EPS8

Summary

EPS8 (EGFR pathway substrate 8, signaling adaptor, HGNC:3420) is a protein-coding gene on chromosome 12p12.3, encoding Epidermal growth factor receptor kinase substrate 8 (Q12929). Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture.

This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.

Source: NCBI Gene 2059 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive nonsyndromic hearing loss 102 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 442 total — 9 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 3
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004447

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3420
Approved symbol	EPS8
Name	EGFR pathway substrate 8, signaling adaptor
Location	12p12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000151491
Ensembl biotype	protein_coding
OMIM	600206
Entrez	2059

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 42 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000281172, ENST00000508018, ENST00000535734, ENST00000535752, ENST00000536793, ENST00000536956, ENST00000540613, ENST00000541465, ENST00000542903, ENST00000543363, ENST00000543468, ENST00000543523, ENST00000543612, ENST00000544064, ENST00000545610, ENST00000545999, ENST00000546261, ENST00000546311, ENST00000642278, ENST00000642939, ENST00000644374, ENST00000645775, ENST00000646123, ENST00000646828, ENST00000646918, ENST00000647087, ENST00000647224, ENST00000880408, ENST00000880409, ENST00000880410, ENST00000880411, ENST00000880412, ENST00000880413, ENST00000880414, ENST00000880415, ENST00000880416, ENST00000880417, ENST00000880418, ENST00000880419, ENST00000959881, ENST00000959882, ENST00000959883, ENST00000959884, ENST00000959885, ENST00000959886, ENST00000959887, ENST00000959888, ENST00000959889, ENST00000959890, ENST00000959891

RefSeq mRNA: 10 — MANE Select: NM_004447 NM_001413831, NM_001413832, NM_001413833, NM_001413834, NM_001413835, NM_001413836, NM_001413837, NM_001413838, NM_001413839, NM_004447

CCDS: CCDS31753

Canonical transcript exons

ENST00000281172 — 21 exons

Exon	Start	End
ENSE00000999912	15665756	15665892
ENSE00000999920	15669387	15669536
ENSE00001147104	15681226	15681302
ENSE00001284194	15682893	15682972
ENSE00002256471	15789161	15789388
ENSE00003460983	15623158	15623287
ENSE00003482165	15647127	15647260
ENSE00003485592	15631442	15631664
ENSE00003530752	15666440	15666522
ENSE00003543499	15640703	15640846
ENSE00003567846	15654145	15654293
ENSE00003572431	15669664	15669825
ENSE00003574487	15624227	15624407
ENSE00003597853	15662026	15662099
ENSE00003604054	15660614	15660740
ENSE00003623002	15650823	15651006
ENSE00003660243	15658079	15658153
ENSE00003670502	15641722	15641830
ENSE00003685095	15658497	15658585
ENSE00003788771	15670856	15670923
ENSE00003842645	15620134	15621430

