EPS8L2

Summary

EPS8L2 (EPS8 signaling adaptor L2, HGNC:21296) is a protein-coding gene on chromosome 11p15.5, encoding Epidermal growth factor receptor kinase substrate 8-like protein 2 (Q9H6S3). Stimulates guanine exchange activity of SOS1.

This gene encodes a member of the EPS8 gene family. The encoded protein, like other members of the family, is thought to link growth factor stimulation to actin organization, generating functional redundancy in the pathways that regulate actin cytoskeletal remodeling.

Source: NCBI Gene 64787 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive 106 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 427 total — 18 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_022772

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21296
Approved symbol	EPS8L2
Name	EPS8 signaling adaptor L2
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21935, FLJ22171, MGC3088
Ensembl gene	ENSG00000177106
Ensembl biotype	protein_coding
OMIM	614988
Entrez	64787

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 34 protein_coding, 15 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000318562, ENST00000524474, ENST00000524763, ENST00000524973, ENST00000526198, ENST00000526380, ENST00000526651, ENST00000526909, ENST00000527199, ENST00000527807, ENST00000527832, ENST00000528770, ENST00000529346, ENST00000529680, ENST00000530093, ENST00000530118, ENST00000530452, ENST00000530636, ENST00000531348, ENST00000531393, ENST00000531471, ENST00000532545, ENST00000533256, ENST00000533500, ENST00000533816, ENST00000534027, ENST00000534449, ENST00000534679, ENST00000534755, ENST00000614442, ENST00000650127, ENST00000856465, ENST00000856466, ENST00000856467, ENST00000856468, ENST00000856469, ENST00000856470, ENST00000856471, ENST00000856472, ENST00000856473, ENST00000856474, ENST00000856475, ENST00000856476, ENST00000856477, ENST00000856478, ENST00000856479, ENST00000856480, ENST00000856481, ENST00000856482, ENST00000856483, ENST00000856484, ENST00000912218, ENST00000961515, ENST00000961516

RefSeq mRNA: 1 — MANE Select: NM_022772 NM_022772

CCDS: CCDS31328

Canonical transcript exons

ENST00000318562 — 21 exons

Exon	Start	End
ENSE00002140807	706231	706288
ENSE00002163664	726901	727727
ENSE00003474718	721565	721691
ENSE00003480552	726304	726484
ENSE00003542299	709330	709451
ENSE00003542638	720062	720223
ENSE00003561420	721064	721206
ENSE00003587235	723241	723353
ENSE00003594075	720830	720909
ENSE00003600661	722673	722805
ENSE00003605847	726098	726170
ENSE00003608656	726619	726751
ENSE00003625340	722091	722165
ENSE00003632052	721285	721352
ENSE00003633327	709553	709608
ENSE00003635713	710422	710486
ENSE00003640675	725728	725847
ENSE00003643094	722401	722549
ENSE00003651137	724724	724829
ENSE00003652403	721903	721991
ENSE00003688403	720597	720746

