EYA2

Summary

EYA2 (EYA transcriptional coactivator and phosphatase 2, HGNC:3520) is a protein-coding gene on chromosome 20q13.12, encoding Protein phosphatase EYA2 (O00167). Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5.

This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may be post-translationally modified and may play a role in eye development. A similar protein in mice can act as a transcriptional activator. Alternative splicing results in multiple transcript variants, but the full-length natures of all of these variants have not yet been determined.

Source: NCBI Gene 2139 — RefSeq curated summary.

At a glance

• GWAS associations: 125
• Clinical variants (ClinVar): 89 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005244

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3520
Approved symbol	EYA2
Name	EYA transcriptional coactivator and phosphatase 2
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	EAB1
Ensembl gene	ENSG00000064655
Ensembl biotype	protein_coding
OMIM	601654
Entrez	2139

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000317304, ENST00000327619, ENST00000357410, ENST00000458636, ENST00000471081, ENST00000475856, ENST00000479843, ENST00000497428, ENST00000611592, ENST00000858534, ENST00000858535, ENST00000858536, ENST00000858537, ENST00000858538, ENST00000931918, ENST00000957905, ENST00000957907

RefSeq mRNA: 2 — MANE Select: NM_005244 NM_005244, NM_172110

CCDS: CCDS13403, CCDS54471

Canonical transcript exons

ENST00000327619 — 16 exons

Exon	Start	End
ENSE00000510299	47016181	47016297
ENSE00000662641	47004942	47005084
ENSE00000662642	47001428	47001473
ENSE00001685426	46990001	46990119
ENSE00003137905	47074158	47074335
ENSE00003225968	47072185	47072252
ENSE00003618852	47089239	47089381
ENSE00003712387	47183291	47183391
ENSE00003712718	47188053	47188844
ENSE00003725170	47169139	47169197
ENSE00003735013	47143059	47143148
ENSE00003737632	47179798	47179912
ENSE00003745403	47172707	47172867
ENSE00003747249	47180815	47180936
ENSE00003748252	47097085	47097168
ENSE00003843808	46894843	46894987

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 93.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9244 / max 486.1184, expressed in 927 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185074	4.2294	782
185071	2.6776	761
185075	0.5480	248
185072	0.3002	131
185073	0.1567	87
185070	0.0124	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	93.82	gold quality
calcaneal tendon	UBERON:0003701	93.40	gold quality
parotid gland	UBERON:0001831	90.17	gold quality
esophagus mucosa	UBERON:0002469	89.96	gold quality
nasal cavity mucosa	UBERON:0001826	89.62	gold quality
nasal cavity epithelium	UBERON:0005384	89.07	gold quality
esophagus squamous epithelium	UBERON:0006920	89.04	gold quality
epithelium of esophagus	UBERON:0001976	88.83	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.29	gold quality
right uterine tube	UBERON:0001302	87.55	gold quality
saliva-secreting gland	UBERON:0001044	87.21	gold quality
minor salivary gland	UBERON:0001830	87.11	gold quality
tibial nerve	UBERON:0001323	86.63	gold quality
mucosa of transverse colon	UBERON:0004991	86.38	gold quality
lower esophagus mucosa	UBERON:0035834	86.04	gold quality
endocervix	UBERON:0000458	85.42	gold quality
mouth mucosa	UBERON:0003729	84.48	gold quality
ectocervix	UBERON:0012249	84.07	gold quality
prostate gland	UBERON:0002367	83.95	gold quality
vagina	UBERON:0000996	83.93	gold quality
endometrium	UBERON:0001295	83.86	gold quality
left lobe of thyroid gland	UBERON:0001120	83.32	gold quality
right lobe of thyroid gland	UBERON:0001119	83.21	gold quality
thyroid gland	UBERON:0002046	82.55	gold quality
sural nerve	UBERON:0015488	81.89	gold quality
esophagus	UBERON:0001043	81.81	gold quality
epithelium of nasopharynx	UBERON:0001951	81.81	silver quality
tendon	UBERON:0000043	81.74	gold quality
omental fat pad	UBERON:0010414	81.12	gold quality
peritoneum	UBERON:0002358	81.08	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	53.44
E-ANND-3	yes	9.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, E2F1, MEOX1, MYOD1, PROX1, SIX1

miRNA regulators (miRDB)

57 targeting EYA2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-7151-5P	99.37	67.82	613

Literature-anchored findings (GeneRIF, showing 24)

