EFNA1

Summary

EFNA1 (ephrin A1, HGNC:3221) is a protein-coding gene on chromosome 1q22, encoding Ephrin-A1 (P20827). Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development.

This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNA class ephrin which binds to the EPHA2, EPHA4, EPHA5, EPHA6, and EPHA7 receptors. Two transcript variants that encode different isoforms were identified through sequence analysis.

Source: NCBI Gene 1942 — RefSeq curated summary.

At a glance

• GWAS associations: 40
• Clinical variants (ClinVar): 28 total
• Druggable target: yes
• MANE Select transcript: NM_004428

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3221
Approved symbol	EFNA1
Name	ephrin A1
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	LERK1, ECKLG, GMAN
Ensembl gene	ENSG00000169242
Ensembl biotype	protein_coding
OMIM	191164
Entrez	1942

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000368406, ENST00000368407, ENST00000469878, ENST00000474413, ENST00000497282, ENST00000899924

RefSeq mRNA: 2 — MANE Select: NM_004428 NM_004428, NM_182685

CCDS: CCDS1091, CCDS1092

Canonical transcript exons

ENST00000368407 — 5 exons

Exon	Start	End
ENSE00001829147	155127876	155128069
ENSE00003480979	155131339	155131634
ENSE00003562322	155133730	155133780
ENSE00003662252	155133503	155133568
ENSE00003850051	155133955	155134899

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 99.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8779 / max 554.0224, expressed in 1180 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5570	20.8421	1127
5571	2.4853	777
5572	1.1350	534
5569	0.3290	153
5573	0.0864	36

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.21	gold quality
right lung	UBERON:0002167	98.03	gold quality
skin of abdomen	UBERON:0001416	97.91	gold quality
skin of leg	UBERON:0001511	97.90	gold quality
upper lobe of left lung	UBERON:0008952	97.56	gold quality
left lobe of thyroid gland	UBERON:0001120	97.49	gold quality
upper lobe of lung	UBERON:0008948	97.37	gold quality
liver	UBERON:0002107	97.26	gold quality
right lobe of thyroid gland	UBERON:0001119	97.01	gold quality
zone of skin	UBERON:0000014	96.97	gold quality
thyroid gland	UBERON:0002046	96.80	gold quality
minor salivary gland	UBERON:0001830	96.39	gold quality
parotid gland	UBERON:0001831	96.15	gold quality
saliva-secreting gland	UBERON:0001044	96.01	gold quality
metanephros cortex	UBERON:0010533	95.88	gold quality
rectum	UBERON:0001052	95.81	gold quality
lung	UBERON:0002048	95.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.70	gold quality
mucosa of transverse colon	UBERON:0004991	95.63	gold quality
endometrium epithelium	UBERON:0004811	95.57	gold quality
apex of heart	UBERON:0002098	95.56	gold quality
lower esophagus mucosa	UBERON:0035834	95.42	gold quality
mouth mucosa	UBERON:0003729	95.38	gold quality
duodenum	UBERON:0002114	95.25	gold quality
body of pancreas	UBERON:0001150	95.14	gold quality
visceral pleura	UBERON:0002401	94.78	gold quality
placenta	UBERON:0001987	94.59	gold quality
prostate gland	UBERON:0002367	94.59	gold quality
body of stomach	UBERON:0001161	94.45	gold quality
jejunal mucosa	UBERON:0000399	94.42	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	889.70
E-MTAB-8271	yes	400.29
E-GEOD-98556	yes	290.92
E-GEOD-135922	yes	39.62
E-GEOD-134144	yes	38.26
E-HCAD-10	yes	30.40
E-MTAB-6678	yes	16.69
E-CURD-112	yes	10.58
E-MTAB-9388	yes	6.99
E-MTAB-5061	yes	6.66
E-MTAB-10137	no	6.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, EPAS1, GLI2, HIC1, TCF3

miRNA regulators (miRDB)

67 targeting EFNA1, 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-9-5P	100.00	72.28	2361
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-6731-5P	99.28	67.42	2375