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 99.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.1765 / max 546.0132, expressed in 1512 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112242	10.9807	1170
112240	2.8047	863
112243	1.4238	688
112246	0.8364	310
112239	0.5073	213
112233	0.4595	193
112249	0.2950	142
112234	0.2283	110
112241	0.2200	126
112244	0.1308	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.55	gold quality
metanephros cortex	UBERON:0010533	99.43	gold quality
esophagus mucosa	UBERON:0002469	98.79	gold quality
left lobe of thyroid gland	UBERON:0001120	98.57	gold quality
right lobe of thyroid gland	UBERON:0001119	98.56	gold quality
minor salivary gland	UBERON:0001830	98.27	gold quality
right lobe of liver	UBERON:0001114	98.07	gold quality
right uterine tube	UBERON:0001302	98.07	gold quality
cervix squamous epithelium	UBERON:0006922	98.07	silver quality
mucosa of transverse colon	UBERON:0004991	98.04	gold quality
mouth mucosa	UBERON:0003729	97.81	gold quality
skin of abdomen	UBERON:0001416	97.67	gold quality
skin of leg	UBERON:0001511	97.64	gold quality
amniotic fluid	UBERON:0000173	97.40	gold quality
thyroid gland	UBERON:0002046	97.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.92	gold quality
saliva-secreting gland	UBERON:0001044	96.80	gold quality
body of pancreas	UBERON:0001150	96.63	gold quality
right lung	UBERON:0002167	96.41	gold quality
tongue squamous epithelium	UBERON:0006919	96.29	gold quality
sural nerve	UBERON:0015488	96.10	gold quality
vagina	UBERON:0000996	95.88	gold quality
squamous epithelium	UBERON:0006914	95.74	gold quality
esophagus squamous epithelium	UBERON:0006920	95.51	gold quality
zone of skin	UBERON:0000014	95.50	gold quality
gingival epithelium	UBERON:0001949	95.45	gold quality
epithelium of esophagus	UBERON:0001976	95.23	gold quality
gingiva	UBERON:0001828	95.09	gold quality
upper lobe of left lung	UBERON:0008952	95.06	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	93.80
E-ANND-3	yes	9.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting EPS8L2, 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-3163	100.00	77.23	8605
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-3691-5P	98.62	65.88	552
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-582-3P	96.69	67.38	1019
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-6735-3P	96.10	63.81	600
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-4749-5P	92.16	62.26	179

Literature-anchored findings (GeneRIF, showing 1)

• frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells’ stereocilia previously implicated in progressive deafness in the mouse (PMID:26282398)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	eps8l2	ENSDARG00000058108
danio_rerio	eps8b	ENSDARG00000069011
mus_musculus	Eps8l2	ENSMUSG00000025504
rattus_norvegicus	Eps8l2	ENSRNOG00000018336
drosophila_melanogaster	aru	FBGN0029095
drosophila_melanogaster	CG8907	FBGN0038466
caenorhabditis_elegans		WBGENE00001330

Paralogs (3): EPS8L1 (ENSG00000131037), EPS8 (ENSG00000151491), EPS8L3 (ENSG00000198758)

Protein

Protein identifiers

Epidermal growth factor receptor kinase substrate 8-like protein 2 — Q9H6S3 (reviewed: Q9H6S3)

Alternative names: Epidermal growth factor receptor pathway substrate 8-related protein 2

All UniProt accessions (10): Q9H6S3, A0A3B3ISQ4, E9PLH1, E9PLN2, E9PM34, E9PN68, E9PNT0, E9PNY4, H0YD62, H0YF37

UniProt curated annotations — full annotation on UniProt →

Function. Stimulates guanine exchange activity of SOS1. May play a role in membrane ruffling and remodeling of the actin cytoskeleton. In the cochlea, is required for stereocilia maintenance in adult hair cells.

Subunit / interactions. Interacts with ABI1. Part of a complex that contains SOS1, ABI1 and EPS8L2. Associates with F-actin.

Subcellular location. Cytoplasm. Cell projection. Stereocilium.

Tissue specificity. Detected in fibroblasts and placenta.

Disease relevance. Deafness, autosomal recessive, 106 (DFNB106) [MIM:617637] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the EPS8 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H6S3-1	1	yes
Q9H6S3-2	2
Q9H6S3-3	3

RefSeq proteins (1): NP_073609* (*=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 (31 total): modified residue 5, helix 5, sequence conflict 4, strand 4, compositionally biased region 4, domain 2, splice variant 2, turn 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1WWU	SOLUTION NMR
1WXB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6S3-F1	73.67	0.37

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 (5): 303, 449, 469, 570, 240

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: 138 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, CHUANG_OXIDATIVE_STRESS_RESPONSE_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_RUFFLE_ASSEMBLY, TGACCTY_ERR1_Q2, GOCC_RUFFLE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, RYTTCCTG_ETS2_B, GOBP_SENSORY_PERCEPTION, GOMF_ACTIN_BINDING

GO Biological Process (4): Rho protein signal transduction (GO:0007266), sensory perception of sound (GO:0007605), regulation of Rho protein signal transduction (GO:0035023), positive regulation of ruffle assembly (GO:1900029)