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.3324 / max 656.8180, expressed in 1746 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129943	31.5289	1648
129942	2.0224	793
129944	1.9982	1103
129948	1.6896	601
129945	1.0409	466
129947	0.2888	156
129946	0.2608	122
129935	0.2437	95
129934	0.1744	67
129933	0.0359	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.76	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.62	gold quality
colonic mucosa	UBERON:0000317	98.57	gold quality
calcaneal tendon	UBERON:0003701	98.56	gold quality
cartilage tissue	UBERON:0002418	98.51	gold quality
corpus epididymis	UBERON:0004359	98.45	gold quality
pericardium	UBERON:0002407	98.20	gold quality
cauda epididymis	UBERON:0004360	98.20	gold quality
popliteal artery	UBERON:0002250	98.17	gold quality
tibial artery	UBERON:0007610	98.16	gold quality
artery	UBERON:0001637	98.06	gold quality
synovial joint	UBERON:0002217	97.99	gold quality
bronchial epithelial cell	CL:0002328	97.93	gold quality
blood vessel layer	UBERON:0004797	97.91	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.86	gold quality
seminal vesicle	UBERON:0000998	97.73	gold quality
right coronary artery	UBERON:0001625	97.73	gold quality
saphenous vein	UBERON:0007318	97.71	gold quality
parietal pleura	UBERON:0002400	97.70	gold quality
palpebral conjunctiva	UBERON:0001812	97.66	gold quality
vena cava	UBERON:0004087	97.65	gold quality
aorta	UBERON:0000947	97.63	gold quality
adipose tissue	UBERON:0001013	97.63	gold quality
left coronary artery	UBERON:0001626	97.59	gold quality
urinary bladder	UBERON:0001255	97.49	gold quality
pleura	UBERON:0000977	97.47	gold quality
connective tissue	UBERON:0002384	97.47	gold quality
endocervix	UBERON:0000458	97.45	gold quality
coronary artery	UBERON:0001621	97.40	gold quality
body of uterus	UBERON:0009853	97.20	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	2209.51
E-GEOD-180759	yes	1824.76
E-HCAD-35	yes	1709.09
E-GEOD-135922	yes	551.87
E-MTAB-10287	yes	61.16
E-MTAB-6701	yes	49.48
E-CURD-119	yes	43.57
E-MTAB-8410	yes	20.20
E-HCAD-11	yes	19.61
E-MTAB-6678	yes	13.59
E-CURD-46	yes	9.14
E-GEOD-134144	yes	9.14
E-ENAD-27	yes	6.33
E-CURD-112	no	2.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Involved in the growth factor-controlled regulation of cell proliferation and differentiation in the seminiferous epithelium. (PMID:15273867)
• These results support a model whereby the synergic bundling activity of the IRSp53-Eps8 complex, regulated by Cdc42, contributes to the generation of actin bundles, thus promoting filopodial protrusions. (PMID:17115031)
• Eps8 is essential for actin dynamics and cell interactions, independent of Eps8-like gene products. (PMID:17537571)
• These findings implicate the involvement of Eps8 in chemoresistance and show its importance in prognosis of cervical cancer patients. (PMID:18566210)
• overexpression of EPS8 in HN4 cells was sufficient to induce growth of non-tumorigenic cells in orthotopic transplantation assays. EPS8 expression in samples of squamous cell carcinoma showed variable expression levels and paralleled expression of MMP-9 (PMID:19008210)
• A role of Eps8 in amplifying growth factor receptor signaling in human pituitary tumors to promote proliferation and cell survival. (PMID:19116338)
• Results show that alphavbeta6- and alpha5beta1-integrin-dependent activation of Rac1 was mediated through Eps8. (PMID:19448673)
• the crystal structures of human LanCL1, both free of and complexed with glutathione, revealing glutathione binding to a zinc ion at the putative active site formed by conserved GxxG motifs (PMID:19528316)
• Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells (PMID:20184880)
• Overexpression of EPS8 induced expression of the chemokine ligands CXCL5 and CXCL12 in a FOXM1-dependent manner, which was blocked by LY294002 or a dominant-negative form of AKT (PMID:20351091)
• IRSp53, through its interaction with Eps8, not only affects cell migration but also dictates cellular growth in cancer cells. (PMID:20418908)
• Study implicates that the integrity of SOS1/EPS8/ABI1 tri-complex is a determinant of ovarian cancer metastasis. (PMID:21118970)
• critical role for JNK2 and EPS8 in receptor tyrosine kinase signaling and trafficking to convey distinctly different effects on cell migration. (PMID:21357683)
• Studied generation of filopodia with regards to the dynamic interaction established by Eps8, IRSp53 and VASP with actin filaments. (PMID:21814501)
• The ITSN2 interacts with Eps8 and stimulates the degradation of Eps8 proteins. (PMID:22449706)
• Eps8 is a key regulator of the LPS-stimulated TLR4-MyD88 interaction and contributes to macrophage phagocytosis (PMID:22493489)
