EPHA6

Summary

EPHA6 (EPH receptor A6, HGNC:19296) is a protein-coding gene on chromosome 3q11.2, encoding Ephrin type-A receptor 6 (Q9UF33). Receptor tyrosine kinase which binds promiscuously GPI-anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.

Predicted to enable transmembrane-ephrin receptor activity. Predicted to be involved in axon guidance and ephrin receptor signaling pathway. Predicted to be located in membrane. Predicted to be active in dendrite and plasma membrane.

Source: NCBI Gene 285220 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 148 total
• GTEx eGene: eQTL in 9 tissues, sQTL in 1 (q < 0.05)
• ChEMBL bioactivity: 32 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.63 (unconstrained)
• MANE Select transcript: NM_001080448
• Notable: 148 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19296
Approved symbol	EPHA6
Name	EPH receptor A6
Location	3q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ35246
Ensembl gene	ENSG00000080224
Ensembl biotype	protein_coding
OMIM	600066
Entrez	285220

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000389672

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

ENST00000389672, ENST00000470610, ENST00000477384, ENST00000502694, ENST00000503760, ENST00000506349, ENST00000506569, ENST00000508345, ENST00000514100, ENST00001107654, ENST00001120908, ENST00001126399, ENST00001144971

RefSeq mRNA: 4 — MANE Select: NM_001080448 NM_001080448, NM_001278300, NM_001278301, NM_173655

CCDS: CCDS46876, CCDS54616, CCDS63697

Canonical transcript exons

ENST00000389672 — 18 exons

Exon	Start	End
ENSE00001240911	97483934	97484059
ENSE00001240916	97479294	97479364
ENSE00001379960	96866825	96866889
ENSE00001506609	97747423	97747572
ENSE00001506610	97735925	97736118
ENSE00001506613	97405150	97405274
ENSE00001506614	97243952	97244287
ENSE00001506615	97226264	97226419
ENSE00001547374	96987330	96987993
ENSE00001748047	97610793	97610854
ENSE00001890551	96814594	96815008
ENSE00002031193	97748587	97761532
ENSE00002185698	97532358	97532543
ENSE00002389452	97720261	97720410
ENSE00002428001	97637873	97638082
ENSE00003602369	97448568	97448730
ENSE00003606306	97592612	97592737
ENSE00003619005	97475352	97475460

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 84.88.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8955 / max 132.8861, expressed in 388 samples.

Highest expression (Bgee): testis, sperm, male germ line stem cell (sensu Vertebrata) in testis, cortical plate, primordial germ cell in gonad.

Genetic regulation across tissues (GTEx eQTL / sQTL)

EPHA6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

10 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Muscularis	eqtl	8.7e-51	+0.79	3:96335388:T:C
Esophagus Gastroesophageal Junction	eqtl	1.7e-17	+0.55	3:96335388:T:C
Testis	sqtl	2.2e-14	-1.18	3:97620805:A:C
Artery Aorta	eqtl	5.1e-06	+0.26	3:96224065:T:C
Testis	eqtl	9.8e-05	-0.10	3:97645378:C:A
Thyroid	eqtl	3.6e-03	+0.22	3:96962152:G:GA
Artery Tibial	eqtl	6.0e-03	-0.44	3:97068292:G:A
Nerve Tibial	eqtl	2.3e-02	-0.74	3:96607766:C:G
Brain Caudate basal ganglia	eqtl	3.2e-02	-0.75	3:96161398:G:GT
Esophagus Mucosa	eqtl	4.6e-02	+0.85	3:97018677:T:C

FANTOM5 promoters

9 alternative TSS:

Promoter ID	TPM avg	Samples expressed
37501	1.1614	308
37500	0.2575	139
37499	0.2258	128
37502	0.2008	84
37504	0.0156	2
202851	0.0128	6
37505	0.0082	3
37503	0.0081	3
37508	0.0053	3