Literature-anchored findings (GeneRIF, showing 40)

• The interaction between EphA2 and this ligand protein is necessary for induction of maximal neovascularization by VEGF. (PMID:12496364)
• This protein, an EphA ligand, stimulated protein degradation by EphA2. (PMID:12496371)
• Ephrin-A1 stimulation of Jurkat T cells induces tyrosine phosphorylation of EphA3 receptors and cytoplasmic proteins, including c-cbl proto-oncogene, and causes down-regulation of endogenous EphA3 receptors from the cell surface and their degradation. (PMID:12794130)
• A new ephrin-A1 isoform, ephrin-A1b, lacks a segment of 22 amino acids (residues 131-152). Exon 3 is spliced out in its transcript. It may regulate the function of its ephrin-A1a counterpart. (PMID:14692877)
• This study demonstrates for the first time significantly reduced ephrin-A1 expression in T cells of asthma patients. (PMID:14707054)
• found ephrin-A1 expressed exclusively in the invasive extravillous trophoblast in preeclampsia and normal placenta (PMID:15193868)
• ephrin-A1 is expressed by venule endothelial cells (PMID:15585656)
• EPHA2 and EFNA1 expression may influence the behavior of human gastric cancer. (PMID:15649254)
• low molecular weight protein-tyrosine phosphatase acts as terminator of EphA2 signaling causing efficient negative feedback loop on biological response mediated by ephrinA1; tyrosine phosphorylation main event orchestrating repulsive response (PMID:16051609)
• High expression of Ephrin A-1 is associated with urinary bladder carcinoma. (PMID:16428472)
• Activation of ERK-1/2 plays an essential role in ephrin-A1-mediated cell migration, whixh is inhibited by green tea catechin epigallocatechin gallate. (PMID:17049832)
• Ephrin-A1 serves as a critical negative regulator in the tumorigenesis of gliomas by down-regulating EphA2 and FAK. (PMID:17332925)
• Increasing ephrin-A expression enhances T-cell interactions not only with purified integrin ligands but also endothelial cells, while EphA activation down-regulates these interactions. (PMID:17980912)
• Soluble monmomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. (PMID:18794797)
• The function of EphA2 and ephrinA1 in tumorigenesis and tumor progression is complex and seems to be dependent on cell type and microenvironment (PMID:19074825)
• Increased expression of EphA2 and EphrinA-1 plays an important role in the progression human gastric adenocarcinoma. (PMID:19101799)
• The crystal structures of an A-class complex between EphA2 and ephrin-A1 and of unbound EphA2, are presented. (PMID:19525919)
• EFNA1 may be a useful serum marker for the detection of hepatocellular carinoma development and progression. (PMID:19642143)
• EphA2 and EphrinA1 are highly expressed in renal cell carcinoma, and positively correlated with histological differentiation, clinical stage and angiogenesis. (PMID:19950554)
• up-regulation of EphA2 and down-regulation of Ephrina1 may correlate with poor prognosis for patients with high-grade glioma (PMID:20571968)
• This study demonstrated that the Eph-ephrin A system can promote intercellular dissociation in Ishikawa cells suggesting an important role in the initial step of embryo implantation by opening the endometrial epithelial cell barrier. (PMID:21138904)
• Osteosarcoma samples were characterized using genome-wide microarrays: increased expression of the EphA2 receptor and its ligand EFNA1 was detected. (PMID:21166698)
• The Eph-ephrinA system can promote cell attachment along with intercellular dissociation. (PMID:21349856)
