical Bowel Preparation Only Prior Rectal Surgery
NCT04297423	Phase 4	COMPLETED	Two Low Volume Regimens for Colorectal Cancer Screening Colonoscopy
NCT04874207	Phase 4	COMPLETED	Evaluation of Treatment PERSOnalization Based on Its Therapeutic Monitoring in Patients With Metastatic Colorectal Cancer Treated With REgorafenib
NCT04874883	Phase 4	UNKNOWN	Effect of the Use of Symbiotics in Patients With Colon Cancer
NCT04973007	Phase 4	TERMINATED	Comparison of Contrast Agents in Liver Magnetic Resonance (MR) for the Detection of Hepatic Metastases
NCT05661357	Phase 4	UNKNOWN	Disitamab Vedotin Combined With Fruquintinib for mCRC With HER2 Expression
NCT05726136	Phase 4	RECRUITING	Fluid Challenge and Plasma Volume, During Surgery

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for BRAF across ~30M SureChEMBL compounds — explore on Sugi Predict.