GO Molecular Function (4): actin binding (GO:0003779), cadherin binding (GO:0045296), guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (13): centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), vesicle (GO:0031982), stereocilium bundle (GO:0032421), stereocilium tip (GO:0032426), ruffle membrane (GO:0032587), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), stereocilium (GO:0032420), cell projection (GO:0042995), organelle (GO:0043226)

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	5
stereocilium	2
small GTPase-mediated signal transduction	1
sensory perception of mechanical stimulus	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
ruffle assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of ruffle assembly	1
cytoskeletal protein binding	1
cell adhesion molecule binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
centriole	1
microtubule organizing center	1
cytoplasm	1
membrane	1
cell periphery	1
membrane-bounded organelle	1
cluster of actin-based cell projections	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
cellular_component	1
extracellular vesicle	1
intracellular anatomical structure	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1

Protein interactions and networks

STRING

826 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPS8L2	MYO15A	Q9UKN7	813
EPS8L2	TWF2	Q6IBS0	766
EPS8L2	WHRN	Q9P202	747
EPS8L2	ESPN	B1AK53	744
EPS8L2	MYO3A	Q8NEV4	599
EPS8L2	ESPNL	Q6ZVH7	580
EPS8L2	TMC2	Q8TDI7	567
EPS8L2	CAPZB	P47756	509
EPS8L2	GPSM2	P81274	492
EPS8L2	CCDC60	Q8IWA6	487
EPS8L2	EZR	P15311	472
EPS8L2	PLS1	Q14651	463
EPS8L2	MYO7A	P78427	443
EPS8L2	EPS8	Q12929	438
EPS8L2	UBXN11	Q5T124	433

IntAct

72 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EPS8L2	CTSD	psi-mi:“MI:0915”(physical association)	0.560
EPS8L2	DMWD	psi-mi:“MI:0915”(physical association)	0.560
EPS8L2	GRN	psi-mi:“MI:0915”(physical association)	0.560
EPS8L2	NEFL	psi-mi:“MI:0915”(physical association)	0.560
EPS8L2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
EPS8L2	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
EPS8L2	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
ASTE1	USP47	psi-mi:“MI:0914”(association)	0.530
WASF3	CYFIP1	psi-mi:“MI:0914”(association)	0.530
SLC12A4	LGALS3	psi-mi:“MI:0914”(association)	0.530
SUN2	PIP	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (68): EPS8L2 (Co-fractionation), EPS8L2 (Two-hybrid), EPS8L2 (Two-hybrid), EPS8L2 (Affinity Capture-MS), EPS8L2 (Affinity Capture-MS), EPS8L2 (Affinity Capture-MS), EPS8L2 (Proximity Label-MS), EPS8L2 (Affinity Capture-MS), ABI1 (Affinity Capture-Western), SOS1 (Affinity Capture-Western), ACTG1 (Affinity Capture-Western), EPS8L2 (Two-hybrid), EPS8L2 (Affinity Capture-RNA), EPS8L2 (Affinity Capture-MS), EPS8L2 (Two-hybrid)

ESM2 similar proteins: A5PK26, F8VPU2, O14526, O14976, O15068, O75064, O94887, P00530, P97874, P98150, P98171, Q00653, Q15027, Q15149, Q2HJE1, Q2KHV6, Q3TBD2, Q3U1Y4, Q4LDD4, Q5FVC7, Q5RB40, Q5RC07, Q5U464, Q5ZK62, Q61210, Q64096, Q6DE55, Q6IVG4, Q6P730, Q6ZQK5, Q6ZSZ5, Q8CFD4, Q8K285, Q8K2H4, Q8R5G7, Q8TDY4, Q8WWN8, Q91VS8, Q91ZR2, Q92619