• EYA2 was found to function as transcriptional activator in ovarian cancer cells by Gal4 assay and to promote tumor growth in vivo in xenograft models. (PMID:15705892)
• EYA2 and EYA3 displayed specificity for Tyr-142 of H2A.X (PMID:19351884)
• Based on observation that the dachshund-binding site is located between the catalytic core & Sine Oculis binding sites within ED-Eya2, we propose that catalytic activity can be translated to SO binding through DAC, which acts as a transcriptional switch. (PMID:19858093)
• Expression of EYA2 in lung adenocarcinoma is augmented. (PMID:19950702)
• Data implicate Eya2 as a necessary co-factor for many of the metastasis promoting functions of Six1. (PMID:21706047)
• Studies indicate that the RNA and protein levels of Eya2 is upregulated in ovarian cancer. (PMID:22607316)
• Functional roles of candidate genes EYA2 (20q13) and hsa-miR-375 (2q35) were studied by siRNA-mediated knock-down and overexpression, respectively, in hrHPV-containing cell lines. (PMID:22987659)
• Given that SIX1 and EYA are overexpressed in many tumor types, our data indicate that targeting the SIX1-EYA complex may be a potent approach to inhibit tumor progression in multiple cancer types (PMID:23435380)
• This interaction suggests that CDK6 regulates EYA2 activity, a mechanism that could be important in development and in cancer. (PMID:24196439)
• MIR30A represses Eya2 expression by binding to the 3’-untranslated region of Eya2.The MIR30A/EYA2 axis regulates breast cancer cell proliferation and migration. (PMID:24508260)
• Decreased expression of EYA2 is associated with pancreatic adenocarcinomas. (PMID:24810906)
• SIX1 and EYA are often co-overexpressed in tumors, and the SIX1-EYA2 interaction has been shown to be critical for metastasis in a breast cancer model. (PMID:25555392)
• EYA2 functions as a stimulant in lung adenocarcinoma pathogenesis. (PMID:26329363)
• results demonstrate that overexpression of miR-30a in lung adenocarcinoma A549 cells can inhibit cell migration and invasion, which is partially attributed to the decrease of EYA2 expression (PMID:26837415)
• High EYA2 expression is associated with acute myeloid leukemia. (PMID:28416638)
• EYA2 knockdown led to decreased metastatic spread of breast cancer cells to the lung and greatly attenuated the ability of EGFR to regulate the epithelial-to-mesenchymal transition markers. (PMID:28703807)
• our data indicate that Eya2 may serve as a potential oncoprotein in human astrocytoma. Eya2 regulates astrocytoma cell proliferation and invasion, possibly through the regulation of ERK signaling. (PMID:28901379)
• study revealed that miR-219a-5p function as tumour suppressor regulates osteosarcoma cell invasiveness by repressing EYA2 expression. (PMID:30449183)
• The inhibition of AKT attenuated EYA2-induced Bcl-2 upregulation. In conclusion, our data demonstrated that Eya2 was upregulated in prostate cancers. EYA2 promotes cell proliferation and invasion as well as cancer progression by regulating docetaxel sensitivity and mitochondrial membrane potential, possibly via the AKT/Bcl-2 axis. (PMID:31317026)
• MicroRNA-219 inhibits cell viability and metastasis in papillary thyroid carcinoma by targeting EYA2. (PMID:33015798)
• EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling. (PMID:34044846)
• Targeting EYA2 tyrosine phosphatase activity in glioblastoma stem cells induces mitotic catastrophe. (PMID:34617969)
• Structure-activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase. (PMID:34761455)
• EYA2 tyrosine phosphatase inhibition reduces MYC and prevents medulloblastoma progression. (PMID:37486991)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eya2	ENSDARG00000018984
mus_musculus	Eya2	ENSMUSG00000017897
rattus_norvegicus	Eya2	ENSRNOG00000019203
drosophila_melanogaster	eya	FBGN0000320
caenorhabditis_elegans	eya-1	WBGENE00001377

Paralogs (3): EYA1 (ENSG00000104313), EYA4 (ENSG00000112319), EYA3 (ENSG00000158161)

Protein

Protein identifiers

Protein phosphatase EYA2 — O00167 (reviewed: O00167)

Alternative names: Eyes absent homolog 2

All UniProt accessions (3): O00167, B1AKW3, E7ETN2

UniProt curated annotations — full annotation on UniProt →

Function. Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5. Tyrosine phosphatase that dephosphorylates ‘Tyr-142’ of histone H2AX (H2AXY142ph) and promotes efficient DNA repair via the recruitment of DNA repair complexes containing MDC1. ‘Tyr-142’ phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Its function as histone phosphatase may contribute to its function in transcription regulation during organogenesis. Plays an important role in hypaxial muscle development together with SIX1 and DACH2; in this it is functionally redundant with EYA1.

