ARAF

Summary

ARAF (A-Raf proto-oncogene, serine/threonine kinase, HGNC:646) is a protein-coding gene on chromosome Xp11.3, encoding Serine/threonine-protein kinase A-Raf (P10398). Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. In precision oncology, ARAF S214C confers sensitivity to Sorafenib in Lung Non-small Cell Carcinoma (CIViC Level C); 2 further curated variant–drug associations are listed below.

Enables protein serine/threonine kinase activity. Involved in negative regulation of apoptotic process; regulation of TOR signaling; and regulation of protein metabolic process. Located in plasma membrane. Biomarker of high grade glioma.

Source: NCBI Gene 369 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Gene–disease (curated): diffuse lymphatic malformation (Limited, GenCC)
• Clinical variants (ClinVar): 116 total — 1 pathogenic, 3 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈11% of expected missense variation)
• GTEx eGene: eQTL in 35 tissues, sQTL in 18 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug, 2 via a complex or family; 9 molecules with ChEMBL bioactivity
• Approved drugs acting on a complex or family including it: 1 — Tovorafenib (RAF serine/threonine protein kinase)
• Precision-oncology evidence (CIViC): 3 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types (inferred from mutation patterns)
• MANE Select transcript: NM_001654

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:646
Approved symbol	ARAF
Name	A-Raf proto-oncogene, serine/threonine kinase
Location	Xp11.3
Locus type	gene with protein product
Status	Approved
Aliases	A-Raf
Ensembl gene	ENSG00000078061
Ensembl biotype	protein_coding
OMIM	311010
Entrez	369

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 26 protein_coding, 10 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000377045

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

ENST00000377045, ENST00000377039, ENST00000469505, ENST00000470206, ENST00000489496, ENST00000895638, ENST00000895640, ENST00000895641, ENST00000895642, ENST00000895643, ENST00000895644, ENST00000895646, ENST00000895647, ENST00000895649, ENST00000895650, ENST00000895651, ENST00000895652, ENST00000895653, ENST00000895655, ENST00000895656, ENST00000914656, ENST00000914657, ENST00000914658, ENST00000914659, ENST00000951037, ENST00000983824, ENST00000983825, ENST00000983826, ENST00001057043, ENST00001057045, ENST00001057047, ENST00001057048, ENST00001057049, ENST00001057050, ENST00001057051, ENST00001057052, ENST00001066741, ENST00001121753, ENST00001134768

RefSeq mRNA: 3 — MANE Select: NM_001654 NM_001256196, NM_001256197, NM_001654

CCDS: CCDS35232, CCDS59164

Canonical transcript exons

ENST00000377045 — 16 exons

Exon	Start	End
ENSE00000669309	47564985	47565139
ENSE00000669315	47566884	47566911
ENSE00000669321	47568718	47568894
ENSE00000669340	47569893	47570024
ENSE00001043742	47566639	47566780
ENSE00001043758	47565252	47565350
ENSE00001093194	47562909	47563063
ENSE00001472613	47569539	47569657
ENSE00001740061	47568987	47569033
ENSE00001832535	47561205	47561251
ENSE00001936221	47571323	47571908
ENSE00003512527	47563226	47563329
ENSE00003548197	47564797	47564899
ENSE00003563389	47570878	47571012
ENSE00003717973	47567230	47567432
ENSE00003738733	47566986	47567131

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 96.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.0830 / max 280.5447, expressed in 1821 samples.

Highest expression (Bgee): hindlimb stylopod muscle, granulocyte, gastrocnemius, body of stomach, apex of heart.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ARAF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 35 tissues and its splicing (sQTL) in 18 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 53 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	sqtl	3.7e-14	-0.99	X:47566536:C:T
Adipose Subcutaneous	eqtl	1.4e-13	-0.16	X:47565216:C:T
Skin Sun Exposed Lower leg	sqtl	1.8e-12	-0.86	X:47566536:C:T
Skin Sun Exposed Lower leg	eqtl	7.6e-10	-0.21	X:47561030:T:A
Breast Mammary Tissue	sqtl	8.2e-10	-0.99	X:47566536:C:T
Nerve Tibial	sqtl	6.4e-09	-0.73	X:47566536:C:T
Brain Spinal cord cervical c-1	eqtl	8.2e-09	+1.83	X:47972096:C:T
Artery Tibial	sqtl	1.8e-08	-0.91	X:47566536:C:T
Skin Not Sun Exposed Suprapubic	sqtl	2.0e-08	-0.79	X:47566536:C:T
Nerve Tibial	eqtl	1.8e-07	-0.12	X:47565216:C:T
Thyroid	eqtl	3.2e-07	-0.16	X:47562002:G:T
Artery Tibial	eqtl	5.0e-07	+0.37	X:47568336:G:A
Skin Not Sun Exposed Suprapubic	eqtl	1.0e-06	-0.20	X:47561030:T:A
Lung	sqtl	6.7e-06	-0.65	X:47566536:C:T
Thyroid	sqtl	9.9e-06	-0.65	X:47566536:C:T
Artery Aorta	eqtl	1.5e-05	-0.14	X:47559452:G:C
Brain Frontal Cortex BA9	eqtl	2.1e-05	-0.11	X:47563786:A:T
Breast Mammary Tissue	eqtl	2.3e-05	-0.12	X:47560580:C:A
Liver	eqtl	4.4e-05	-0.33	X:47561030:T:A
Colon Transverse	sqtl	8.6e-05	-0.92	X:47566536:C:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
196207	41.0830	1821

Top tissues by expression

showing 100 of 286 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	96.98	gold quality
granulocyte	CL:0000094	96.35	gold quality
gastrocnemius	UBERON:0001388	96.00	gold quality
body of stomach	UBERON:0001161	95.51	gold quality
apex of heart	UBERON:0002098	95.30	gold quality
body of pancreas	UBERON:0001150	95.28	gold quality
muscle of leg	UBERON:0001383	95.23	gold quality
right lobe of liver	UBERON:0001114	95.21	gold quality
mucosa of stomach	UBERON:0001199	94.89	gold quality
metanephros cortex	UBERON:0010533	94.72	gold quality
transverse colon	UBERON:0001157	94.71	gold quality
right lobe of thyroid gland	UBERON:0001119	94.67	gold quality
left uterine tube	UBERON:0001303	94.67	gold quality
left coronary artery	UBERON:0001626	94.64	gold quality
upper lobe of left lung	UBERON:0008952	94.64	gold quality
popliteal artery	UBERON:0002250	94.63	gold quality
tibial artery	UBERON:0007610	94.62	gold quality
mucosa of transverse colon	UBERON:0004991	94.60	gold quality
left lobe of thyroid gland	UBERON:0001120	94.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.57	gold quality
left adrenal gland	UBERON:0001234	94.56	gold quality
coronary artery	UBERON:0001621	94.53	gold quality
left adrenal gland cortex	UBERON:0035825	94.47	gold quality
right coronary artery	UBERON:0001625	94.46	gold quality
aorta	UBERON:0000947	94.39	gold quality
right adrenal gland	UBERON:0001233	94.38	gold quality
triceps brachii	UBERON:0001509	94.36	gold quality
right ovary	UBERON:0002118	94.25	gold quality
minor salivary gland	UBERON:0001830	94.24	gold quality
right adrenal gland cortex	UBERON:0035827	94.22	gold quality
left ovary	UBERON:0002119	94.19	gold quality
right lung	UBERON:0002167	94.17	gold quality
thoracic aorta	UBERON:0001515	94.16	gold quality
ascending aorta	UBERON:0001496	94.13	gold quality
gall bladder	UBERON:0002110	94.13	gold quality
descending thoracic aorta	UBERON:0002345	94.13	gold quality
spleen	UBERON:0002106	94.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.09	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.06	gold quality
lower esophagus	UBERON:0013473	94.05	gold quality
rectum	UBERON:0001052	94.01	gold quality
heart left ventricle	UBERON:0002084	94.01	gold quality
upper lobe of lung	UBERON:0008948	93.97	gold quality
body of uterus	UBERON:0009853	93.87	gold quality
endocervix	UBERON:0000458	93.82	gold quality
stomach	UBERON:0000945	93.76	gold quality
cardiac ventricle	UBERON:0002082	93.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.74	gold quality
adrenal cortex	UBERON:0001235	93.72	gold quality
right atrium auricular region	UBERON:0006631	93.67	gold quality
omental fat pad	UBERON:0010414	93.63	gold quality
thyroid gland	UBERON:0002046	93.60	gold quality
peritoneum	UBERON:0002358	93.60	gold quality
saliva-secreting gland	UBERON:0001044	93.39	gold quality
small intestine	UBERON:0002108	93.21	gold quality
skin of abdomen	UBERON:0001416	93.18	gold quality
leukocyte	CL:0000738	93.17	gold quality
right uterine tube	UBERON:0001302	93.17	gold quality
monocyte	CL:0000576	93.13	gold quality
skin of leg	UBERON:0001511	93.04	gold quality
lymph node	UBERON:0000029	93.03	gold quality
mononuclear cell	CL:0000842	93.00	gold quality
smooth muscle tissue	UBERON:0001135	93.00	gold quality
muscle organ	UBERON:0001630	92.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.95	gold quality
adrenal gland	UBERON:0002369	92.94	gold quality
tibial nerve	UBERON:0001323	92.93	gold quality
mouth mucosa	UBERON:0003729	92.85	gold quality
ectocervix	UBERON:0012249	92.83	gold quality
esophagus	UBERON:0001043	92.64	gold quality
heart	UBERON:0000948	92.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.52	gold quality
stromal cell of endometrium	CL:0002255	92.49	gold quality
endometrium epithelium	UBERON:0004811	92.44	gold quality
gluteal muscle	UBERON:0002000	92.41	gold quality
adenohypophysis	UBERON:0002196	92.41	gold quality
fundus of stomach	UBERON:0001160	92.32	gold quality
pancreas	UBERON:0001264	92.20	gold quality
colon	UBERON:0001155	92.14	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.91	gold quality
intestine	UBERON:0000160	91.90	gold quality
large intestine	UBERON:0000059	91.73	gold quality
blood	UBERON:0000178	91.73	gold quality
sigmoid colon	UBERON:0001159	91.71	gold quality
esophagus mucosa	UBERON:0002469	91.71	gold quality
pituitary gland	UBERON:0000007	91.63	gold quality
liver	UBERON:0002107	91.30	gold quality
lower esophagus mucosa	UBERON:0035834	91.26	gold quality
cardiac atrium	UBERON:0002081	91.22	gold quality
olfactory bulb	UBERON:0002264	90.93	silver quality
adult mammalian kidney	UBERON:0000082	90.63	gold quality
zone of skin	UBERON:0000014	90.53	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.39	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.33	gold quality
prostate gland	UBERON:0002367	90.32	gold quality
islet of Langerhans	UBERON:0000006	90.29	gold quality
vermiform appendix	UBERON:0001154	90.28	gold quality
ventricular zone	UBERON:0003053	90.28	gold quality
caecum	UBERON:0001153	90.14	gold quality
ovary	UBERON:0000992	89.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.38