• Ovarian serous carcinomas and ovarian cancer cell lines overexpress EphA2 and EphrinA-1. Tumor patients with higher expression levels of both EphA2 and EphrinA-1 have a significantly poorer clinical outcome. (PMID:21500549)
• Multiple oncogenic signalling pathways are affected by ephrin-A1, from the promotion of a specific pathway in one cell or cancer type to the inhibition of the same pathway in another type of cell or cancer. [Review] (PMID:22040911)
• The EphA2 ligand EphrinA1 induces EphA2 phosphorylation and intracellular internalization and degradation, thus inhibiting breast tumor progression. (PMID:22228563)
• in p-stage I NSCLC patients, those in the higher EphA2 expression and higher ephrin-A1 expression groups shared almost the same clinicopathological backgrounds which are generally considered to be better prognostic factors. (PMID:22236865)
• EphA2 activation by ephrin-A1 induces tumor suppressor gene cdx-2 expression which attenuates cell proliferation, tumor growth and thus may be a promising therapeutic target against NSCLC. (PMID:22824143)
• Increased expression of EFNA1 mRNA is associated with gastric cancer. (PMID:23065816)
• EFNA1 expression is a useful marker for predicting high risk of relapse and cancer-related death in patients who have undergone curative resection for CRC. (PMID:23258614)
• present study showed a high expression of EphA2/ephrinA1 in adenoid cystic carcinoma. EphA2/ephrinA1 can serve as a novel therapy target for adenoid cystic carcinoma. (PMID:23298804)
• Findings suggest that the glycosylation on ephrin-A1 plays a critical role in the binding and activation of the EphA2 receptor. (PMID:23661698)
• The interaction between ephrin-As, Eph receptors and integrin alpha3 is plausibly important for the crosstalk between Eph and integrin signalling pathways at the membrane protrusions and in the migration of brain cancer cells. (PMID:23686814)
• Ephrin-A1 is upregulated in tumor microenvironment and promotes angiogenesis through a coordinated cross-talk with PI3K/Akt-dependent eNOS activation. (PMID:24040255)
• Results suggest that EFNA1 is involved in colorectal tumorigenesis, and rs12904 A>G polymorphism in the 3’ UTR of EFNA1 is associated with CRC susceptibility in a Chinese population. (PMID:24175772)
• Expression of EPHRIN-A1 tends to be associated with worse survival in head and neck cancer. (PMID:24330498)
• EphA2-ephrinA1 trans-endocytosis is sensitive to the mechanical properties of a cell’s microenvironment (PMID:24853748)
• Findings show that EFNA1 expression is a useful marker for predicting a high risk of recurrence in hepatocellular carcinoma patients but not EPHA2. (PMID:24969670)
• ephrin-A1 seems to be remarkably involved in elementary processes of endothelial migration like cellular polarization, migratory direction and speed. (PMID:27742560)
• We created a novel pH-dependent transmembrane peptide, TYPE7, by altering the sequence of the transmembrane domain of EphA2..TYPE7 binds to endogenous EphA2 and reduces Akt phosphorylation and cell migration as effectively as ephrinA1 (PMID:30222105)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	efna1b	ENSDARG00000018787
danio_rerio	efna1a	ENSDARG00000030326
mus_musculus	Efna1	ENSMUSG00000027954
rattus_norvegicus	Efna1	ENSRNOG00000020573
drosophila_melanogaster	Ephrin	FBGN0040324
caenorhabditis_elegans		WBGENE00001163
caenorhabditis_elegans		WBGENE00001164
caenorhabditis_elegans		WBGENE00001165
caenorhabditis_elegans		WBGENE00006869