Subunit / interactions. Interacts with DACH2 and SIX1, and probably with SIX2, SIX4 and SIX5. Interacts with CAPN8. Interacts with GNAZ and GNAI2; this precludes interaction with SIX1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highest expression in muscle with lower levels in kidney, placenta, pancreas, brain and heart.

Cofactor. Binds 1 Mg(2+) ion per subunit.

Similarity. Belongs to the HAD-like hydrolase superfamily. EYA family.

Isoforms (3)

UniProt ID	Names	Canonical?
O00167-1	1	yes
O00167-2	2
O00167-3	3

RefSeq proteins (2): NP_005235, NP_742108 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006545	EYA_dom	Domain
IPR028472	EYA	Family
IPR036412	HAD-like_sf	Homologous_superfamily
IPR038102	EYA_dom_sf	Homologous_superfamily
IPR042577	EYA_dom_metazoan	Domain

Pfam: PF00702

Enzyme classification (BRENDA):

• EC 3.1.3.48 — protein-tyrosine-phosphatase (BRENDA: 59 organisms, 501 substrates, 1326 inhibitors, 270 Km, 165 kcat entries)

Substrate kinetics (BRENDA)

70 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-NITROPHENYL PHOSPHATE	0.0008–148	84
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.0039–0.862	27
P-NITROPHENYL PHOSPHATE	0.0024–10	20
DADEPYLIPQQG	0.0003–0.1	12
PHOSPHOTYROSINE	0.012–30	11
LYSOZYME	0.0003–0.012	5
MYELIN BASIC PROTEIN	0.0001–0.022	5
ACETYL-DADEPY-NH2	0.0228–0.219	4
ACETYL-DADEPYL-NH2	1.1–97.5	4
4,6,8-TRIMETHYL-2-OXO-2H-CHROMEN-7-YL DIHYDROGEN	0.02–0.156	3
SASASPYSASA	0.53–2.3	3
1-NAPHTHYL PHOSPHATE	1.19–1.88	2
3,6-FLUORESCEIN DIPHOSPHATE	15–19	2
4-METHYLUMBELLIFERYL PHOSPHATE	0.953–2.41	2
BOVINE SERUM ALBUMIN	0.0001–0.0003	2

Catalyzed reactions (Rhea), 1 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)

UniProt features (46 total): helix 16, sequence conflict 5, strand 5, turn 5, binding site 3, splice variant 2, sequence variant 2, mutagenesis site 2, compositionally biased region 2, active site 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4EGC	X-RAY DIFFRACTION	1.99
3GEB	X-RAY DIFFRACTION	2.4
3HB0	X-RAY DIFFRACTION	2.5
3HB1	X-RAY DIFFRACTION	2.51
5ZMA	X-RAY DIFFRACTION	3.17
7F8H	X-RAY DIFFRACTION	3.3
7F8G	X-RAY DIFFRACTION	3.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00167-F1	69.07	0.48

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 (2): 274 (nucleophile); 276 (proton donor)

Ligand- & substrate-binding residues (3): 274; 276; 502

Mutagenesis-validated functional residues (2):

Position	Phenotype
516	strongly reduces six1 binding.
532	abolishes interaction with six1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks

MSigDB gene sets: 287 (showing top): BROWNE_HCMV_INFECTION_4HR_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, RAMJAUN_APOPTOSIS_BY_TGFB1_VIA_SMAD4_DN, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_DNA_REPAIR, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_MITOCHONDRIAL_TRANSPORT, GTGCCTT_MIR506, GOBP_NEGATIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, TCF4_Q5, GOBP_CELL_FATE_COMMITMENT_INVOLVED_IN_FORMATION_OF_PRIMARY_GERM_LAYER, AAACCAC_MIR140

GO Biological Process (12): DNA repair (GO:0006281), mesodermal cell fate specification (GO:0007501), striated muscle tissue development (GO:0014706), cell differentiation (GO:0030154), positive regulation of DNA repair (GO:0045739), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), mitochondrial outer membrane permeabilization (GO:0097345), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), multicellular organism development (GO:0007275)