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	172.2
Frontal cortex	tissue	164.0
Skeletal muscle	tissue	127.7	low
Bone marrow	tissue	96.6	medium
Tongue	tissue	79.9
Pancreas	tissue	55.7	medium
Parathyroid gland	tissue	48.8	high
Salivary gland	tissue	42.5	medium
Heart muscle	tissue	41.9	low
Stomach 1	tissue	40.0	high
Liver	tissue	39.1	medium
Lymph node	tissue	37.8	high
Spleen	tissue	37.2	medium
Duodenum	tissue	35.6	high
Thymus	tissue	35.4
Small intestine	tissue	34.8	high
Appendix	tissue	34.8	high
Colon	tissue	34.6	medium
Choroid plexus	tissue	33.9
Lung	tissue	33.7	high
Skin 1	tissue	33.6	medium
Spinal cord	tissue	33.4
Thyroid gland	tissue	33.1	high
Seminal vesicle	tissue	32.6	medium
Vagina	tissue	32.3	medium
Corpus callosum	tissue	32.1
Adipose tissue	tissue	31.8	not detected
Prostate	tissue	31.7	medium
Rectum	tissue	31.3	medium
Fallopian tube	tissue	31.0	high
Gallbladder	tissue	30.5	medium
Esophagus	tissue	30.2	medium
Adrenal gland	tissue	30.0	medium
Pituitary gland	tissue	29.9
Ovary	tissue	29.9	medium
Placenta	tissue	29.5	low
Tonsil	tissue	29.5	medium
Smooth muscle	tissue	29.2	low
Superior colliculi	tissue	29.2
Cervix	tissue	29.0	medium
Medulla oblongata	tissue	28.8
Urinary bladder	tissue	28.5	high
Substantia nigra	tissue	27.5
Endometrium 1	tissue	27.1	medium
Midbrain	tissue	25.1
Kidney	tissue	25.0	medium
Thalamus	tissue	23.3
Periaqueductal gray	tissue	22.6
Nucleus accumbens	tissue	21.8
Pons	tissue	21.6
Hypothalamus	tissue	21.2
Hippocampus	tissue	20.9	low
Locus coeruleus	tissue	20.7
Epididymis	tissue	20.1	medium
Putamen	tissue	19.2
Ventral forebrain	tissue	19.1
Olfactory bulb	tissue	18.2
Breast	tissue	17.9	medium
Septum	tissue	17.8
Cerebellum	tissue	17.4	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (48.3), Area postrema (34.9), Ventral spinal cord (33.4), Dorsal spinal cord (33.1), White matter (32.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERF, ZHX2

miRNA regulators (miRDB)

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

showing 30 of 35 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-3127-5P	97.52	65.24	786
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-1289	97.46	65.37	655

Functional genomics

Regional missense constraint (gnomAD)

ENST00000377045 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈11% 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
X:47,562,968–47,564,811	47 / 66.9	0.70	no
X:47,564,812–47,565,121	18 / 61.1	0.29	yes (p 3.5e-08)
X:47,565,122–47,567,236	154 / 133.6	1.15	no
X:47,567,237–47,571,454	170 / 281.4	0.60	no

Literature-anchored findings (GeneRIF, showing 23)

• In a two-hybrid screen of human fetal liver cDNA library, TH1 was detected as a new interaction partner of A-Raf; this specific interaction may have played a critical role in the activation of A-Raf. (PMID:11952167)
• A-Raf kinase is negatively regulated by trihydrophobin 1 (PMID:14684750)
• mutation analysis of the conserved regions in the ARAF gene in human colorectal adenocarcinoma (PMID:14688025)
• A-Raf residues are identified that bind to specific phosphoinositides, possibly as a mechanism to localize the enzyme to particular membrane microdomains rich in these phospholipids. (PMID:15736953)
• These data reveal that B-RAF is an important mediator of neuronal survival, migration, and dendrite formation and that A-RAF cannot fully compensate for these functions. (PMID:16980614)
• Positive regulation of A-RAF by phosphorylation of isoform-specific hinge segment and identification of novel phosphorylation sites. (PMID:18662992)
• hnRNP H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. (PMID:20145135)
• study investigated role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors; ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and regulate cell signaling in a subtle manner to ensure signaling efficiency (PMID:22926515)
• Ras pathway activation via EGF treatment induced strong binding between B-Raf and C-Raf and a low level of binding between B-Raf and A-Raf. (PMID:23352452)
• show that Araf antagonizes mesendoderm induction and patterning activity of Nodal/Smad2 signals in vertebrate embryos by directly inhibiting Smad2 signalling (PMID:23591895)
• Galpha12-ARAF-ERK pathway stimulates RFFL transcription through the transcription factor c-Myc. (PMID:24114843)
• The study identifies somatic activating ARAF mutations in Langerhans cell histiocytosis. (PMID:24652991)
• Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration. (PMID:25097033)
• analysis of FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma (PMID:25608663)
• Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC. (PMID:25674762)
• This review discusses the regulation of A-Raf protein expression, and the roles of A-Raf in apoptosis and cancer, with a special focus on its role in resistance to Raf inhibitors. [review] (PMID:26508523)
• The constitutive or induced re-localization of A-Raf to the plasma membrane compromises its ability to efficiently sequester and inactivate MST2, thus rendering cells susceptible to apoptosis (PMID:26891695)
• Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway. (PMID:32814086)
• ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma. (PMID:33953400)
• ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers. (PMID:35302851)
• ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1. (PMID:35613620)
• Somatic ARAF mutations in pediatric Langerhans cell histiocytosis: clinicopathologic, genetic and functional profiling. (PMID:37572153)
• A-Raf interacts with MEK1 and activates MEK1 by phosphorylation. (PMID:8621729)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	araf	ENSDARG00000054533
mus_musculus	Araf	ENSMUSG00000001127
rattus_norvegicus	Araf	ENSRNOG00000010838

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88065) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 15 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal rectum morphology	1
small thymus	1
tremors	1
weakness	1
decreased body weight	1
decreased body size	1
abnormal anxiety-related response	1
abnormal suckling behavior	1
limb grasping	1
abnormal motor coordination/balance	1
athetotic walking movements	1
abnormal muscle morphology	1
megacolon	1
abnormal limb posture	1
postnatal lethality, incomplete penetrance	1

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
Caenorhabditis elegans	Q07292	92.4%	Diamond
Caenorhabditis briggsae	Q61UC4	92.4%	Diamond
Xenopus laevis	A7J1T0	91.3%	Diamond
Arabidopsis thaliana	Q8RWL6	80.2%	Diamond
Drosophila melanogaster	P11346	66.3%	Diamond
Plasmodium berghei ANKA	A0A509AH51	53.8%	Diamond
Dictyostelium discoideum	Q55F45	52.7%	Diamond
Plasmodium falciparum 3D7	Q8IIT5	42.1%	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

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
ELK1	protein-coding	2002
CFP	protein-coding	5199
SYN1	protein-coding	6853
TIMP1	protein-coding	7076
MIR4769	ncRNA	100616147
LINC01560	ncRNA	203414
ZNF41	protein-coding	7592
ZNF157	protein-coding	7712

Protein

Protein identifiers

Serine/threonine-protein kinase A-Raf — P10398 (reviewed: P10398)

Alternative names: Proto-oncogene A-Raf, Proto-oncogene A-Raf-1, Proto-oncogene Pks

All UniProt accessions (2): A0A024R178, P10398

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May also regulate the TOR signaling cascade. Phosphorylates PFKFB2. Serves as a positive regulator of myogenic differentiation by inducing cell cycle arrest, the expression of myogenin and other muscle-specific proteins, and myotube formation.