Top tissues by expression

showing 100 of 251 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	84.88	gold quality
right testis	UBERON:0004534	84.27	gold quality
sperm	CL:0000019	83.76	gold quality
testis	UBERON:0000473	82.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.85	gold quality
cortical plate	UBERON:0005343	78.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	70.85	gold quality
stromal cell of endometrium	CL:0002255	69.89	gold quality
calcaneal tendon	UBERON:0003701	69.00	gold quality
prefrontal cortex	UBERON:0000451	68.46	gold quality
left ovary	UBERON:0002119	68.01	gold quality
nucleus accumbens	UBERON:0001882	67.67	gold quality
ventricular zone	UBERON:0003053	67.01	gold quality
caudate nucleus	UBERON:0001873	66.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.54	gold quality
cerebellar cortex	UBERON:0002129	65.49	gold quality
cerebellar hemisphere	UBERON:0002245	65.38	gold quality
putamen	UBERON:0001874	64.96	gold quality
corpus callosum	UBERON:0002336	64.46	gold quality
anterior cingulate cortex	UBERON:0009835	64.34	gold quality
smooth muscle tissue	UBERON:0001135	63.82	gold quality
cerebellum	UBERON:0002037	63.82	gold quality
colonic epithelium	UBERON:0000397	63.49	gold quality
ganglionic eminence	UBERON:0004023	63.13	gold quality
ovary	UBERON:0000992	63.08	gold quality
right frontal lobe	UBERON:0002810	63.00	gold quality
tibialis anterior	UBERON:0001385	62.94	silver quality
amygdala	UBERON:0001876	62.88	gold quality
Brodmann (1909) area 9	UBERON:0013540	62.67	gold quality
pancreatic ductal cell	CL:0002079	62.55	silver quality
neocortex	UBERON:0001950	62.14	gold quality
right ovary	UBERON:0002118	62.08	gold quality
frontal cortex	UBERON:0001870	61.81	gold quality
ileal mucosa	UBERON:0000331	61.65	silver quality
gall bladder	UBERON:0002110	61.57	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	60.22	gold quality
lower esophagus mucosa	UBERON:0035834	59.61	gold quality
tendon	UBERON:0000043	59.09	gold quality
cerebral cortex	UBERON:0000956	58.71	gold quality
brain	UBERON:0000955	58.05	gold quality
forebrain	UBERON:0001890	57.99	gold quality
sural nerve	UBERON:0015488	57.60	silver quality
rectum	UBERON:0001052	57.54	gold quality
deltoid	UBERON:0001476	56.72	gold quality
urinary bladder	UBERON:0001255	56.66	gold quality
ectocervix	UBERON:0012249	56.43	gold quality
colon	UBERON:0001155	55.79	gold quality
endocervix	UBERON:0000458	55.78	gold quality
uterine cervix	UBERON:0000002	55.76	gold quality
thyroid gland	UBERON:0002046	55.54	gold quality
left lobe of thyroid gland	UBERON:0001120	55.42	gold quality
hypothalamus	UBERON:0001898	55.34	gold quality
large intestine	UBERON:0000059	55.29	gold quality
bone marrow cell	CL:0002092	55.25	silver quality
Ammon’s horn	UBERON:0001954	55.22	gold quality
lower esophagus	UBERON:0013473	55.01	gold quality
epithelial cell of pancreas	CL:0000083	54.96	gold quality
lower esophagus muscularis layer	UBERON:0035833	54.96	gold quality
islet of Langerhans	UBERON:0000006	54.80	gold quality
esophagus	UBERON:0001043	54.39	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
right lobe of thyroid gland	UBERON:0001119	54.09	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
right uterine tube	UBERON:0001302	53.80	gold quality
esophagus mucosa	UBERON:0002469	53.64	gold quality
descending thoracic aorta	UBERON:0002345	53.58	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
adult organism	UBERON:0007023	53.50	silver quality
temporal lobe	UBERON:0001871	53.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	53.30	gold quality
intestine	UBERON:0000160	52.95	gold quality
adrenal tissue	UBERON:0018303	52.64	gold quality
thoracic aorta	UBERON:0001515	52.50	gold quality
primary visual cortex	UBERON:0002436	52.42	gold quality
female reproductive system	UBERON:0000474	52.24	gold quality
ascending aorta	UBERON:0001496	52.24	gold quality
prostate gland	UBERON:0002367	51.55	gold quality
vagina	UBERON:0000996	51.40	gold quality
metanephros cortex	UBERON:0010533	51.17	gold quality
aorta	UBERON:0000947	50.88	gold quality
endometrium	UBERON:0001295	50.79	gold quality
fallopian tube	UBERON:0003889	50.58	gold quality
myocardium	UBERON:0002349	50.25	gold quality
hindlimb stylopod muscle	UBERON:0004252	50.06	gold quality
popliteal artery	UBERON:0002250	49.78	gold quality
tibial artery	UBERON:0007610	49.75	gold quality
uterus	UBERON:0000995	49.73	gold quality
occipital lobe	UBERON:0002021	49.26	gold quality
metanephros	UBERON:0000081	49.13	gold quality
fundus of stomach	UBERON:0001160	48.56	gold quality
anatomical system	UBERON:0000467	48.42	gold quality
mucosa of stomach	UBERON:0001199	48.38	gold quality
material anatomical entity	UBERON:0000465	48.33	gold quality
multicellular organism	UBERON:0000468	48.31	gold quality
substantia nigra	UBERON:0002038	48.24	gold quality
apex of heart	UBERON:0002098	48.19	gold quality
transverse colon	UBERON:0001157	47.99	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	47.88	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	99.08
E-HCAD-25	yes	37.97
E-ANND-3	yes	7.32
E-MTAB-6142	no	22.64
E-ENAD-27	no	3.94

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 66 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Nucleus accumbens	tissue	56.9
Postcentral gyrus	tissue	52.3
Hippocampus	tissue	45.0
Hippocampal formation	tissue	45.0
Ventral forebrain	tissue	27.0
Cerebral cortex	tissue	26.5
Occipital cortex	tissue	26.5
Amygdala	tissue	26.1
Septum	tissue	26.0
Olfactory bulb	tissue	22.9
Temporal cortex	tissue	22.9
Superior colliculi	tissue	22.6
Thalamus	tissue	22.4
Entorhinal cortex	tissue	18.2
Motor cortex	tissue	16.6
Midbrain	tissue	16.5
Retrosplenial cortex	tissue	16.4
Basal ganglia	tissue	16.0
Putamen	tissue	15.7
Somatosensory cortex	tissue	15.6
Retrosplenial and cingulate cortex	tissue	13.6
Prefrontal cortex	tissue	13.3
Insular cortex	tissue	13.2
Substantia nigra	tissue	12.6
Pons	tissue	12.3
Locus coeruleus	tissue	12.2
Hypothalamus	tissue	11.1
Medulla oblongata	tissue	9.7
Periaqueductal gray	tissue	9.5
Caudate putamen	tissue	9.3
Frontal cortex	tissue	7.9
Testis	tissue	7.7
Ovary	tissue	3.8
Spinal cord	tissue	3.6
Cerebellum	tissue	2.0
Thyroid gland	tissue	1.8
Fallopian tube	tissue	1.8
Choroid plexus	tissue	1.7
Corpus callosum	tissue	1.6
Smooth muscle	tissue	1.3
Urinary bladder	tissue	1.3
Retina	tissue	1.0
Prostate	tissue	0.9
Esophagus	tissue	0.8
Endometrium 1	tissue	0.8
Gallbladder	tissue	0.8
Cervix	tissue	0.7
Vagina	tissue	0.6
Seminal vesicle	tissue	0.6
Rectum	tissue	0.6
Pancreas	tissue	0.5
Colon	tissue	0.4
Kidney	tissue	0.4
Heart muscle	tissue	0.3
Epididymis	tissue	0.3
Small intestine	tissue	0.3
Breast	tissue	0.2
Adipose tissue	tissue	0.2
Thymus	tissue	0.2
Pituitary gland	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Cerebellar cortex (83.0), Flocculonodular lobe (81.6), Vermis (78.0), Hippocampus, CA1 (54.9), Caudate nucleus (53.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXA13

miRNA regulators (miRDB)

Targeting EPHA6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 43 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-657	99.48	66.02	848
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-3611	98.76	68.76	1290

Functional genomics

gnomAD constraint: pLI 6.03e-05, LOEUF 0.633, missense Z 1.68 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000389672 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:96,814,624–96,866,827	220 / 171.5	1.28	no
3:96,866,828–97,720,276	878 / 999.7	0.88	no
3:97,720,277–97,736,011	37 / 92.9	0.40	no
3:97,736,012–97,748,698	145 / 153.3	0.95	no

Literature-anchored findings (GeneRIF, showing 6)

• During development of the retinal vasculature, migration of ligand-bearing astrocytes is slowed along Eph-A6 expression gradient through repellent Eph-A6 - ephrin-A1 and -A4 signaling. (PMID:20011078)
• Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. (PMID:25583493)
• EphA6 mRNA expression is higher in 112 CaP tumor samples compared with benign tissues from 58 benign prostate hyperplasia patients. Positive correlation was identified between EphA6 expression and vascular invasion, neural invasion, PSA level, and TNM staging in CaP cases. (PMID:26041887)
• Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy…This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy (PMID:27582484)
• The EPHA6 rs4857055 C > T SNP is a novel candidate gene for hypertension in the Korean population. (PMID:29208002)
• our data imply that EPHA6 expression is beneficial for glioblastoma multiforme inhibition, particularly in combination with activation of BMP-2 signaling.These results suggest that EPHA6 expression or protein levels could be used as biomarkers for identification of subsets of glioblastoma multiforme patients who might benefit from BMP treatment. (PMID:31483918)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	epha6	ENSDARG00000022971
mus_musculus	Epha6	ENSMUSG00000055540
rattus_norvegicus	Epha6	ENSRNOG00000029184