Paralogs (7): EFNB1 (ENSG00000090776), EFNA2 (ENSG00000099617), EFNB3 (ENSG00000108947), EFNB2 (ENSG00000125266), EFNA3 (ENSG00000143590), EFNA5 (ENSG00000184349), EFNA4 (ENSG00000243364)

Protein

Protein identifiers

Ephrin-A1 — P20827 (reviewed: P20827)

Alternative names: EPH-related receptor tyrosine kinase ligand 1, Immediate early response protein B61, Tumor necrosis factor alpha-induced protein 4

All UniProt accessions (1): P20827

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. Involved in angiogenesis, regulating vascular endothelial cell differentiation and migration through activation of EPHA2. Acts as a ligand for EPHA3, inhibiting epithelial-to-mesenchymal transition of cardiac cells and playing a role in heart development. May also contribute to dendritic spine morphogenesis.

Subunit / interactions. Monomer. Homodimer. Forms heterodimers with EPHA2. Binds to the receptor tyrosine kinases EPHA2, EPHA3, EPHA4, EPHA5, EPHA6 and EPHA7. Also binds with low affinity to EPHA1.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Brain. Down-regulated in primary glioma tissues compared to the normal tissues. The soluble monomeric form is expressed in the glioblastoma multiforme (GBM) and breast cancer cells (at protein level).

Post-translational modifications. Undergoes proteolysis by a metalloprotease to give rise to a soluble monomeric form. N-Glycosylation is required for binding to EPHA2 receptor and inducing its internalization.

Induction. By TNF and IL1B/interleukin-1 beta.

Similarity. Belongs to the ephrin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P20827-1	1	yes
P20827-2	2

RefSeq proteins (2): NP_004419, NP_872626 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001799	Ephrin_RBD	Domain
IPR008972	Cupredoxin	Homologous_superfamily
IPR019765	Ephrin_CS	Conserved_site
IPR031328	Ephrin	Family
IPR034252	Ephrin-A_Ecto	Domain

Pfam: PF00812

UniProt features (25 total): strand 9, helix 4, chain 2, disulfide bond 2, signal peptide 1, sequence variant 1, sequence conflict 1, propeptide 1, domain 1, lipid moiety-binding region 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3HEI	X-RAY DIFFRACTION	2
3CZU	X-RAY DIFFRACTION	2.65
3MBW	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20827-F1	79.94	0.57

Functional residue map

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

Post-translational modifications (1): 182

Disulfide bonds (2): 51–92, 80–140

Glycosylation sites (1): 26

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: 407 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_DENDRITIC_SPINE_DEVELOPMENT, MODULE_416, MODULE_92, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_POSITIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, GOBP_DENDRITIC_SPINE_DEVELOPMENT, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP

GO Biological Process (31): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), aortic valve morphogenesis (GO:0003180), mitral valve morphogenesis (GO:0003183), endocardial cushion to mesenchymal transition involved in heart valve formation (GO:0003199), axon guidance (GO:0007411), negative regulation of epithelial to mesenchymal transition (GO:0010719), notochord formation (GO:0014028), central nervous system neuron differentiation (GO:0021953), negative regulation of cell adhesion mediated by integrin (GO:0033629), substrate adhesion-dependent cell spreading (GO:0034446), negative regulation of MAPK cascade (GO:0043409), positive regulation of MAPK cascade (GO:0043410), regulation of blood vessel endothelial cell migration (GO:0043535), regulation of angiogenesis (GO:0045765), ephrin receptor signaling pathway (GO:0048013), regulation of axonogenesis (GO:0050770), protein stabilization (GO:0050821), negative regulation of dendritic spine morphogenesis (GO:0061002), negative regulation of thymocyte apoptotic process (GO:0070244), positive regulation of amyloid-beta formation (GO:1902004), positive regulation of intracellular signal transduction (GO:1902533), positive regulation of amyloid precursor protein catabolic process (GO:1902993), obsolete negative regulation of proteolysis involved in protein catabolic process (GO:1903051), cell-cell signaling (GO:0007267), negative regulation of macromolecule metabolic process (GO:0010605), cell migration (GO:0016477), regulation of cell adhesion mediated by integrin (GO:0033628), regulation of peptidyl-tyrosine phosphorylation (GO:0050730), positive regulation of peptidyl-tyrosine phosphorylation (GO:0050731), regulation of biological quality (GO:0065008)

GO Molecular Function (4): ephrin receptor binding (GO:0046875), receptor ligand activity (GO:0048018), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), plasma membrane (GO:0005886), focal adhesion (GO:0005925), side of membrane (GO:0098552), 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
cellular anatomical structure	3
anatomical structure formation involved in morphogenesis	2
axonogenesis	2
MAPK cascade	2
regulation of MAPK cascade	2
regulation of anatomical structure morphogenesis	2
signaling receptor binding	2
membrane	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
aortic valve development	1
heart valve morphogenesis	1
mitral valve development	1
atrioventricular valve morphogenesis	1
heart valve formation	1
endocardial cushion to mesenchymal transition	1
neuron projection guidance	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
nervous system development	1
notochord morphogenesis	1
central nervous system development	1
neuron differentiation	1
negative regulation of cell adhesion	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
cell-substrate adhesion	1
negative regulation of intracellular signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
angiogenesis	1
regulation of vasculature development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
regulation of neuron projection development	1
regulation of protein stability	1

Protein interactions and networks

STRING

1114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFNA1	EPHA1	P21709	999
EFNA1	EPHA4	P54764	999
EFNA1	EPHA2	P29317	999
EFNA1	EPHA10	Q5JZY3	993
EFNA1	EPHA3	P29320	948
EFNA1	EPHA5	P54756	946
EFNA1	EPHA8	P29322	919
EFNA1	EPHA7	Q15375	914
EFNA1	EIF4B	P23588	887
EFNA1	EPHB2	P29323	870
EFNA1	EPHB1	P54762	841
EFNA1	EPHB6	O15197	831
EFNA1	NGEF	Q8N5V2	791
EFNA1	NTRK2	Q16620	757
EFNA1	EPHB4	P54760	741

IntAct

22 interactions, top by confidence:

A	B	Type	Score
EPHA2	EFNA1	psi-mi:“MI:0407”(direct interaction)	0.820
EFNA1	EPHA2	psi-mi:“MI:0915”(physical association)	0.820
EPHA2	EFNA1	psi-mi:“MI:0915”(physical association)	0.820
EFNA1	EPHA2	psi-mi:“MI:0407”(direct interaction)	0.820
EPHA4	EFNA1	psi-mi:“MI:0407”(direct interaction)	0.620
EFNA1	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.620
EFNA1	PPBP	psi-mi:“MI:0915”(physical association)	0.550
EFNA1	GAREM1	psi-mi:“MI:0915”(physical association)	0.400
EFNA1	CLPTM1L	psi-mi:“MI:0915”(physical association)	0.400
HSCB	EFNA1	psi-mi:“MI:0915”(physical association)	0.370
XRCC6	EFNA1	psi-mi:“MI:0915”(physical association)	0.370
EFNA1	INPPL1	psi-mi:“MI:0914”(association)	0.350
HUNK	EFNA1	psi-mi:“MI:0915”(physical association)	0.000
EFNA1	EEF1G	psi-mi:“MI:0915”(physical association)	0.000
EFNA1	KAT5	psi-mi:“MI:0915”(physical association)	0.000
EFNA1	SUMO2	psi-mi:“MI:0915”(physical association)	0.000
EFNA1	PPBP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (104): GAREM (Affinity Capture-MS), EFNA1 (Affinity Capture-RNA), EFNA1 (Affinity Capture-RNA), EFNA1 (Affinity Capture-MS), PPBP (Two-hybrid), EEF1G (Two-hybrid), KAT5 (Two-hybrid), EPHA4 (Affinity Capture-Western), EFNA1 (Reconstituted Complex), CLPTM1L (Affinity Capture-MS), EFNA1 (Affinity Capture-MS), EFNA1 (Affinity Capture-MS), EFNA1 (Affinity Capture-MS), EFNA1 (Affinity Capture-MS), EFNA1 (Two-hybrid)

ESM2 similar proteins: A0MTF4, M3X9S6, O35757, O35793, O54693, O60565, O70326, O73753, O73754, O73755, O88273, P09858, P12034, P15656, P20827, P21214, P27090, P30371, P39905, P41271, P48540, P48807, P49767, P50291, P61811, P61812, P97401, P97553, P97953, Q06880, Q06AS9, Q07257, Q07731, Q20FD0, Q38L25, Q61477, Q6DF53, Q6NW40, Q6NZ13, Q7TQ33

Diamond homologs: O08542, O08543, O08545, O35393, O43921, O73612, O73874, P20827, P52793, P52794, P52795, P52796, P52797, P52798, P52799, P52800, P52801, P52802, P52803, P52804, P79727, P79728, P97553, P97605, P98172, Q06AS9, Q15768, Q3ZC64, O13097, O44516

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
EFNA1	up-regulates	EPHA8	binding
HIC1	“down-regulates quantity by repression”	EFNA1	“transcriptional regulation”
EFNA1	up-regulates	EPHA1	binding
EFNA1	up-regulates	EPHA2	binding
EFNA1	up-regulates	EPHA3	binding
EFNA1	up-regulates	EPHA4	binding
EFNA1	up-regulates	EPHA5	binding
EFNA1	up-regulates	EPHA6	binding
EFNA1	up-regulates	EPHA7	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

564 predictions. Top by Δscore:

Variant	Effect	Δscore
1:155131324:T:TA	acceptor_gain	1.0000
1:155131326:T:TA	acceptor_gain	1.0000
1:155131328:T:TA	acceptor_gain	1.0000
1:155131330:T:TA	acceptor_gain	1.0000
1:155131337:A:AG	acceptor_gain	1.0000
1:155131337:AG:A	acceptor_gain	1.0000
1:155131337:AGGT:A	acceptor_loss	1.0000
1:155131338:G:A	acceptor_loss	1.0000
1:155131338:G:GT	acceptor_gain	1.0000
1:155131338:GG:G	acceptor_gain	1.0000
1:155131338:GGT:G	acceptor_gain	1.0000
1:155131630:CATCT:C	donor_gain	1.0000
1:155131631:ATCT:A	donor_gain	1.0000
1:155131632:TCT:T	donor_gain	1.0000
1:155131633:CT:C	donor_gain	1.0000
1:155131634:TG:T	donor_loss	1.0000
1:155131635:G:GG	donor_gain	1.0000
1:155131635:GTG:G	donor_loss	1.0000
1:155131636:T:A	donor_loss	1.0000
1:155133569:G:GG	donor_gain	1.0000
1:155133726:TCAG:T	acceptor_loss	1.0000
1:155133728:A:AG	acceptor_gain	1.0000
1:155133729:G:GA	acceptor_gain	1.0000
1:155133777:GCAG:G	donor_gain	1.0000
1:155133780:GGT:G	donor_loss	1.0000
1:155131338:GGTT:G	acceptor_gain	0.9900
1:155131338:GGTTC:G	acceptor_gain	0.9900
1:155131597:C:T	donor_gain	0.9900
1:155131610:G:GT	donor_gain	0.9900
1:155131614:G:GT	donor_gain	0.9900

AlphaMissense

1356 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:155131520:T:A	C92S	0.999
1:155131521:G:C	C92S	0.999
1:155131604:T:C	F120L	0.999
1:155131606:C:A	F120L	0.999
1:155131606:C:G	F120L	0.999
1:155128052:G:C	W25C	0.998
1:155128052:G:T	W25C	0.998
1:155128050:T:A	W25R	0.997
1:155128050:T:C	W25R	0.997
1:155131397:T:A	C51S	0.997
1:155131398:G:C	C51S	0.997
1:155131516:G:C	W90C	0.997
1:155131516:G:T	W90C	0.997
1:155131569:T:C	F108S	0.997
1:155131577:T:C	F111L	0.997
1:155131579:C:A	F111L	0.997
1:155131579:C:G	F111L	0.997
1:155131605:T:G	F120C	0.997
1:155131397:T:C	C51R	0.996
1:155131520:T:C	C92R	0.996
1:155131605:T:C	F120S	0.996
1:155131398:G:A	C51Y	0.995
1:155133542:T:C	L143S	0.995
1:155128045:T:A	V23D	0.994
1:155128051:G:C	W25S	0.994
1:155131399:T:G	C51W	0.994
1:155131569:T:G	F108C	0.994
1:155131521:G:A	C92Y	0.993
1:155131522:C:G	C92W	0.993
1:155131634:T:C	S130P	0.993