Subunit / interactions. Interacts with TH1L/NELFD.

Tissue specificity. Predominantly in urogenital tissues.

Post-translational modifications. Dephosphorylation of Ser-214 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.

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

Miscellaneous. Has a wider tissue distribution than isoform 1, and acts as a dominant-negative antagonist.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P10398-1	1	yes
P10398-2	2, DA-Raf1

RefSeq proteins (3): NP_001243125, NP_001243126, NP_001645* (*=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)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. 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
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	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 (72 total): helix 18, strand 16, binding site 10, modified residue 9, sequence conflict 4, sequence variant 3, domain 2, splice variant 2, region of interest 2, turn 2, chain 1, zinc finger region 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

7 structures by resolution:

PDB	Title	Method	Resolution (Å)
8VSL	Binary structure of 14-3-3 sigma and ARAF phosphopeptide (pS214)	X-RAY DIFFRACTION	1.42
8VSM	Ternary structure of 14-3-3 sigma, ARAF phosphopeptide (pS214) and compound 78 (1124378)	X-RAY DIFFRACTION	1.5
8VSN	Ternary structure of 14-3-3 sigma, ARAF phosphopeptide (pS214) and compound 79 (1124379)	X-RAY DIFFRACTION	1.91
9AXM	Crystal structure of ARAF/MEK1 complex with NST-628 and a RAF dimer	X-RAY DIFFRACTION	2.42
9ZDQ	Cryo-EM structure of ARAF-MEK1 complex with GDC-0879 and a covalent MEK inhibitor …	ELECTRON MICROSCOPY	2.51
1WXM	Solution Structure of the N-terminal Ras-binding Domain (RBD) in Human a-Raf Kinase	SOLUTION NMR
2MSE	NMR data-driven model of GTPase KRas-GNP:ARafRBD complex tethered to a lipid-bilayer …	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10398-F1	70.99	0.34

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, TKL Ser/Thr protein kinases, Predicted intracellular proteins, Plasma proteins, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane

Antibody reliability (HPA): IH approved · 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 (1)

Position	Role
429	proton acceptor

Ligand- & substrate-binding residues (10)

Position	Role
115	Zn(2+)
125	Zn(2+)
128	Zn(2+)
133	Zn(2+)
136	Zn(2+)
144	Zn(2+)
316–324	ATP
336	ATP
99	Zn(2+)
112	Zn(2+)

Post-translational modifications (9)

Type	Positions
Phosphoserine	157, 162, 186, 214, 257, 269
Phosphothreonine	181, 253, 318

Function

Pathways and Gene Ontology

Reactome pathways

11 curated (TAS) of 20; 13 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

20 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-5675221	Negative regulation of MAPK pathway	curated
R-HSA-5673000	RAF activation	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-5683057	MAPK family signaling cascades	—
R-HSA-5684996	MAPK1/MAPK3 signaling	—
R-HSA-5673001	RAF/MAP kinase cascade	—
R-HSA-162582	Signal Transduction	—

MSigDB gene sets: 261 (showing top): GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, KEGG_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PEPTIDYL_SERINE_PHOSPHORYLATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, KEGG_PATHWAYS_IN_CANCER, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, KEGG_PROSTATE_CANCER, KEGG_RENAL_CELL_CARCINOMA, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, MORF_PML, KEGG_COLORECTAL_CANCER

GO Biological Process (8): MAPK cascade (GO:0000165), regulation of TOR signaling (GO:0032006), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), positive regulation of peptidyl-serine phosphorylation (GO:0033138), protein modification process (GO:0036211), negative regulation of apoptotic process (GO:0043066), protein phosphorylation (GO:0006468), signal transduction (GO:0007165)

GO Molecular Function (11): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), zinc ion binding (GO:0008270), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Oncogenic MAPK signaling	7
RAF/MAP kinase cascade	3
Signaling by MRAS-complex mutants	2
Signaling by RAS mutants	1
Disease	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

43 GO namespaces:

Category	Terms
protein kinase activity	2
cellular anatomical structure	2
cytoplasm	2
intracellular signaling cassette	1
TOR signaling	1
regulation of intracellular signal transduction	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
protein metabolic process	1
macromolecule modification	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
phosphorylation	1
protein modification process	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
MAPK cascade	1
protein serine/threonine kinase activity	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
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of apoptotic process	BP	direct assay
positive regulation of peptidyl-serine phosphorylation	BP	direct assay
regulation of TOR signaling	BP	mutant phenotype
regulation of proteasomal ubiquitin-dependent protein catabolic process	BP	mutant phenotype
plasma membrane	CC	direct assay
protein serine/threonine kinase activity	MF	direct assay

Protein interactions and networks

IntAct

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

showing 30 of 52 partners by confidence:

Partner	Interaction type	MIscore	Records
MAP2K2	physical association	0.910	4
YWHAG	physical association	0.910	2
YWHAZ	association	0.900	3
BRAF	proximity	0.890	3
HRAS	direct interaction	0.850	3
HSP90AB1	association	0.810	6
YWHAE	physical association	0.810	4
SFN	physical association	0.760	2
RAF1	association	0.640	2
PIK3R1	direct interaction	0.610	3
SMAD4	physical association	0.550	6
NELFCD	physical association	0.550	5
TIMM50	physical association	0.550	3
BAG2	association	0.530	2
PKM	physical association	0.520	2
IRAK2	physical association	0.500	1
IRF7	physical association	0.500	1
TIRAP	physical association	0.500	1
HERC2	physical association	0.400	2
TCOF1	physical association	0.400	1
ASS1	physical association	0.370	4
PRPF6	physical association	0.370	4
COPS3	physical association	0.370	3
CPS1	physical association	0.370	3
EFEMP1	physical association	0.370	3
NUDT14	physical association	0.370	3
PBK	physical association	0.370	3
RABGGTB	physical association	0.370	3
RRAS2	physical association	0.370	3
TIMM44	physical association	0.370	3