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715), RET (ENSG00000165731), AXL (ENSG00000167601), ROR2 (ENSG00000169071), ALK (ENSG00000171094), INSR (ENSG00000171105), ERBB4 (ENSG00000178568), CSF1R (ENSG00000182578), EPHB3 (ENSG00000182580), EPHA10 (ENSG00000183317), ROR1 (ENSG00000185483), EPHB4 (ENSG00000196411), NTRK1 (ENSG00000198400), DDR1 (ENSG00000204580)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:108034) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal liver morphology	1
enlarged liver	1
abnormal spleen morphology	1
abnormal cued conditioning behavior	1
abnormal spatial learning	1
abnormal contextual conditioning behavior	1
abnormal skin morphology	1
abnormal kidney morphology	1
abnormal epididymis morphology	1
enlarged epididymis	1
abnormal inhibitory learning	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
Pan troglodytes	P0C0K6	99.3%	Diamond
Macaca fascicularis	Q1KL86	98.0%	Diamond
Xenopus laevis	Q91694	98.0%	Diamond
Gallus gallus	O42422	97.5%	Diamond
Coturnix japonica	Q90344	96.6%	Diamond
Caenorhabditis elegans	O61460	51.7%	Diamond
Drosophila melanogaster	P83097	32.9%	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
CRYBG3	protein-coding	131544
ARL6	protein-coding	84100
RIOX2	protein-coding	84864
GABRR3	protein-coding	200959

Protein

Protein identifiers

Ephrin type-A receptor 6 — Q9UF33 (reviewed: Q9UF33)

Alternative names: EPH homology kinase 2, EPH-like kinase 12

All UniProt accessions (7): A0A0B4J1T8, B4DXM2, E7EU71, Q9UF33, H0Y8K5, H0Y9V0, J3KR66

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase which binds promiscuously GPI-anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling.

Subunit / interactions. Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts (via SAM domain) with ANKS1A (via SAM domain).

Subcellular location. Membrane.

Tissue specificity. Expressed in brain and testis.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UF33-1	1	yes
Q9UF33-2	2
Q9UF33-3	3

RefSeq proteins (4): NP_001073917, NP_001265229, NP_001265230, NP_775926 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001090	EPH_LBD	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001426	Tyr_kinase_rcpt_V_CS	Conserved_site
IPR001660	SAM	Domain
IPR003961	FN3_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011641	Tyr-kin_ephrin_A/B_rcpt-like	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016257	EPH	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR027936	EPH_TM	Domain
IPR034280	EphA6_rcpt_lig-bd	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR042746	EPH-A6_SAM	Domain
IPR050449	Ephrin_rcpt_TKs	Family

Pfam: PF00041, PF00536, PF01404, PF07699, PF07714, PF14575, PF25599

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (29 total): splice variant 6, domain 5, modified residue 4, glycosylation site 3, binding site 2, topological domain 2, sequence variant 2, signal peptide 1, chain 1, short sequence motif 1, active site 1, transmembrane region 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UF33-F1	78.90	0.44

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Tyr protein kinases, Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mid piece

Antibody reliability (HPA): IH uncertain · IF approved

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
798	proton acceptor

Ligand- & substrate-binding residues (2)

Position	Role
637–645	ATP
663	ATP

Post-translational modifications (4)

Type	Positions
Phosphotyrosine	606, 612, 831, 978

Glycosylation sites (3)

Type	Positions
N-linked (glcnac…) asparagine	343, 397, 410

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-422475	Axon guidance	—
R-HSA-1266738	Developmental Biology	—
R-HSA-2682334	EPH-Ephrin signaling	electronic
R-HSA-3928665	EPH-ephrin mediated repulsion of cells	electronic
R-HSA-3928663	EPHA-mediated growth cone collapse	electronic
R-HSA-9675108	Nervous system development	—

MSigDB gene sets: 88 (showing top): GOBP_NEUROGENESIS, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_IL3RA, GOBP_EPHRIN_RECEPTOR_SIGNALING_PATHWAY, GOMF_TRANSMEMBRANE_RECEPTOR_PROTEIN_KINASE_ACTIVITY, GOCC_NEURON_PROJECTION, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY, GOCC_SOMATODENDRITIC_COMPARTMENT, PID_EPHA_FWDPATHWAY, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_EPHRIN_RECEPTOR_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING

GO Biological Process (4): axon guidance (GO:0007411), ephrin receptor signaling pathway (GO:0048013), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169)

GO Molecular Function (10): transmembrane-ephrin receptor activity (GO:0005005), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), ephrin receptor activity (GO:0005003), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): plasma membrane (GO:0005886), dendrite (GO:0030425), membrane (GO:0016020)

Reactome top-level categories

4 top-level categories:

Category	Pathways
EPH-Ephrin signaling	2
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

28 GO namespaces:

Category	Terms
axonogenesis	1
neuron projection guidance	1
cell surface receptor protein tyrosine kinase signaling pathway	1
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
ephrin receptor activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein kinase activity	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
transmembrane receptor protein tyrosine kinase activity	1
ephrin receptor signaling pathway	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
cellular anatomical structure	1

Protein interactions and networks

STRING

showing 17 of 644 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHA6	KRT1	P04264	717
EPHA6	KRT10	P13645	717
EPHA6	EFNA5	P52803	625
EPHA6	EFNA1	P20827	575
EPHA6	EFNA2	O43921	565
EPHA6	EFNA3	P52797	536
EPHA6	EFNA4	P52798	525
EPHA6	SLIT1	O75093	490
EPHA6	SEMA4F	O95754	460
EPHA6	EFNB1	P98172	449
EPHA6	EFNB3	Q15768	434
EPHA6	EFNB2	P52799	431
EPHA6	HTR1F	P30939	430
EPHA6	NT5C	Q8TCD5	370
EPHA6	SLITRK4	Q8IW52	370
EPHA6	SUSD2	Q9UGT4	370
EPHA6	LPXN	O60711	370

IntAct

Human interaction partners of EPHA6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 83 partners by confidence:

Partner	Interaction type	MIscore	Records
EPHA2	physical association	0.650	1
EPHB4	physical association	0.500	1
PATJ	direct interaction	0.440	9
GRIP1	direct interaction	0.440	5
MAGI2	direct interaction	0.440	5
GRIP2	direct interaction	0.440	4
DLG1	direct interaction	0.440	3
DLG3	direct interaction	0.440	3
DLG4	direct interaction	0.440	3
FRMPD2	direct interaction	0.440	3
MPDZ	direct interaction	0.440	3
NHERF4	direct interaction	0.440	3
SCRIB	direct interaction	0.440	3
WHRN	direct interaction	0.440	3
APBA1	direct interaction	0.440	2
APBA2	direct interaction	0.440	2
DLG2	direct interaction	0.440	2
GRID2IP	direct interaction	0.440	2
IL16	direct interaction	0.440	2
LNX1	direct interaction	0.440	2
LNX2	direct interaction	0.440	2
MAGI1	direct interaction	0.440	2
PDZK1	direct interaction	0.440	2
AHNAK	direct interaction	0.440	1
APBA3	direct interaction	0.440	1
ARHGAP21	direct interaction	0.440	1
ARHGEF11	direct interaction	0.440	1
ARHGEF12	direct interaction	0.440	1
CARD11	direct interaction	0.440	1
CASK	direct interaction	0.440	1

BioGRID (56 interactions; top human partners by supporting records): EPHA2 (Affinity Capture-MS; 4 records), GPHA2 (Affinity Capture-MS; 3 records), CALM3 (Affinity Capture-MS; 2 records), DEFA5 (Affinity Capture-MS; 2 records), EFNA4 (Affinity Capture-MS; 2 records), HGS (Affinity Capture-MS; 2 records), HSPA1B (Affinity Capture-MS; 2 records), MYH14 (Affinity Capture-MS; 2 records), PROC (Affinity Capture-MS; 2 records), TRIP11 (Affinity Capture-MS; 2 records), AHSG (Proximity Label-MS), ARHGAP32 (Proximity Label-MS), ATP5B (Cross-Linking-MS (XL-MS)), BAGE2 (Affinity Capture-MS), CDC37 (Proximity Label-MS)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
EFNA1	up-regulates	EPHA6	binding
EFNA2	up-regulates	EPHA6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Ras activation upon Ca2+ influx through NMDA receptor	5	51.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	49.4×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	49.4×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	46.1×	8e-13
Dopamine Neurotransmitter Release Cycle	5	45.1×	2e-06
Long-term potentiation	5	43.3×	2e-06
Neurexins and neuroligins	11	39.4×	4e-13
Protein-protein interactions at synapses	7	33.8×	8e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	79.9×	2e-16
protein localization to synapse	6	57.5×	9e-08
receptor clustering	7	54.6×	9e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	43.4×	4e-08
protein-containing complex assembly	9	12.8×	2e-06
cell-cell adhesion	10	12.7×	5e-07
regulation of small GTPase mediated signal transduction	6	10.8×	7e-04
protein localization to plasma membrane	6	8.2×	2e-03

Disease & clinical

Genetic variants

Variant evidence for EPHA6: 148 ClinVar records (0 pathogenic / likely pathogenic); 8 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	132
Likely benign	3
Benign	2

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 20 predictions of 5,295):

Position(s)	Effect	Δscore	Sites
3:96815009	donor_loss	1.0000	2
3:96866814	acceptor_gain	1.0000
3:96866818	acceptor_gain	1.0000
3:96987325	acceptor_gain	1.0000
3:96987328	acceptor_loss	1.0000
3:97226261	acceptor_gain	1.0000
3:97226262–97226263	acceptor_loss	1.0000	6
3:97405272	donor_gain	1.0000
3:97448558	acceptor_gain	1.0000
3:97448566–97448567	acceptor_loss	1.0000	5

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Prostate Adenocarcinoma)

Disease associations

OMIM: gene MIM:600066 | disease phenotypes:

GWAS associations

8 associations:

Study	Trait	p-value
GCST005168_1	Systolic blood pressure	3e-8
GCST012489_79	Heel bone mineral density x serum urate levels interaction	4e-8
GCST002041_3	Blood trace element (Cu levels)	3e-7
GCST003425_7	Longevity	5e-7
GCST001762_748	Obesity-related traits	2e-6
GCST011947_10	White matter hyperintensity volume	2e-6
GCST008152_105	Weight	3e-6
GCST002040_5	Blood trace element (Zn levels)	5e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0004627	IGF-1 measurement
EFO:0005267	serum copper measurement
EFO:0006335	systolic blood pressure
EFO:0004338	body weight
EFO:0005665	white matter hyperintensity measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363043 (PROTEIN FAMILY), CHEMBL4526 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 573,504 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

32 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1173655	AFATINIB	4	15,878
CHEMBL2105712	AFATINIB DIMALEATE	4	3,441
CHEMBL288441	BOSUTINIB	4	12,869
CHEMBL601719	CRIZOTINIB	4	15,133
CHEMBL5416410	DASATINIB	4	674
CHEMBL553	ERLOTINIB	4	109,860
CHEMBL1287853	FEDRATINIB	4	3,770
CHEMBL939	GEFITINIB	4	119,425
CHEMBL255863	NILOTINIB	4	39,362
CHEMBL502835	NINTEDANIB	4	8,978
CHEMBL576982	QUIZARTINIB	4	4,647
CHEMBL1336	SORAFENIB	4	87,476
CHEMBL535	SUNITINIB	4	80,232
CHEMBL24828	VANDETANIB	4	43,290
CHEMBL377300	BRIVANIB	3	1,784
CHEMBL31965	CANERTINIB	3	8,307
CHEMBL491473	CEDIRANIB	3	9,464
CHEMBL603469	LESTAURTINIB	3
CHEMBL223360	LINIFANIB	3	4,094
CHEMBL572881	MOTESANIB	3	4,820
CHEMBL575448	BMS-754807	2
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230609	FORETINIB	2
CHEMBL607707	PELITINIB	2
CHEMBL475251	R-406	2
CHEMBL558752	RAF-265	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL572878	TOZASERTIB	2
CHEMBL574738	AST-487	1
CHEMBL1908397	KW-2449	1
CHEMBL259084	MLN-8054	1

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

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

3 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs301927	cyclophosphamide, epirubicin, paclitaxel	Toxicity	Allele G is associated with increased likelihood of Peripheral Nervous System Diseases when treated with cyclophosphamide, epirubicin and paclitaxel in women with Breast Neoplasms as compared to allele A.	PMID:24599932
rs301927	paclitaxel	Toxicity	Allele G is associated with increased risk of Peripheral Nervous System Diseases when treated with paclitaxel in women with Breast Neoplasms and Ovarian Neoplasms as compared to allele A.	PMID:26133776
rs301927	paclitaxel	Toxicity	Genotype AA is associated with decreased risk of Peripheral Nervous System Diseases when treated with paclitaxel in women with Breast Neoplasms as compared to genotypes AG + GG.	PMID:26133777

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type XIII RTKs: Ephrin receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 20 [PMID: 23489211]	Inhibition	5.82	pIC50

Binding affinities (BindingDB)