GO Molecular Function (7): magnesium ion binding (GO:0000287), protein tyrosine phosphatase activity (GO:0004725), histone H2AXY142 phosphatase activity (GO:0140793), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Double Strand Break Response	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular membrane-bounded organelle	2
cytoplasm	2
DNA metabolic process	1
DNA damage response	1
cell fate specification	1
mesodermal cell fate commitment	1
muscle tissue development	1
cellular developmental process	1
DNA repair	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
signal transduction in absence of ligand	1
extrinsic apoptotic signaling pathway	1
apoptotic signaling pathway	1
positive regulation of mitochondrial membrane permeability involved in apoptotic process	1
extrinsic apoptotic signaling pathway in absence of ligand	1
negative regulation of signal transduction in absence of ligand	1
negative regulation of extrinsic apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1
cellular component organization	1
chromatin organization	1
cellular response to stress	1
multicellular organismal process	1
anatomical structure development	1
metal ion binding	1
phosphoprotein phosphatase activity	1
histone phosphatase activity	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EYA2	SIX1	Q15475	964
EYA2	SIX4	Q9UIU6	892
EYA2	PAX3	P23760	873
EYA2	SIX2	Q9NPC8	844
EYA2	MYOG	P15173	755
EYA2	MEOX1	P50221	740
EYA2	DACH2	Q96NX9	727
EYA2	DACH1	Q9UI36	723
EYA2	MYOD1	P15172	681
EYA2	PAX7	P23759	655
EYA2	SIX6	O95475	611
EYA2	MEOX2	P50222	546
EYA2	SALL1	Q9NSC2	506
EYA2	SIX5	Q8N196	505
EYA2	SOX10	P56693	500

IntAct

17 interactions, top by confidence:

A	B	Type	Score
SIX1	EYA2	psi-mi:“MI:0407”(direct interaction)	0.690
EYA2	SIX1	psi-mi:“MI:0915”(physical association)	0.690
SIX2	EYA2	psi-mi:“MI:0914”(association)	0.530
EYA2	CCDC85C	psi-mi:“MI:0915”(physical association)	0.400
EYA2	AATK	psi-mi:“MI:0915”(physical association)	0.370
EYA2	ROR2	psi-mi:“MI:0915”(physical association)	0.370
EYA2	DDI1	psi-mi:“MI:0915”(physical association)	0.370
EYA2	RBPMS	psi-mi:“MI:0915”(physical association)	0.370
EYA2	TFAP2A	psi-mi:“MI:0915”(physical association)	0.370
TFAP2C	EYA2	psi-mi:“MI:0915”(physical association)	0.370
SIX2	EYA4	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350

BioGRID (135): DMRTB1 (Two-hybrid), RBPMS (Two-hybrid), SIX1 (Two-hybrid), SIX4 (Proximity Label-MS), ZNF609 (Proximity Label-MS), TRPS1 (Proximity Label-MS), NCOR2 (Proximity Label-MS), CGN (Proximity Label-MS), ARID1A (Proximity Label-MS), ARID1B (Proximity Label-MS), KMT2D (Proximity Label-MS), BCOR (Proximity Label-MS), NCOR1 (Proximity Label-MS), TFAP2A (Proximity Label-MS), GSE1 (Proximity Label-MS)

ESM2 similar proteins: A0A068A9T3, A0A0F0I5G4, A0A0S6XAX9, A0A1U8QIH0, A0A345BJN6, A0A455LJ99, A0A7M4BDQ2, A2QA83, B0XYJ1, B0Y8Y9, B0Y9W4, B6GVZ2, B7ZSG3, B8N0E6, G0KYB3, G0LEU0, I1S2J8, I1S491, K3VDP7, O00167, O09102, O13493, P10069, P20945, P32338, P50902, Q00856, Q03347, Q05159, Q08427, Q09838, Q12531, Q28GD5, Q2U9L6, Q2UQZ5, Q4WRE4, Q4WW99, Q58DB6, Q58L83, Q5B7I8

Diamond homologs: O00167, O08575, O82162, O95677, P97480, P97767, Q05201, Q58DB6, Q99502, Q99504, Q9YH98, Q9YH99, Q9YHA0, Q9YHA1, Q9Z191, O17670

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3440 predictions. Top by Δscore:

Variant	Effect	Δscore
20:46989997:TCA:T	acceptor_loss	1.0000
20:46989998:CA:C	acceptor_loss	1.0000
20:46989999:AG:A	acceptor_gain	1.0000
20:46990000:GG:G	acceptor_gain	1.0000
20:46990000:GGT:G	acceptor_gain	1.0000
20:46990000:GGTA:G	acceptor_gain	1.0000
20:46990000:GGTAC:G	acceptor_gain	1.0000
20:46990116:CAAG:C	donor_loss	1.0000
20:46990117:AAG:A	donor_loss	1.0000
20:46990120:G:A	donor_loss	1.0000
20:46990121:T:G	donor_loss	1.0000
20:47005085:G:GG	donor_gain	1.0000
20:47074290:G:GT	donor_gain	1.0000
20:47095919:G:T	donor_gain	1.0000
20:47143146:G:GT	donor_gain	1.0000
20:47172705:A:AG	acceptor_gain	1.0000
20:47172706:G:GA	acceptor_gain	1.0000
20:47172706:GC:G	acceptor_gain	1.0000
20:47172706:GCA:G	acceptor_gain	1.0000
20:47172706:GCAC:G	acceptor_gain	1.0000
20:47172706:GCACA:G	acceptor_gain	1.0000
20:47172865:GTG:G	donor_gain	1.0000
20:47172872:GTACT:G	donor_gain	1.0000
20:47180813:A:AG	acceptor_gain	1.0000
20:47180814:G:GG	acceptor_gain	1.0000
20:47180932:GACAG:G	donor_gain	1.0000
20:47180933:ACAG:A	donor_loss	1.0000
20:47180934:CAG:C	donor_loss	1.0000
20:47180935:AG:A	donor_loss	1.0000
20:47180936:GGTAG:G	donor_loss	1.0000

AlphaMissense

3514 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:47097092:T:C	F271S	1.000
20:47097097:T:A	W273R	1.000
20:47097097:T:C	W273R	1.000
20:47097101:A:C	D274A	1.000
20:47097104:T:G	L275W	1.000
20:47097106:G:C	D276H	1.000
20:47097107:A:C	D276A	1.000
20:47097107:A:T	D276V	1.000
20:47097110:A:T	E277V	1.000
20:47097116:T:A	I279K	1.000
20:47097137:T:C	L286P	1.000
20:47143083:G:C	G305R	1.000
20:47143084:G:A	G305D	1.000
20:47143107:T:C	F313L	1.000
20:47143109:C:A	F313L	1.000
20:47143109:C:G	F313L	1.000
20:47143114:T:C	L315P	1.000
20:47143116:G:C	A316P	1.000
20:47143134:T:C	F322L	1.000
20:47143136:C:A	F322L	1.000
20:47143136:C:G	F322L	1.000
20:47143144:T:C	L325P	1.000
20:47169178:G:C	D340H	1.000
20:47172808:T:C	L380P	1.000
20:47172811:C:A	A381D	1.000
20:47172816:C:A	R383S	1.000
20:47172817:G:C	R383P	1.000
20:47172823:G:C	R385P	1.000
20:47179869:T:A	W424R	1.000
20:47179869:T:C	W424R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001479 (20:46949336 G>T), RS1000006222 (20:47109046 G>A), RS1000014090 (20:46935812 A>G), RS1000024300 (20:46926398 C>T), RS1000029479 (20:46974870 A>G), RS1000053786 (20:47081334 A>T), RS1000067562 (20:47013918 T>A), RS1000072078 (20:46896040 C>G,T), RS1000099330 (20:47120322 G>A), RS1000101184 (20:47161327 A>G), RS1000104725 (20:47167807 G>A), RS1000134679 (20:46990629 G>A), RS1000151144 (20:47089790 C>G,T), RS1000152220 (20:47035384 C>A,T), RS1000159165 (20:46958136 A>C,G)

Disease associations

OMIM: gene MIM:601654 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

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

GWAS associations

125 associations (top):