BioGRID (544 interactions; top human partners by supporting records): YWHAG (Affinity Capture-MS; 11 records), YWHAZ (Affinity Capture-MS; 10 records), MAP2K2 (Affinity Capture-MS; 9 records), YWHAH (Affinity Capture-MS; 9 records), CDC37 (Affinity Capture-MS; 8 records), YWHAB (Affinity Capture-MS; 8 records), BRAF (Co-localization; 7 records), MAP2K1 (Affinity Capture-MS; 7 records), YWHAE (Affinity Capture-MS; 7 records), YWHAQ (Affinity Capture-MS; 6 records), FKBP5 (Affinity Capture-MS; 5 records), HSP90AA1 (Affinity Capture-MS; 5 records), KRAS (Two-hybrid; 5 records), NELFCD (Two-hybrid; 5 records), NONO (Affinity Capture-MS; 4 records)

SIGNOR signaling

showing 13 of 15 signaling interactions:

A	Effect	B	Mechanism
2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol	down-regulates	ARAF	“chemical inhibition”
ARAF	up-regulates	MAP2K2	phosphorylation
HRAS	up-regulates	ARAF	binding
NRAS	up-regulates	ARAF	binding
ARAF	up-regulates	MAP2K1	phosphorylation
PAK1	up-regulates	ARAF	phosphorylation
ARAF	up-regulates	MEK1/2	phosphorylation
ARAF	“up-regulates activity”	SLC9A3R2	phosphorylation
KSR2	“up-regulates activity”	ARAF	binding
KSR1	“up-regulates activity”	ARAF	binding
ARAF	“down-regulates quantity by destabilization”	SMAD2	phosphorylation
SRC	up-regulates	ARAF	phosphorylation
SRC	“up-regulates activity”	ARAF	phosphorylation

Protein complexes (CORUM) (2)

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

2 complexes by size:

Complex	Subunits	Members
ARAF-MITF complex	2	ARAF, MITF
ARAF-PIK3R1 complex	2	ARAF, PIK3R1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 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	5	77.7×	1e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	68.5×	1e-06
Activation of BH3-only proteins	5	50.7×	6e-06
FOXO-mediated transcription	5	34.3×	2e-05
Intrinsic Pathway for Apoptosis	5	29.9×	4e-05
SARS-CoV-1-host interactions	6	21.5×	2e-05
TP53 Regulates Metabolic Genes	7	18.5×	1e-05
SARS-CoV-1 Infection	6	17.5×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	5	24.3×	5e-04
regulation of protein localization	5	20.1×	8e-04
MAPK cascade	5	15.0×	1e-03
intracellular protein localization	6	12.3×	1e-03
positive regulation of ERK1 and ERK2 cascade	6	10.0×	2e-03
protein phosphorylation	7	9.3×	1e-03
protein stabilization	7	9.2×	1e-03
negative regulation of apoptotic process	9	6.1×	1e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ARAF has recently become increasingly considered for its oncogenic potential. Its potential as a target for informing clinical action was demonstrated by a single case of advanced lung adenocarcinoma harboring an S214C mutation that, when treated with sorafenib, acheived near-complete clinical remission. This finding has brought new focus on ARAF as a marker that should be assayed for in cancer treatment.

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — CHOL, LUAD, SCLC.

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 ARAF: 116 ClinVar records (4 pathogenic / likely pathogenic); 4 CIViC cancer variants. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	45
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (4)

Showing all 4 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
3391953	GRCh37/hg19 Xp11.3-11.23(chrX:44182604-47607117)x1	Pathogenic	criteria provided, single submitter	1
148196	GRCh38/hg38 Xp11.3-11.23(chrX:44765664-49343053)x3	Likely pathogenic	no assertion criteria provided	1
155022	GRCh38/hg38 Xp11.3-11.23(chrX:44632305-47607180)x2	Likely pathogenic	no assertion criteria provided	1
442436	GRCh37/hg19 Xp11.3-11.23(chrX:46326268-48801984)x2	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ARAF’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.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 1,461):

Position(s)	Effect	Δscore	Sites
X:47563330–47563331	donor_loss	1.0000	4
X:47564785	acceptor_gain	1.0000	2
X:47564795	acceptor_loss	1.0000
X:47566781–47566782	donor_loss	1.0000	5
X:47567126	donor_gain	1.0000
X:47568716–47568717	acceptor_loss	1.0000	6
X:47569875	acceptor_gain	1.0000
X:47569880	acceptor_gain	1.0000
X:47569891–47569892	acceptor_loss	1.0000	3
X:47570025	donor_loss	1.0000	2

AlphaMissense

2,028 missense substitutions predicted likely pathogenic (of 3,964 scored), across 409 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
M370	9	0.975	0.998
M473	9	0.968	0.994
M417	9	0.963	1.000
D447	8	1.000	1.000
H363	8	0.999	1.000
D429	8	0.999	1.000
F448	8	0.999	1.000
D491	8	0.999	1.000
H99	8	0.998	1.000
H133	8	0.998	1.000
H421	8	0.998	1.000
H427	8	0.998	1.000
F436	8	0.997	1.000
F369	8	0.996	1.000
F351	8	0.995	1.000
F560	8	0.995	0.999
H395	8	0.989	0.999
F132	8	0.987	1.000
D418	8	0.976	0.995
N434	8	0.976	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.98e-05

Disease associations

OMIM: gene MIM:311010 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
diffuse lymphatic malformation	Limited	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
Segmental overgrowth disorders - Deep sequencing	green
Mosaic skin disorders - Deep sequencing	amber

Mondo (1): diffuse lymphatic malformation (MONDO:0015408)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1169596 (SINGLE PROTEIN), CHEMBL3559685 (PROTEIN FAMILY)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ARAF 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.

1 curated-mechanism drugs:

Drug	Modality	Max phase
LY-3009120	Small molecule	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 ARAF — the drug acts on the assembly or class, not necessarily on this subunit alone.

2 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
TOVORAFENIB	RAF serine/threonine protein kinase	3	4
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: 121,910 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

9 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2028663	DABRAFENIB	4	13,060
CHEMBL1336	SORAFENIB	4	87,476
CHEMBL1229517	VEMURAFENIB	4	16,487
CHEMBL4583691	NAPORAFENIB	3	1,253
CHEMBL206834	BAFETINIB	2	1,086
CHEMBL3977543	BELVARAFENIB	2	718
CHEMBL5095099	EXARAFENIB	2	52
CHEMBL1738757	REBASTINIB	2	1,567
CHEMBL3577124	LY-3009120	1	211

Clinical evidence (CIViC)

Drug × variant × indication, from 4 curated evidence items; also 3 oncogenic, 1 functional. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

3 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
ARAF S214C	Sorafenib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID17 +1
BRAF V600E AND ARAF S490T	Cetuximab + Vemurafenib + Irinotecan	Colorectal Cancer	Resistance	CIViC C	EID1905
ARAF S214C	Trametinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID41

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.

1 CIViC assertions:

Molecular profile	Disease	Therapy	Type	AMP tier	Significance
ARAF S214F	Cancer		Oncogenic		Likely Oncogenic

CIViC curated variants (4)

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

S214C (missense variant), S214F, V145L, S490T (missense variant).

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — RAF family

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
exarafenib	Inhibition	8.62	pIC50
lifirafenib	Inhibition	8.25	pIC50
LY3009120	Inhibition	7.36	pIC50

Binding affinities (BindingDB)

145 measured of 540 human assays (541 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.2 nM	US-10709712: Biaryl amide compounds as kinase inhibitors
CHEMBL4060057	IC50	0.7 nM
5-[[(1S,1aR,6bS)-1-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-5-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one	IC50	1.2 nM	US-10576087: Fused tricyclic compounds as Raf kinase inhibitors
CHEMBL4466555	IC50	2.6 nM
CHEMBL4438236	IC50	2.7 nM
4-[4-[(5-tert-butyl-2-quinolin-6-ylpyrazol-3-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	IC50	5.5 nM
CHEMBL4080362	IC50	6.3 nM
CHEMBL4066939	IC50	8.5 nM
5-[[(1R,1aS,6bR)-1-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-5-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one	IC50	8.8 nM	US-10576087: Fused tricyclic compounds as Raf kinase inhibitors
CHEMBL4075036	IC50	13 nM
CHEMBL4282601	IC50	13 nM
CHEMBL4104590	IC50	14 nM
CHEMBL4289810	IC50	18 nM
CHEMBL4087837	IC50	19 nM
PLX-4032	IC50	19 nM
1-(3,3-dimethylbutyl)-3-[4-fluoro-3-[2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl]phenyl]urea	IC50	20 nM	US-9187474: Raf inhibitor compounds
CHEMBL4085294	IC50	21 nM
CHEMBL4082425	IC50	22 nM
CHEMBL4586402	IC50	32 nM
CHEMBL4060531	IC50	35 nM
CHEMBL4101882	IC50	43 nM
4-amino-N-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	44 nM	US-9156852: Thieno[3,2-D]pyrimidine derivatives having inhibitory activity for protein kinases
(S)-N-(3-(2-(((R)-1-hydroxypropan-2- yl)amino)-6-morpholinopyridin-4-yl)-4- methylphenyl)-3-(2,2,2- trifluoroethyl)pyrrolidine-1-carboxamide	IC50	107 nM
1-(3-fluoro-3-methylbutyl)-3-[2-fluoro-4-methyl-5-[2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl]phenyl]urea	IC50	170 nM	US-9187474: Raf inhibitor compounds
CHEMBL4436132	IC50	182 nM
G6416 (GW5074)	IC50	279 nM
N-[5-[2-(2-acetamido-4-pyridinyl)-6-propan-2-yloxy-4-pyridinyl]-2-fluoro-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[6-cyclopropyl-4-[2-methyl-5-[[2-(trifluoromethyl)pyridine-4-carbonyl]amino]phenyl]-2-pyridinyl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-[3-[2-(2-acetamido-4-pyridinyl)-6-(2-hydroxypropan-2-yl)-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-[3-[2-(2-amino-4-pyridinyl)-1-methyl-6-oxo-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[2-ethoxy-5-[2-methyl-5-[[2-(trifluoromethyl)pyridine-4-carbonyl]amino]phenyl]-3-pyridinyl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-[3-[5-[2-(cyclopropanecarbonylamino)-4-pyridinyl]-6-ethoxy-3-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[4-[5-[[2-(2-cyanopropan-2-yl)-4-pyridinyl]carbamoyl]-2-methylphenyl]-2-pyridinyl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-methyl-4-[6-[2-methyl-5-[(1-propan-2-ylpyrazol-4-yl)carbamoyl]phenyl]pyrazin-2-yl]pyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-[3-[5-(2-acetamido-4-pyridinyl)-1-(2-hydroxyethyl)-6-oxo-3-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
2-(2-cyanopropan-2-yl)-N-[6-methyl-5-[3-(6-oxo-5,7-dihydropyrrolo[2,3-d]pyrimidin-4-yl)phenyl]-3-pyridinyl]pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
2-(2-cyanopropan-2-yl)-N-[5-[3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl]-6-methyl-3-pyridinyl]pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-[5-[5-(2-acetamido-4-pyridinyl)-1-methyl-6-oxo-3-pyridinyl]-2-fluoro-4-methylphenyl]-2-(2-cyanopropan-2-yl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-[3-[6-[2-(2-methoxyethylamino)-4-pyridinyl]pyrazin-2-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
2-(2-cyanopropan-2-yl)-N-[4-methyl-3-[3-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]phenyl]pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
6-[(dimethylamino)methyl]-N-[4-methyl-3-[6-[2-(methylcarbamoyl)-4-pyridinyl]pyrazin-2-yl]phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[6-[5-[[2-(2-cyanopropan-2-yl)pyridine-4-carbonyl]amino]-2-methylphenyl]pyrazin-2-yl]-N-cyclopropylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[6-[5-[[3-(2-cyanopropan-2-yl)benzoyl]amino]-2-methylphenyl]pyrazin-2-yl]-N-cyclopropylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
N-[5-[2-(2-acetamido-4-pyridinyl)-1-methyl-6-oxo-4-pyridinyl]-2-fluoro-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[4-[5-[[2-(2-cyanopropan-2-yl)pyridine-4-carbonyl]amino]-2-methyl-3-pyridinyl]-2-pyridinyl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[4-[5-[[2-(2-cyanopropan-2-yl)pyridine-4-carbonyl]amino]-2-methylphenyl]-2-pyridinyl]-N-cyclopropylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[4-[5-[[2-(2-cyanopropan-2-yl)pyridine-4-carbonyl]amino]-2-methylphenyl]-6-cyclopropyl-2-pyridinyl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[4-[5-[[2-(2-cyanopropan-2-yl)pyridine-4-carbonyl]amino]-4-fluoro-2-methylphenyl]pyrimidin-2-yl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[6-[5-[[2-(2-cyanopropan-2-yl)pyridine-4-carbonyl]amino]-4-fluoro-2-methylphenyl]pyrazin-2-yl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof
4-[4-[5-[[2-(2-cyanopropan-2-yl)pyridine-4-carbonyl]amino]-2-methyl-3-pyridinyl]pyrimidin-2-yl]-N-methylpyridine-2-carboxamide	IC50	300 nM	US-12319655: RAF kinase inhibitors and methods of use thereof

ChEMBL bioactivities

46 potent at pChembl≥5 of 48 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL4466555
8.92	IC50	1.2	nM	LY-3009120
8.68	IC50	2.1	nM	VEMURAFENIB
8.62	IC50	2.4	nM	EXARAFENIB
8.25	IC50	5.6	nM	CHEMBL4207519
8.15	IC50	7.1	nM	SORAFENIB
8.07	IC50	8.6	nM	CHEMBL4438236
7.92	IC50	12	nM	SORAFENIB
7.84	IC50	14.6	nM	GW305074X
7.75	IC50	17.8	nM	CHEMBL4060057
7.60	IC50	25.3	nM	CHEMBL4075036
7.60	IC50	25.3	nM	CHEMBL4282601
7.58	IC50	26	nM	DABRAFENIB
7.52	IC50	30.1	nM	CHEMBL4289810
7.51	IC50	31	nM	CHEMBL3891833
7.47	IC50	34.1	nM	CHEMBL4087837
7.45	IC50	35.7	nM	CHEMBL4436132
7.42	IC50	37.6	nM	CHEMBL4080362
7.39	IC50	40.7	nM	CHEMBL4104590
7.38	IC50	42.2	nM	CHEMBL4085294
7.36	IC50	44	nM	LY-3009120
7.36	IC50	43.4	nM	CHEMBL4066939
7.33	Kd	47	nM	DABRAFENIB
7.33	IC50	46.9	nM	CHEMBL4082425
7.28	IC50	52.4	nM	CHEMBL4586402
7.24	IC50	57.4	nM	CHEMBL4060531
6.92	IC50	120	nM	CHEMBL3963155
6.82	IC50	152	nM	BELVARAFENIB
6.74	IC50	183	nM	CHEMBL4542639
6.71	IC50	194	nM	CHEMBL4101882
6.68	IC50	211	nM	CHEMBL4447617
6.64	IC50	230	nM	REBASTINIB
6.56	IC50	276	nM	CHEMBL4436132
6.38	IC50	414	nM	NAPORAFENIB
6.02	IC50	950	nM	VEMURAFENIB
6.00	IC50	1000	nM	CHEMBL3934468
5.95	IC50	1130	nM	VEMURAFENIB
5.87	Kd	1339	nM	CHEMBL5653589
5.67	Kd	2138	nM	VEMURAFENIB
5.67	ED50	2149	nM	CHEMBL5653589
5.54	Kd	2893	nM	BAFETINIB
5.15	IC50	7058	nM	CHEMBL4866102
5.09	Kd	8152	nM	CHEMBL3752910

PubChem BioAssay actives

43 with measured affinity, of 364 total; 32 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
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-(7H-purin-6-yl)cyclopropanecarbonyl]amino]benzamide	1534569: Inhibition of human ARAF using MEK1 as substrate by [gamma-33P]-ATP assay	ic50	0.0010	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl]urea	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0012	uM
Vemurafenib	1480958: Inhibition of ARAF (unknown origin) 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	0.0021	uM
(3S)-N-[3-[2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide	2099113: Inhibition of ARAF (unknown origin) by ADP-Glo assay	ic50	0.0024	uM
5-[[(1S,1aR,6bS)-1-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-5-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one	1380332: Inhibition of ARAF (unknown origin)	ic50	0.0056	uM
Sorafenib	1480958: Inhibition of ARAF (unknown origin) 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	0.0071	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0086	uM
3-[(3,5-dibromo-4-hydroxyphenyl)methylidene]-5-iodo-1H-indol-2-one	1531585: Inhibition of human ARAF using MEK1 as substrate by [gamma-33P]-ATP assay	ic50	0.0146	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0178	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0253	uM
N-[3-chloro-4-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1408848: Inhibition of ARAF (unknown origin)	ic50	0.0253	uM
Dabrafenib	1226910: Competitive binding affinity to ARAF in human A375 cells after 15 mins in presence of ATP analogue	ic50	0.0260	uM
N-[3-chloro-4-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[2-[2-(4-methylpiperazin-1-yl)ethylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1408852: Inhibition of ARAF (unknown origin) after 20 mins in presence of 33P-gamma-ATP by hotspot kinase	ic50	0.0301	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-3-[[1-[6-[3-(dimethylamino)propylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]-4-methylbenzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0341	uM
4-methyl-N-[4-[(1-methylpiperidin-4-yl)methoxy]-3-(trifluoromethyl)phenyl]-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0357	uM
4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]-N-[4-[(1-methylpiperidin-4-yl)methoxy]-3-(trifluoromethyl)phenyl]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0376	uM
4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]-N-[4-(3-morpholin-4-ylpropoxy)-3-(trifluoromethyl)phenyl]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0407	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-[(1-methylpiperidin-4-yl)methylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0422	uM
4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]-N-[4-(1-methylpiperidin-4-yl)oxy-3-(trifluoromethyl)phenyl]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0434	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-(2-pyrrolidin-1-ylethylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0469	uM
4-methyl-N-[4-(1-methylpiperidin-4-yl)oxy-3-(trifluoromethyl)phenyl]-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0524	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-(2-piperidin-1-ylethylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.0574	uM
4-amino-N-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide	2116944: Inhibition of ARAF (unknown origin)	ic50	0.1520	uM
N-[4-[4-amino-3-(methylcarbamoyl)phenoxy]phenyl]-4-chloro-3-(trifluoromethyl)benzamide	1594028: Inhibition of human ARAF using human His6-tagged MEK1 (K97R) as substrate preincubated for 20 mins followed by [33P-gamma]ATP addition and measured after 2 hrs by filter-binding assay	ic50	0.1830	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[2-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (unknown origin) 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	0.1940	uM
2-amino-5-[4-[(4-methoxybenzoyl)amino]phenoxy]-N-methylbenzamide	1594028: Inhibition of human ARAF using human His6-tagged MEK1 (K97R) as substrate preincubated for 20 mins followed by [33P-gamma]ATP addition and measured after 2 hrs by filter-binding assay	ic50	0.2110	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168226: Inhibition of human ARAF preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.2300	uM
N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	2116944: Inhibition of ARAF (unknown origin)	ic50	0.4140	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147878: Binding affinity to human ARAF incubated for 45 mins by Kinobead based pull down assay	kd	1.3388	uM
4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide	1424915: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.8930	uM
6-(3-phenylmethoxyphenyl)-5-pyrimidin-4-ylimidazo[2,1-b][1,3]thiazole	1772919: Inhibition of A-RAF (unknown origin) incubated for 40 mins in presence of Mg/ATP mix by [gamma p33]-ATP based scintillation counting method	ic50	7.0580	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147878: Binding affinity to human ARAF incubated for 45 mins by Kinobead based pull down assay	kd	8.1519	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, increases expression	2
Resveratrol	affects reaction, increases activity, increases expression	2
Benzo(a)pyrene	decreases methylation, increases methylation, affects methylation, decreases expression	2
Dexamethasone	affects binding, decreases reaction, increases reaction, affects cotreatment, increases expression	2
Estradiol	increases activity, increases expression, decreases reaction	2
Valproic Acid	increases methylation, increases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects expression	1
aflatoxin B2	decreases methylation	1
coumarin	affects phosphorylation	1
avobenzone	increases expression	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Irinotecan	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzophenoneidum	increases expression	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Diclofenac	affects expression	1
Environmental Pollutants	affects expression	1
Fenbendazole	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	decreases expression	1
Methylnitronitrosoguanidine	increases expression	1