26 measured of 87 human assays (89 total across all organisms); most potent 26 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
CEP-701	KD	3.4 nM
4-[4-[(5-tert-butyl-2-quinolin-6-ylpyrazol-3-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	IC50	5.5 nM
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	5.6 nM	US-8822500: Tyrosine kinase inhibitors
Staurosporine, 8	IC50	6.5 nM
ASP-3026	IC50	10 nM
N-[4-[[(2-hydroxy-1H-indol-3-yl)-phenylmethylidene]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide	KI	15 nM	US-10981896: Indolinone derivatives as inhibitors of maternal embryonic leucine zipper kinase
CHEMBL1240703	KD	15 nM
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide	IC50	17 nM
PKC-412	KD	110 nM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	KD	120 nM	US-9145414: 1,2,4-triazine-6-carboxamide derivative
3-({4-[(5-hydroxy-2-methylphenyl)amino]pyrimidin-2-yl}amino)benzamide	KD	129 nM
CHEMBL1908397	KD	650 nM
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide	KD	740 nM
(9S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione	IC50	743 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
CHEMBL5653589	KD	1440 nM
CHEMBL2322989	IC50	2300 nM
3-(4-morpholin-4-ylpyrido[2,3]furo[2,4-b]pyrimidin-2-yl)phenol	KD	2400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
SUNITINIB MALATE	KD	3500 nM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide	KD	3900 nM	US-20250129067: PLATELET-DERIVED GROWTH FACTOR RECEPTOR (PDGFR) ALPHA INHIBITORS AND USES THEREOF
(4-chlorophenyl)-[4-(4-pyridylmethyl)phthalazin-1-yl]amine	KD	8800 nM
1-{4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}-N-(6-fluoropyridin-3-yl)-2-methyl-L-prolinamide	KD	13000 nM

ChEMBL bioactivities

78 potent at pChembl≥5 of 80 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.96	Kd	1.1	nM	FORETINIB
7.93	IC50	11.8	nM	STAUROSPORINE
7.77	IC50	17	nM	REBASTINIB
7.70	Kd	20	nM	CHEMBL249097
7.69	IC50	20.3	nM	STAUROSPORINE
7.69	IC50	20.4	nM	STAUROSPORINE
7.44	Kd	36	nM	CEDIRANIB
7.30	Kd	50	nM	VANDETANIB
7.27	IC50	54	nM	CRIZOTINIB
7.19	Kd	65	nM	VANDETANIB
7.19	Kd	65	nM	CRIZOTINIB
7.16	Kd	70	nM	CHEMBL386051
7.14	Kd	72	nM	CANERTINIB
6.92	Kd	120	nM	TAE-684
6.92	Kd	120	nM	R-406
6.72	Kd	190	nM	BRIVANIB
6.68	Kd	210	nM	CHEMBL1241674
6.62	Kd	240	nM	SORAFENIB
6.62	Kd	240	nM	STAUROSPORINE
6.58	IC50	263	nM	CHEMBL3752910
6.57	Kd	270	nM	CANERTINIB
6.54	Kd	290	nM	STAUROSPORINE
6.48	Kd	330	nM	LINIFANIB
6.47	Kd	340	nM	AFATINIB DIMALEATE
6.47	Kd	340	nM	AFATINIB
6.43	Kd	370	nM	SORAFENIB
6.42	Kd	380	nM	AST-487
6.37	Kd	430	nM	DORAMAPIMOD
6.36	Kd	440	nM	ERLOTINIB
6.31	Kd	490	nM	MOTESANIB
6.24	Kd	580	nM	MLN-8054
6.23	Kd	590	nM	GEFITINIB
6.19	Kd	640	nM	NILOTINIB
6.03	Kd	930	nM	ERLOTINIB
6.03	Kd	940	nM	NINTEDANIB
6.02	Kd	960	nM	SUNITINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.96	Kd	1100	nM	BOSUTINIB
5.92	Kd	1200	nM	SB-203580
5.92	Kd	1200	nM	LESTAURTINIB
5.85	Kd	1400	nM	GEFITINIB
5.82	IC50	1500	nM	CHEMBL2322989
5.82	Kd	1500	nM	RAF-265
5.82	Kd	1500	nM	KW-2449
5.70	Kd	2000	nM	SUNITINIB
5.70	Kd	2000	nM	DORAMAPIMOD
5.70	Kd	2000	nM	SU-014813
5.68	Kd	2100	nM	DASATINIB

PubChem BioAssay actives

73 with measured affinity, of 278 total; 41 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
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624748: Binding constant for EPHA6 kinase domain	kd	0.0011	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1531676: Inhibition of human EPHA6 using poly[Glu:Tyr] (4:1) as substrate by [gamma-33P]-ATP assay	ic50	0.0118	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168201: Inhibition of human wild type EPHA6 using PolyEY as substrate preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.0170	uM
3-[[4-(5-hydroxy-2-methylanilino)pyrimidin-2-yl]amino]benzamide	389074: Binding affinity to human EPHA6	kd	0.0200	uM
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline	624748: Binding constant for EPHA6 kinase domain	kd	0.0360	uM
Vandetanib	436015: Binding constant for EPHA6 kinase domain	kd	0.0500	uM
Crizotinib	2161827: Inhibition of human N-terminal GST-fused EPHA6 cytoplasmic domain (683 to 1130(end) residues) expressed in baculovirus expression system using Blk/Lyntide as substrate measured after 1 hr by off-chip mobility shift assay relative to control	ic50	0.0540	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624748: Binding constant for EPHA6 kinase domain	kd	0.0700	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	256567: Average Binding Constant for EPHA6; NA=Not Active at 10 uM	kd	0.0720	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624748: Binding constant for EPHA6 kinase domain	kd	0.1200	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624748: Binding constant for EPHA6 kinase domain	kd	0.1200	uM
(2R)-1-[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]oxypropan-2-ol	624748: Binding constant for EPHA6 kinase domain	kd	0.1900	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624748: Binding constant for EPHA6 kinase domain	kd	0.2100	uM
Sorafenib	256567: Average Binding Constant for EPHA6; NA=Not Active at 10 uM	kd	0.2400	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147744: Inhibition of Nano Luc-fused full length C-terminal EPHA6 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.2630	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	436015: Binding constant for EPHA6 kinase domain	kd	0.3300	uM
Afatinib	624748: Binding constant for EPHA6 kinase domain	kd	0.3400	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	436015: Binding constant for EPHA6 kinase domain	kd	0.3800	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	256567: Average Binding Constant for EPHA6; NA=Not Active at 10 uM	kd	0.4300	uM
Erlotinib	436015: Binding constant for EPHA6 kinase domain	kd	0.4400	uM
N-(3,3-dimethyl-1,2-dihydroindol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide	436015: Binding constant for EPHA6 kinase domain	kd	0.4900	uM
4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	436015: Binding constant for EPHA6 kinase domain	kd	0.5800	uM
Gefitinib	436015: Binding constant for EPHA6 kinase domain	kd	0.5900	uM
Nilotinib	624748: Binding constant for EPHA6 kinase domain	kd	0.6400	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624748: Binding constant for EPHA6 kinase domain	kd	0.9400	uM
Sunitinib	436015: Binding constant for EPHA6 kinase domain	kd	0.9600	uM
Bosutinib	624748: Binding constant for EPHA6 kinase domain	kd	1.1000	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507924: Binding affinity to EPHA6	kd	1.2000	uM
4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine	436015: Binding constant for EPHA6 kinase domain	kd	1.2000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624748: Binding constant for EPHA6 kinase domain	kd	1.5000	uM
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	436015: Binding constant for EPHA6 kinase domain	kd	1.5000	uM
(2S)-2-[[(4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	728714: Displacement of ephrin-A1-Fc from EphA6 receptor Fc ectodomain (unknown origin) after 1 hr by ELISA	ic50	1.5000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	436015: Binding constant for EPHA6 kinase domain	kd	2.0000	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	624748: Binding constant for EPHA6 kinase domain	kd	2.1000	uM
4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]phenol	436015: Binding constant for EPHA6 kinase domain	kd	2.2000	uM
(2S)-2-[[(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1260964: Displacement of biotinylated ephrin-A1-Fc from EphA6 (unknown origin) preincubated for 1 hr followed by biotinylated-ephrin-A1-Fc addition measured after 4 hrs by ELISA	ic50	3.5000	uM
Fedratinib	624748: Binding constant for EPHA6 kinase domain	kd	3.9000	uM
(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide	256567: Average Binding Constant for EPHA6; NA=Not Active at 10 uM	kd	4.1000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624748: Binding constant for EPHA6 kinase domain	kd	4.4000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	624748: Binding constant for EPHA6 kinase domain	kd	4.7000	uM
Quizartinib	624748: Binding constant for EPHA6 kinase domain	kd	9.1000	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	5
Aflatoxin B1	decreases methylation	2
aristolochic acid I	decreases expression	1
sodium arsenite	increases expression	1
ferrous chloride	increases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Acetaminophen	affects expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Copper	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Triclosan	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Permethrin	increases expression	1

ChEMBL screening assays

128 unique, capped per target: 128 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1024910	Binding	Binding affinity to human EPHA6 at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — *J Med Chem*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F5H4	EDITGENE EPHA6 Knockout HAP1 Cell Line	Cancer cell line	Male
CVCL_SM16	HAP1 EPHA6 (-) 1	Cancer cell line	Male
CVCL_SM17	HAP1 EPHA6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for EPHA6 across ~30M SureChEMBL compounds — explore on Sugi Predict.