Study	Trait	p-value
GCST001524_17	Visceral adipose tissue/subcutaneous adipose tissue ratio	4.000000e-06
GCST001859_14	Thiazide-induced adverse metabolic effects in hypertensive patients	4.000000e-06
GCST002782_147	Waist-to-hip ratio adjusted for body mass index	3.000000e-10
GCST002782_148	Waist-to-hip ratio adjusted for body mass index	6.000000e-11
GCST002782_149	Waist-to-hip ratio adjusted for body mass index	6.000000e-10
GCST002782_150	Waist-to-hip ratio adjusted for body mass index	2.000000e-10
GCST004505_38	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	1.000000e-08
GCST004505_39	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	2.000000e-07
GCST004507_20	Waist-to-hip ratio adjusted for BMI (joint analysis main effects and smoking interaction)	3.000000e-07
GCST004567_124	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	3.000000e-08
GCST004576_4	Waist-to-hip ratio adjusted for body mass index	6.000000e-06
GCST004576_5	Waist-to-hip ratio adjusted for body mass index	4.000000e-08
GCST004578_50	Waist-to-hip ratio adjusted for BMI in active individuals	6.000000e-09
GCST004578_63	Waist-to-hip ratio adjusted for BMI in active individuals	6.000000e-06
GCST004794_2	Brain volume in infants (intracranial brain volume)	8.000000e-07
GCST005956_29	Waist-to-hip ratio adjusted for BMI	4.000000e-10
GCST005957_10	Waist-to-hip ratio adjusted for BMI (age <50)	5.000000e-06
GCST005958_17	Waist-to-hip ratio adjusted for BMI (age >50)	3.000000e-06
GCST005962_25	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-09
GCST006288_409	Heel bone mineral density	7.000000e-10
GCST006288_686	Heel bone mineral density	1.000000e-16
GCST006288_85	Heel bone mineral density	1.000000e-06
GCST006483_30	Lung function (FVC)	4.000000e-08
GCST006867_87	Type 2 diabetes	2.000000e-09
GCST006979_544	Heel bone mineral density	2.000000e-12
GCST006979_545	Heel bone mineral density	8.000000e-39
GCST007429_84	Lung function (FVC)	2.000000e-22
GCST007430_9	Peak expiratory flow	9.000000e-08
GCST007432_202	FEV1	8.000000e-18
GCST008074_55	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-07

EFO canonical traits (19, from GWAS)

EFO ID	Trait name
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004530	triglyceride measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0008369	infant intracranial volume measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0004329	alcohol drinking
EFO:0006781	coffee consumption measurement
EFO:0004847	age at onset
EFO:0007800	body fat percentage
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293275 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,239,369 (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
CHEMBL388590	BENZBROMARONE	4	8,245
CHEMBL858	EDETIC ACID	3	1,231,124

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 27 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.75	IC50	1800	nM	CHEMBL4463681
5.64	IC50	2300	nM	CHEMBL3191598
5.46	IC50	3450	nM	CHEMBL4459891
5.40	IC50	4000	nM	CHEMBL4530754
5.14	IC50	7300	nM	CHEMBL1975051

PubChem BioAssay actives

5 with measured affinity, of 6 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
3-fluoro-N-[(E)-(5-pyridin-2-ylsulfanylfuran-2-yl)methylideneamino]benzamide	1802882: Isothermal Titration Calorimetry (ITC) from Article 10.1074/jbc.M114.566729: “Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2-mediated cell migration.”	kd	0.8000	uM
3-fluoro-N-[(E)-(5-pyridin-2-ylsulfanylthiophen-2-yl)methylideneamino]benzamide	1802881: Eya Phosphatase Assay from Article 10.1074/jbc.M114.566729: “Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2-mediated cell migration.”	ic50	2.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
sodium arsenite	affects methylation, decreases expression	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
chromium hexavalent ion	decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Cadmium	decreases expression, increases abundance, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
bisphenol F	decreases methylation, affects cotreatment	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases methylation, affects cotreatment	1
trichostatin A	increases expression	1
zinc chromate	decreases expression, increases abundance	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases 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, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Benzbromarone	decreases activity	1
Carbamazepine	affects expression	1
N-Nitrosopyrrolidine	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Selenium	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tretinoin	increases expression	1

ChEMBL screening assays

36 unique, capped per target: 33 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614315	Functional	PUBCHEM_BIOASSAY: qHTS Assay for Inhibitors of the Phosphatase Activity of Eya2. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID488939]	PubChem BioAssay data set
CHEMBL4257241	Binding	Inhibition of human Eya2 catalytic domain by p-nitrophenylphosphate assay	Use of small molecule inhibitors targeting eya tyrosine phosphatase

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3HK	Panc 3.014-EYA2	Cancer cell line	Male
CVCL_C3HL	Panc 02.05-EYA2	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome