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 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 148 total
• Druggable target: yes — 32 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001080448

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: 9 — 5 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000389672, ENST00000470610, ENST00000477384, ENST00000502694, ENST00000503760, ENST00000506349, ENST00000506569, ENST00000508345, ENST00000514100

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.

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

251 total, 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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXA13

miRNA regulators (miRDB)

43 targeting EPHA6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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)

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): Q9UF33, A0A0B4J1T8, B4DXM2, E7EU71, 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), 1 shown:

• 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

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

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

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): 798 (proton acceptor)

Ligand- & substrate-binding residues (2): 637–645; 663

Post-translational modifications (4): 606, 612, 831, 978

Glycosylation sites (3): 343, 397, 410

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-3928663	EPHA-mediated growth cone collapse
R-HSA-3928665	EPH-ephrin mediated repulsion of cells

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

Rollup of top-2 pathways:

Category	Pathways
EPH-Ephrin signaling	2
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

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
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

1594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHA6	KRT1	P04264	713
EPHA6	KRT10	P13645	712
EPHA6	EFNA5	P52803	705
EPHA6	EFNA2	O43921	702
EPHA6	EFNB2	P52799	643
EPHA6	EFNA1	P20827	589
EPHA6	NCR1	O76036	583
EPHA6	EFNA3	P52797	520
EPHA6	EFNA4	P52798	517
EPHA6	HTR1F	P30939	499
EPHA6	EFNB1	P98172	498
EPHA6	SEMA4F	O95754	493
EPHA6	SLIT1	O75093	474
EPHA6	EPHA3	P29320	458
EPHA6	EFNB3	Q15768	456
EPHA6	EPHB1	P54762	456

IntAct

143 interactions, top by confidence:

A	B	Type	Score
EPHA2	EPHA6	psi-mi:“MI:0915”(physical association)	0.650
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
GPHA2	PLXNA2	psi-mi:“MI:0914”(association)	0.530
EPHA2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
EPHA6	EPHB4	psi-mi:“MI:0915”(physical association)	0.500
EPHA6	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	LIN7B	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	DLG5	psi-mi:“MI:0407”(direct interaction)	0.440
NHERF4	EPHA6	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF6	EPHA6	psi-mi:“MI:0407”(direct interaction)	0.440
EPHA6	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (56): EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-RNA), EPHA6 (Negative Genetic), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA6 (Affinity Capture-MS), EPHA2 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2K1Q8, A2VE04, A4QP81, G5ECB2, O08680, O13146, O62714, O75899, O88871, O88917, O88923, O94910, O95490, O97817, O97827, O97831, P29319, P35384, P48442, P54755, P54757, P54758, Q07497, Q21540, Q5TZ24, Q5U9X3, Q61703, Q62413, Q6INU7, Q6ZNA5, Q7TT41, Q80T41, Q80TR1, Q80TS3, Q8BG22, Q8BXJ9, Q8C7U7, Q8JZZ7, Q8K385, Q8MSU3

Diamond homologs: O08644, O08680, O09127, O13146, O13147, O13148, O15197, O35346, O42422, O45539, O73875, O73878, P00523, P00525, P00527, P00530, P00541, P00542, P00543, P05480, P07332, P09324, P09759, P09760, P0C0K6, P0C0K7, P12931, P13115, P13116, P14084, P14085, P14234, P14238, P15054, P16591, P16879, P18106, P21709, P24604, P28693

SIGNOR signaling

2 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 101 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	40.2×	7e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	38.3×	7e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	38.3×	7e-06
Assembly and cell surface presentation of NMDA receptors	10	35.7×	2e-11
Dopamine Neurotransmitter Release Cycle	5	35.0×	9e-06
Long-term potentiation	5	33.5×	1e-05
Neurexins and neuroligins	11	30.5×	1e-11
Protein-protein interactions at synapses	7	26.2×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	66.6×	3e-15
protein localization to synapse	6	47.9×	4e-07
receptor clustering	7	45.5×	5e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	36.1×	2e-07
ephrin receptor signaling pathway	5	17.9×	5e-04
protein-containing complex assembly	9	10.7×	1e-05
cell-cell adhesion	10	10.6×	4e-06
regulation of small GTPase mediated signal transduction	6	9.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

7209 predictions. Top by Δscore:

Variant	Effect	Δscore
3:96815009:G:GA	donor_loss	1.0000
3:96866814:T:G	acceptor_gain	1.0000
3:96866817:A:AG	acceptor_gain	1.0000
3:96866818:A:G	acceptor_gain	1.0000
3:96866823:A:AG	acceptor_gain	1.0000
3:96866823:AGTT:A	acceptor_gain	1.0000
3:96866824:G:GG	acceptor_gain	1.0000
3:96866824:GT:G	acceptor_gain	1.0000
3:96866824:GTT:G	acceptor_gain	1.0000
3:96866824:GTTG:G	acceptor_gain	1.0000
3:96866824:GTTGT:G	acceptor_gain	1.0000
3:96866887:GGG:G	donor_gain	1.0000
3:96866888:GG:G	donor_gain	1.0000
3:96866888:GGG:G	donor_gain	1.0000
3:96866889:GG:G	donor_gain	1.0000
3:96987325:T:TA	acceptor_gain	1.0000
3:96987325:TGCAG:T	acceptor_loss	1.0000
3:96987326:GCAGT:G	acceptor_loss	1.0000
3:96987327:CAGTG:C	acceptor_loss	1.0000
3:96987328:A:AG	acceptor_gain	1.0000
3:96987328:A:T	acceptor_loss	1.0000
3:96987328:AGT:A	acceptor_gain	1.0000
3:96987328:AGTG:A	acceptor_gain	1.0000
3:96987328:AGTGG:A	acceptor_gain	1.0000
3:96987329:G:GT	acceptor_gain	1.0000
3:96987329:GT:G	acceptor_gain	1.0000
3:96987329:GTG:G	acceptor_gain	1.0000
3:96987329:GTGG:G	acceptor_gain	1.0000
3:96987329:GTGGG:G	acceptor_gain	1.0000
3:97226260:ACAG:A	acceptor_loss	1.0000

AlphaMissense

7459 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000119 (3:97567452 A>G), RS1000002752 (3:97525579 A>G), RS1000005818 (3:97375840 T>G), RS1000013011 (3:97564183 A>C,G), RS1000014488 (3:96955465 G>T), RS1000022137 (3:97569327 A>G), RS1000026157 (3:96977258 C>T), RS1000031749 (3:97661060 T>G), RS1000033705 (3:97151280 T>G), RS1000035693 (3:97434694 A>G), RS1000040392 (3:96935705 A>G,T), RS1000054220 (3:97419298 C>T), RS1000054440 (3:97241933 G>A), RS1000054659 (3:97352777 C>T), RS1000057498 (3:97035282 T>A)

Disease associations

OMIM: gene MIM:600066 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001762_823	Obesity-related traits	2.000000e-06
GCST002040_5	Blood trace element (Zn levels)	5.000000e-06
GCST002041_3	Blood trace element (Cu levels)	3.000000e-07
GCST003425_7	Longevity	5.000000e-07
GCST005168_1	Systolic blood pressure	3.000000e-08
GCST008152_80	Weight	3.000000e-06
GCST011947_20	White matter hyperintensity volume	2.000000e-06
GCST012489_151	Heel bone mineral density x serum urate levels interaction	4.000000e-08

EFO canonical traits (7, from GWAS)

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

32 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 561,723 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL2105712	AFATINIB DIMALEATE	4	3,215
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL939	GEFITINIB	4	117,814
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL377300	BRIVANIB	3	1,721
CHEMBL491473	CEDIRANIB	3	9,098
CHEMBL572881	MOTESANIB	3	4,642
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230609	FORETINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL1738757	REBASTINIB	2
CHEMBL475251	R-406	2
CHEMBL558752	RAF-265	2
CHEMBL572878	TOZASERTIB	2
CHEMBL575448	BMS-754807	2
CHEMBL607707	PELITINIB	2
CHEMBL1908397	KW-2449	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs301927	EPHA6		0.00	0

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

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	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	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

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM16	HAP1 EPHA6 (-) 1	Cancer cell line	Male
CVCL_SM17	HAP1 EPHA6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.