• silencing of the protein by siRNA abrogated the migratory and invasive capacity of three different glioblastoma cell lines both in 2-dimensional and 3-dimensional in vitro assays. (PMID:22683923)
• The loss of EPS8 expression in colorectal adenomas and carcinomas suggests that down regulation of this gene contributes to the development of a subset of colorectal cancers. (PMID:22876043)
• Eps8 is frequently expressed in OSCC. The aberrant expression of Eps8 closely correlated with poor survival in patients with OSCC. (PMID:22897151)
• Eps8 functions as a key coordinator in the interplay between FGFR signalling and trafficking. (PMID:23203811)
• We found that Eps8 mediates cell proliferation and survival of glioma cells, at least in part, by affecting phosphorylated ERK and Akt/beta-catenin activities. (PMID:23229386)
• Identify Fbxw5-driven fluctuation of Eps8 levels as an important mechanism that contributes to cell-shape changes during entry into-and exit from-mitosis. (PMID:23314863)
• Novel binding partners and differentially regulated phosphorylation sites clarify Eps8 as a multi-functional adaptor. (PMID:23626693)
• results suggest that Eps8 may serve as a prognostic factor of responsiveness to chemotherapy in AML patients (PMID:24409660)
• EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8-/- mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction (PMID:24741995)
• determined the alpha-synuclein-binding domain of beta-III tubulin and demonstrated that a short fragment containing this domain can suppress alpha-synuclein accumulation in the primary cultured cells (PMID:25031323)
• Eps8 is overexpressed in human breast cancers, possibly by regulating ERK signaling, MMP9, p53 and EMT-like transition to affect breast cancer cell growth, migration and invasion. (PMID:25333707)
• Eps8 is a crucial mediator of Src- and FAK-regulated processes. (PMID:25359883)
• These results indicate that employing the native and modified epitopes identified here in Eps8-based immunotherapy for HLA-A2.1 positive cancer patients may result in efficient anticancer immune responses for diverse tumor types. (PMID:25376540)
• EPS8, as MDR1 and WT1, may be a clinically valuable biomarker for assessing the outcome of ALL patients. (PMID:25843487)
• Erk activity promotes actin bundling by Eps8 to enhance cortex tension and drive the bleb-based migration of cancer cells under non-adhesive confinement. (PMID:26163656)
• Eps8 is required for continuous membrane blebbing. (PMID:26976596)
• Immunohistochemistry revealed that Eps8 was significantly increased in cervical cancer specimens compared with squamous intraepithelial lesion and normal cervical tissues. Additionally, it was revealed that Eps8 expression not only correlated with cervical cancer progression, but also exhibited a close correlation with the epithelialmesenchymal transition (EMT) markers, Ecadherin and vimentin. (PMID:27573546)
• These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration (PMID:28214294)
• Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in pancreatic ductal adenocarcinoma cells modulates alphavbeta6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-beta1 activation (Rho-dependent) functional phenotype (PMID:28608476)
• Eps8 is involved in tumor invasion but not necessarily the development of regional lymph node metastasis (PMID:29107665)
• Data showed that chronic myeloid leukemia (CML) patients expressed a higher level of EPS8 mRNA in bone marrow mononuclear cells. Functional results revealed that EPS8 regulated multiple biological functions such as proliferation, apoptosis, cell cycle, drug sensitivity of CML cells possibly by mediating the regulation of the BCR-ABL/AKT/mTOR signalling pathway. (PMID:29192326)
• LncRNA DSCAM-AS1 acts as a competing endogenous RNA of miR-137 and regulates EPS8 to promote cell reproduction and suppresses cell apoptosis in Tamoxifen-resistant breast cancer (PMID:30203615)
• Comparative analyses revealed that Eps8 protein was abundant in exosomes derived from metastatic pancreatic tumors and ascites and that the amount of exosomal Eps8 was quantitatively correlated with the in vitro cell migratory activity. (PMID:30431134)
• we focused on EPS8 because its expression had the greatest impact on patient prognosis (overall survival, p < 0.0001). Overexpression of EPS8 was detected in PDAC clinical specimens. Knockdown assays with siEPS8 showed that its overexpression enhanced cancer cell proliferation, migration, and invasion (PMID:30858505)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	eps8a	ENSDARG00000102128
mus_musculus	Eps8	ENSMUSG00000015766
rattus_norvegicus	Eps8	ENSRNOG00000007047

Paralogs (3): EPS8L1 (ENSG00000131037), EPS8L2 (ENSG00000177106), EPS8L3 (ENSG00000198758)

Protein

Protein identifiers

Epidermal growth factor receptor kinase substrate 8 — Q12929 (reviewed: Q12929)

All UniProt accessions (10): Q12929, A0A2R8Y4W2, A0A2R8YE63, F5GYM8, F5H0R8, F5H1B5, F5H2B8, F5H3Q6, F5H714, H0YFG1

UniProt curated annotations — full annotation on UniProt →

Function. Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture. Depending on its association with other signal transducers, can regulate different processes. Together with SOS1 and ABI1, forms a trimeric complex that participates in transduction of signals from Ras to Rac by activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. Acts as a direct regulator of actin dynamics by binding actin filaments and has both barbed-end actin filament capping and actin bundling activities depending on the context. Displays barbed-end actin capping activity when associated with ABI1, thereby regulating actin-based motility process: capping activity is auto-inhibited and inhibition is relieved upon ABI1 interaction. Also shows actin bundling activity when associated with BAIAP2, enhancing BAIAP2-dependent membrane extensions and promoting filopodial protrusions. Involved in the regulation of processes such as axonal filopodia growth, stereocilia length, dendritic cell migration and cancer cell migration and invasion. Acts as a regulator of axonal filopodia formation in neurons: in the absence of neurotrophic factors, negatively regulates axonal filopodia formation via actin-capping activity. In contrast, it is phosphorylated in the presence of BDNF leading to inhibition of its actin-capping activity and stimulation of filopodia formation. Component of a complex with WHRN and MYO15A that localizes at stereocilia tips and is required for elongation of the stereocilia actin core. Indirectly involved in cell cycle progression; its degradation following ubiquitination being required during G2 phase to promote cell shape changes.

Subunit / interactions. Homodimer. Part of a complex consisting of ABI1, EPS8 and SOS1. Interacts with MYO15A and WHRN. Interacts with LANCL1. Interacts with EGFR; mediates EPS8 phosphorylation. Interacts with BAIAP2. Interacts with SHB.

Subcellular location. Cytoplasm. Cell cortex. Cell projection. Ruffle membrane. Growth cone. Stereocilium. Synapse. Synaptosome.

Tissue specificity. Expressed in all tissues analyzed, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in all epithelial and fibroblastic lines examined and in some, but not all, hematopoietic cells.

Post-translational modifications. Ubiquitinated by the SCF(FBXW5) E3 ubiquitin-protein ligase complex during G2 phase, leading to its transient degradation and subsequent cell shape changes required to allow mitotic progression. Reappears at the midzone of dividing cells. Phosphorylation at Ser-625 and Thr-629 by MAPK following BDNF treatment promotes removal from actin and filopodia formation. Phosphorylated by several receptor tyrosine kinases.

Disease relevance. Deafness, autosomal recessive, 102 (DFNB102) [MIM:615974] A form of non-syndromic deafness characterized by profound hearing loss affecting all frequencies. Vestibular function is unaffected. The disease is caused by variants affecting the gene represented in this entry. Defects in EPS8 are associated with some cancers, such as pancreatic, oral squamous cell carcinomas or pituitary cancers. Contributes to cell transformation in response to growth factor treatment and is overexpressed in a number of tumors, indicating that EPS8 levels must be tightly regulated.

Domain organisation. The effector region is required for activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. It mediates both barbed-end actin capping and actin bundling activities. The capping activity is mediated by an amphipathic helix that binds within the hydrophobic pocket at the barbed ends of actin blocking further addition of actin monomers, while the bundling activity is mediated by a compact 4 helix bundle, which contacts 3 actin subunits along the filament. The SH3 domain mediates interaction with SHB.

Similarity. Belongs to the EPS8 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q12929-1	1	yes
Q12929-2	2

RefSeq proteins (10): NP_001400760, NP_001400761, NP_001400762, NP_001400763, NP_001400764, NP_001400765, NP_001400766, NP_001400767, NP_001400768, NP_004438* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013625	PTB	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR033928	EPS8_PTB	Domain
IPR035462	Eps8_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR039801	EPS8-like	Family
IPR041418	SAM_3	Domain
IPR055093	EPS8_2nd	Domain

Pfam: PF00018, PF08416, PF18016, PF22975

UniProt features (53 total): region of interest 11, modified residue 11, sequence conflict 7, compositionally biased region 6, strand 6, helix 6, domain 2, sequence variant 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7TZK	X-RAY DIFFRACTION	1.43
2E8M	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12929-F1	70.77	0.32

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 (11): 58, 223, 317, 476, 625, 629, 659, 662, 685, 811, 815

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 430 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, GOBP_RESPONSE_TO_ETHANOL, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_ADULT_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (17): Rho protein signal transduction (GO:0007266), adult locomotory behavior (GO:0008344), regulation of cell shape (GO:0008360), exit from mitosis (GO:0010458), Rac protein signal transduction (GO:0016601), regulation of actin filament length (GO:0030832), regulation of Rho protein signal transduction (GO:0035023), dendritic cell migration (GO:0036336), behavioral response to ethanol (GO:0048149), barbed-end actin filament capping (GO:0051016), actin filament bundle assembly (GO:0051017), actin crosslink formation (GO:0051764), actin polymerization-dependent cell motility (GO:0070358), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), positive regulation of ruffle assembly (GO:1900029), cellular response to leukemia inhibitory factor (GO:1990830), actin cytoskeleton organization (GO:0030036)

GO Molecular Function (3): actin binding (GO:0003779), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (18): plasma membrane (GO:0005886), brush border (GO:0005903), cell cortex (GO:0005938), postsynaptic density (GO:0014069), NMDA selective glutamate receptor complex (GO:0017146), growth cone (GO:0030426), vesicle (GO:0031982), stereocilium (GO:0032420), stereocilium tip (GO:0032426), ruffle membrane (GO:0032587), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), membrane (GO:0016020), stereocilium bundle (GO:0032421), cell projection (GO:0042995), neuron projection (GO:0043005), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
small GTPase-mediated signal transduction	2
adult behavior	2
regulation of biological quality	2
cell periphery	2
cluster of actin-based cell projections	2
stereocilium	2
locomotory behavior	1
regulation of cell morphogenesis	1
mitotic cell cycle phase transition	1
mitotic nuclear division	1
regulation of cellular component size	1
regulation of actin cytoskeleton organization	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
mononuclear cell migration	1
response to ethanol	1
actin filament capping	1
cellular component assembly	1
actin filament bundle organization	1
actin filament organization	1
cell motility	1
ruffle assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of ruffle assembly	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
cytoskeleton organization	1
actin filament-based process	1
cytoskeletal protein binding	1
GTPase binding	1
binding	1
membrane	1
microvillus	1
apical part of cell	1
cytoplasm	1
asymmetric synapse	1
postsynaptic specialization	1
ionotropic glutamate receptor complex	1
site of polarized growth	1

Protein interactions and networks

STRING

1340 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPS8	ABI1	Q8IZP0	999
EPS8	SOS1	Q07889	997
EPS8	BAIAP2	Q9UQB8	982
EPS8	MYO15A	Q9UKN7	955
EPS8	WHRN	Q9P202	941
EPS8	USP6NL	Q92738	935
EPS8	LANCL1	O43813	848
EPS8	EGFR	P00533	815
EPS8	ESPN	B1AK53	803
EPS8	PALLD	Q8WX93	789
EPS8	WASF2	Q9Y6W5	776
EPS8	GPSM2	P81274	759
EPS8	RASA1	P20936	758
EPS8	CDC42	P21181	751
EPS8	WASL	O00401	747

IntAct

147 interactions, top by confidence:

A	B	Type	Score
EPS8	BAIAP2	psi-mi:“MI:0915”(physical association)	0.890
BAIAP2	EPS8	psi-mi:“MI:0915”(physical association)	0.890
BAIAP2L1	EPS8	psi-mi:“MI:0407”(direct interaction)	0.720
BAIAP2L1	EPS8	psi-mi:“MI:0915”(physical association)	0.720
BAIAP2	EPS8	psi-mi:“MI:0407”(direct interaction)	0.720
EPS8	BAIAP2	psi-mi:“MI:0915”(physical association)	0.720
EGFR	EPS8	psi-mi:“MI:0915”(physical association)	0.710
EPS8	EGFR	psi-mi:“MI:0915”(physical association)	0.710
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
HNRNPC	EPS8	psi-mi:“MI:0915”(physical association)	0.560
GRB2	EPS8	psi-mi:“MI:0915”(physical association)	0.560
RUNX1T1	EPS8	psi-mi:“MI:0915”(physical association)	0.560
EPS8	GOLGA8DP	psi-mi:“MI:0915”(physical association)	0.560
BYSL	EPS8	psi-mi:“MI:0915”(physical association)	0.560
EPS8	INPP5J	psi-mi:“MI:0915”(physical association)	0.560
EPS8	SMARCE1	psi-mi:“MI:0915”(physical association)	0.560
EPS8	BORCS6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (147): EPS8 (Two-hybrid), EPS8 (Two-hybrid), GRB2 (Two-hybrid), HNRNPC (Two-hybrid), SMARCE1 (Two-hybrid), BAIAP2 (Two-hybrid), INPP5J (Two-hybrid), C17orf59 (Two-hybrid), C19orf25 (Two-hybrid), GOLGA8EP (Two-hybrid), EPS8 (Two-hybrid), BLOC1S6 (Two-hybrid), EPS8 (Affinity Capture-MS), CCDC85B (Two-hybrid), AIMP2 (Two-hybrid)

ESM2 similar proteins: A0JMA8, A1XD93, A1XD94, A1XD95, A1XD97, A4UMC5, A4UMC6, B3DJT0, B5DFC8, E7EXT2, E7F187, F1M3L7, F7AEX0, O14617, O54774, P52590, P53569, P57740, P78344, P79398, Q06AK6, Q0IIX9, Q12929, Q17784, Q17CQ8, Q29RR5, Q2KI89, Q5R4H4, Q5R5K8, Q5R629, Q5R7J9, Q5TYV4, Q5U2Y6, Q5ZII9, Q62448, Q66J74, Q6DI35, Q865S1, Q8BH74, Q8IQ05

Diamond homologs: A0JNB0, A1CAL7, A1DEZ0, A1Y2K1, A2QGW1, A5DR93, A5E1V8, A6QTM4, A6ZR73, A7F1F4, B0Y3Z4, B2ANF9, B2VV00, B3LRN4, B5VHP4, B6HR44, B6QEE0, B8MD74, B8NEM4, B8R1V5, C0S7Q7, C1GJ63, C4JLG3, C4QVD6, C4Y1G1, C5DE38, C5DQY5, C5FH98, C5GIQ8, C5JGE5, C5MB30, C6HFQ7, C7GKW5, C7Z504, C9SA05, D1ZRK4, D4ARB8, D4DA58, D6PVB4, D6PVB5

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PTK6	“up-regulates activity”	EPS8	phosphorylation
MAPK3	“down-regulates activity”	EPS8	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	5
Uncertain significance	194
Likely benign	129
Benign	43

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1214371	NM_004447.6(EPS8):c.462del (p.Glu155fs)	Pathogenic
1342940	NM_004447.6(EPS8):c.1424T>G (p.Leu475Ter)	Pathogenic
1452443	NM_004447.6(EPS8):c.409del (p.Gln137fs)	Pathogenic
155761	NM_004447.6(EPS8):c.88C>T (p.Gln30Ter)	Pathogenic
2127162	NM_004447.6(EPS8):c.1802_1817del (p.Pro601fs)	Pathogenic
2701594	NM_004447.6(EPS8):c.179C>G (p.Ser60Ter)	Pathogenic
3601073	NM_004447.6(EPS8):c.1048C>T (p.Gln350Ter)	Pathogenic
3601074	NM_004447.6(EPS8):c.517-1G>T	Pathogenic
3601077	NM_004447.6(EPS8):c.811-1G>A	Pathogenic
3065304	NM_004447.6(EPS8):c.676C>T (p.Gln226Ter)	Likely pathogenic
3601075	NM_004447.6(EPS8):c.600-1G>A	Likely pathogenic
3601076	NM_004447.6(EPS8):c.694C>T (p.Arg232Ter)	Likely pathogenic
997681	NM_004447.6(EPS8):c.1435-2A>T	Likely pathogenic
997682	GRCh37/hg19 12p12.3(chr12:15800060-15865927)	Likely pathogenic

SpliceAI

4663 predictions. Top by Δscore:

Variant	Effect	Δscore
12:15621431:C:CC	acceptor_gain	1.0000
12:15623283:CAGTC:C	acceptor_gain	1.0000
12:15623285:GTC:G	acceptor_gain	1.0000
12:15623285:GTCC:G	acceptor_loss	1.0000
12:15623287:CCTAA:C	acceptor_loss	1.0000
12:15623288:C:CC	acceptor_gain	1.0000
12:15623288:CTA:C	acceptor_loss	1.0000
12:15623289:T:C	acceptor_loss	1.0000
12:15624222:CTCA:C	donor_loss	1.0000
12:15624224:CACAC:C	donor_loss	1.0000
12:15624225:A:AC	donor_gain	1.0000
12:15624225:A:AT	donor_loss	1.0000
12:15624226:C:CT	donor_gain	1.0000
12:15624226:CA:C	donor_gain	1.0000
12:15624226:CACA:C	donor_gain	1.0000
12:15624226:CACAG:C	donor_gain	1.0000
12:15624404:CTTC:C	acceptor_gain	1.0000
12:15624408:C:CC	acceptor_gain	1.0000
12:15624408:CTAG:C	acceptor_loss	1.0000
12:15631427:C:A	donor_gain	1.0000
12:15631440:A:AC	donor_gain	1.0000
12:15631440:ACGGT:A	donor_gain	1.0000
12:15631441:C:CC	donor_gain	1.0000
12:15631441:CGGTC:C	donor_gain	1.0000
12:15631663:TT:T	acceptor_gain	1.0000
12:15631665:C:CC	acceptor_gain	1.0000
12:15640698:CTCA:C	donor_loss	1.0000
12:15640700:CA:C	donor_loss	1.0000
12:15640701:A:AC	donor_gain	1.0000
12:15640702:C:CC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002784 (12:15631331 C>A,G,T), RS1000026198 (12:15730216 T>C), RS1000030290 (12:15684707 G>C), RS1000080354 (12:15773405 CAGA>C), RS1000119351 (12:15682503 G>A,C), RS1000121796 (12:15757304 A>G), RS1000140712 (12:15645931 A>T), RS1000151295 (12:15638274 T>C), RS1000160693 (12:15737267 T>C), RS1000197685 (12:15625227 C>T), RS1000201139 (12:15771465 G>A), RS1000258508 (12:15787717 A>G), RS1000265911 (12:15743093 T>C), RS1000266686 (12:15688034 C>T), RS1000308635 (12:15776786 C>A,T)

Disease associations

OMIM: gene MIM:600206 | disease phenotypes: MIM:615974, MIM:617637, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 102	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 102	Moderate	AR

Mondo (3): autosomal recessive nonsyndromic hearing loss 102 (MONDO:0014428), hearing loss, autosomal recessive 106 (MONDO:0033198), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (2): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003577	Congenital onset
HP:0012715	Profound hearing impairment

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000189_30	Protein quantitative trait loci	7.000000e-07
GCST009391_1883	Metabolite levels	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004459	ferritin measurement
EFO:0010414	triacylglycerol 52:2 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564609	Deafness, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression	6
bisphenol S	increases expression, decreases expression, affects cotreatment, decreases methylation	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
Air Pollutants	increases oxidation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Dexamethasone	decreases expression, increases expression, affects cotreatment	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Colforsin	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
bisphenol A	affects localization	1
methylselenic acid	increases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
hydroxyhydroquinone	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
afimoxifene	decreases expression, decreases reaction	1
sodium arsenite	increases expression	1
doxifluridine	increases response to substance	1
manganese chloride	decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
cupric chloride	increases expression	1
1-UFT protocol	increases response to substance	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
mithramycin A	decreases expression	1

Clinical trials (associated diseases)

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