dbSNP variants (sampled 300 via entrez): RS1000178789 (1:155133130 C>T), RS1000375546 (1:155127377 T>C,G), RS1000514476 (1:155131718 G>A,T), RS1000730338 (1:155134216 G>A), RS1000746747 (1:155127684 G>C), RS1000753562 (1:155132134 T>G), RS1000929021 (1:155130494 AGGAGAGAGGGGAGAGAGGGGAGAGG>A), RS1000985800 (1:155128317 A>G), RS1001112499 (1:155125965 G>A), RS1001469071 (1:155128146 C>A,G,T), RS1001498820 (1:155127754 C>T), RS1001589723 (1:155126861 C>A,G), RS1001734157 (1:155132690 TGTG>T), RS1001801323 (1:155126670 C>G,T), RS1001832364 (1:155126405 C>T)

Disease associations

OMIM: gene MIM:191164 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST001277_10	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-15
GCST001762_45	Obesity-related traits	5.000000e-06
GCST001942_19	Prostate cancer	2.000000e-08
GCST004131_70	Inflammatory bowel disease	6.000000e-08
GCST004132_44	Crohn’s disease	2.000000e-07
GCST005748_10	Digit length ratio (right hand)	1.000000e-13
GCST005749_12	Digit length ratio (left hand)	7.000000e-17
GCST005749_13	Digit length ratio (left hand)	3.000000e-16
GCST005750_2	Digit length ratio	3.000000e-17
GCST006586_45	Urinary albumin excretion	7.000000e-09
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST007400_18	Systemic lupus erythematosus	8.000000e-07
GCST009308_6	Emotional recognition	6.000000e-06
GCST010002_367	Refractive error	5.000000e-13
GCST010696_19	Cortical thickness (min-P)	2.000000e-10
GCST010697_10	Cortical surface area (min-P)	3.000000e-10
GCST010698_59	Subcortical volume (min-P)	9.000000e-10
GCST010699_20	Brain morphology (min-P)	7.000000e-10
GCST010700_5	Cortical thickness (MOSTest)	8.000000e-17
GCST010701_66	Cortical surface area (MOSTest)	1.000000e-09
GCST010702_43	Subcortical volume (MOSTest)	3.000000e-10
GCST010703_253	Brain morphology (MOSTest)	4.000000e-14
GCST010796_1642	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_1643	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_1644	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-10

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004841	digit length ratio
EFO:0004285	albuminuria
EFO:0004341	body fat distribution
EFO:0008354	cognitive function measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004327	electrocardiography
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291975 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.69	IC50	2042	nM	CHEMBL2322989
5.29	Ki	5100	nM	URSOCHOLANIC ACID

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 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
(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	1927073: Inhibition of EPhA2-ephrin-A1 (unknown origin) protein-protein interaction	ic50	2.0417	uM
(4R)-4-[(5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid	1927073: Inhibition of EPhA2-ephrin-A1 (unknown origin) protein-protein interaction	ki	5.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, decreases expression	9
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	7
trichostatin A	increases expression, affects expression, affects cotreatment	4
Oxygen	decreases reaction, increases expression	4
bisphenol A	affects expression, decreases expression, increases expression	3
Fulvestrant	increases expression	3
Benzo(a)pyrene	decreases expression, increases expression	3
Lithocholic Acid	affects binding, decreases reaction, increases phosphorylation	3
Cyclosporine	increases expression, decreases expression	3
afimoxifene	decreases expression, decreases reaction	2
nickel sulfate	increases expression, affects cotreatment	2
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression, decreases expression	2
entinostat	increases expression, affects cotreatment	2
belinostat	affects cotreatment, increases expression	2
Zoledronic Acid	increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Glyphosate	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cisplatin	affects expression, decreases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cadmium Chloride	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases reaction, increases expression	1
Glupearl 19S	increases expression	1
bufotalin	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5230257	Binding	Inhibition of EPhA2-ephrin-A1 (unknown origin) protein-protein interaction	Recent advances in steroid amino acid conjugates: Old scaffolds with new dimensions. — Eur 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_B1QR	Abcam HeLa EFNA1 KO	Cancer cell line	Female
CVCL_E0CC	Ubigene HeLa EFNA1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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