ChEMBL screening assays

92 unique, capped per target: 92 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1176703	Binding	Inhibition of ARAF at 10 uM	Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors. — *Bioorg Med Chem*

Cellosaurus cell lines

18 cell lines: 15 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2RX	Abcam HEK293T ARAF KO	Transformed cell line	Female
CVCL_B8BE	Abcam HCT 116 ARAF KO	Cancer cell line	Male
CVCL_B8SI	Abcam MCF-7 ARAF KO	Cancer cell line	Female
CVCL_B9DH	Abcam A-549 ARAF KO	Cancer cell line	Male
CVCL_D7KA	Ubigene A-549 ARAF KO	Cancer cell line	Male
CVCL_D8HF	Ubigene HCT 116 ARAF KO	Cancer cell line	Male
CVCL_D8ZD	Ubigene HEK293 ARAF KO	Transformed cell line	Female
CVCL_D9XR	Ubigene HeLa ARAF KO	Cancer cell line	Female
CVCL_SD15	HAP1 ARAF (-) 1	Cancer cell line	Male
CVCL_SD16	HAP1 ARAF (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 206 trials:

NCT	Phase	Status	Title
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	Phase 3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	Phase 1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	Phase 1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02399527	Not specified	RECRUITING	Lymphatic Anomalies Registry for the Assessment of Outcome Data
NCT03001180	Not specified	RECRUITING	Identification of Biomarkers for Patients with Vascular Anomalies
NCT03479476	Phase 2/3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	Phase 1/2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	Early Phase 1	TERMINATED	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders
NCT02862808	Not specified	COMPLETED	Molecular Diagnosis of Syndromic or Isolated Severe Intellectual Disability Using Whole Exome Sequencing : a Pilot Study
NCT02881333	Not specified	UNKNOWN	Various Type of Genetic Events in Patients With Intellectual Disability
NCT02889068	Not specified	COMPLETED	Targeted Next Generation Sequencing and Intellectual Disability
NCT02914951	Not specified	ENROLLING_BY_INVITATION	Cognitive-Behavioral Therapy for Irritability in Children With Autism Spectrum Disorder and Intellectual Disability
NCT02919826	Not specified	COMPLETED	Dialectical Behaviour Group Therapy for Adults With Intellectual Disabilities
NCT02934854	Not specified	WITHDRAWN	Biomarker for Creatine Deficiency Syndromes (BioCDS)
NCT03033797	Not specified	UNKNOWN	Augmentative and Alternative Communication in Games With Virtual Reality in Intellectual Disabilities
NCT03135236	Not specified	COMPLETED	Parents as the Primary Sexuality Educators for Their Young Adults With Down Syndrome
NCT03139760	Not specified	COMPLETED	POWERSforID: A Telehealth Weight Management System for Adults With Intellectual Disability
NCT03203226	Not specified	COMPLETED	The Feldenkrais Method for People With Intellectual Disability
NCT03212092	Not specified	COMPLETED	Reducing Aggression Among People With an Intellectual Disability
NCT03218462	Not specified	COMPLETED	Effect of Sensory Adapted Dental Environment on Dental Anxiety of Children With Intellectual and Developmental Disabilities
NCT03234231	Not specified	UNKNOWN	Supervised Brushing Programme for Intellectual Disabled Students
NCT03348124	Not specified	UNKNOWN	Prevention Among Young People With Intellectual Disability
NCT03424772	Not specified	UNKNOWN	Whole Genome Sequencing in the Detection of Rare Undiagnosed Genetic Diseases in Children in China
NCT03426059	Not specified	COMPLETED	Mapping the Phenotype in Adults With Phelan-McDermid Syndrome
NCT03492060	Not specified	RECRUITING	Longitudinal Study of Neurogenetic Disorders
NCT03501914	Not specified	COMPLETED	A Pilot Trial of Mindfulness Based Intervention Program for People With Intellectual Disabilities in a Low Income Setting

Predicted chemistry — Sugi Predict

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