Diamond homologs: A1CAL7, A1DEZ0, A2QGW1, A5DR93, A5E1V8, A6QTM4, A7F1F4, B0Y3Z4, B2ANF9, B2VV00, B6HR44, B6QEE0, B8MD74, B8NEM4, B8R1V5, B9W8T5, C0S7Q7, C1GJ63, C4JLG3, C4QVD6, C4Y1G1, C4YDC4, C5DE38, C5FH98, C5GIQ8, C5JGE5, C5MB30, C6HFQ7, C7Z504, C9SA05, D1ZRK4, D4ARB8, D4DA58, D6PVB4, D6PVB5, E3QNZ1, E3RIP0, E5AD87, E6RET3, E9EM69

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	7
Uncertain significance	198
Likely benign	144
Benign	37

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1334120	NM_022772.4(EPS8L2):c.148_149insGGACA (p.Ser50fs)	Pathogenic
1334121	NM_022772.4(EPS8L2):c.1430dup (p.Val478fs)	Pathogenic
1454470	NM_022772.4(EPS8L2):c.530_531dup (p.Lys178fs)	Pathogenic
2029463	NM_022772.4(EPS8L2):c.421C>T (p.Gln141Ter)	Pathogenic
2819321	NM_022772.4(EPS8L2):c.1704del (p.Ala569fs)	Pathogenic
3601078	NM_022772.4(EPS8L2):c.1197G>A (p.Trp399Ter)	Pathogenic
3601081	NM_022772.4(EPS8L2):c.961dup (p.Ile321fs)	Pathogenic
3601082	NM_022772.4(EPS8L2):c.996del (p.Lys333fs)	Pathogenic
3609141	NM_022772.4(EPS8L2):c.318del (p.Ile106fs)	Pathogenic
4077394	NM_022772.4(EPS8L2):c.818_827dup (p.Ala279fs)	Pathogenic
4293253	NM_022772.4(EPS8L2):c.1176G>A (p.Trp392Ter)	Pathogenic
433529	NM_022772.4(EPS8L2):c.1014del (p.Ser339fs)	Pathogenic
433530	NM_022772.4(EPS8L2):c.738del (p.Val247fs)	Pathogenic
4531328	NM_022772.4(EPS8L2):c.1412dup (p.Asp473fs)	Pathogenic
4695087	NM_022772.4(EPS8L2):c.1304G>A (p.Trp435Ter)	Pathogenic
4717064	NM_022772.4(EPS8L2):c.863dup (p.Lys290fs)	Pathogenic
4719360	NM_022772.4(EPS8L2):c.1908del (p.Trp636fs)	Pathogenic
4814128	NM_022772.4(EPS8L2):c.1623delinsAT (p.Pro542fs)	Pathogenic
3601079	NM_022772.4(EPS8L2):c.1317dup (p.Leu440fs)	Likely pathogenic
3601080	NM_022772.4(EPS8L2):c.357_361dup (p.Gln121fs)	Likely pathogenic
3613309	NM_022772.4(EPS8L2):c.984+2T>G	Likely pathogenic
3779620	NM_022772.4(EPS8L2):c.883A>T (p.Lys295Ter)	Likely pathogenic
4077395	NM_022772.4(EPS8L2):c.1878C>A (p.Tyr626Ter)	Likely pathogenic
4077396	NM_022772.4(EPS8L2):c.767C>G (p.Thr256Arg)	Likely pathogenic
4687936	NM_022772.4(EPS8L2):c.1412del (p.Pro471fs)	Likely pathogenic

SpliceAI

4365 predictions. Top by Δscore:

Variant	Effect	Δscore
11:698977:C:CG	donor_gain	1.0000
11:706286:CAGGT:C	donor_loss	1.0000
11:706289:G:T	donor_loss	1.0000
11:706290:T:G	donor_loss	1.0000
11:709551:A:AG	acceptor_gain	1.0000
11:709552:G:GG	acceptor_gain	1.0000
11:710349:G:A	acceptor_gain	1.0000
11:710487:G:A	donor_loss	1.0000
11:710488:T:G	donor_loss	1.0000
11:720059:CAGCA:C	acceptor_loss	1.0000
11:720060:A:AG	acceptor_gain	1.0000
11:720060:A:G	acceptor_loss	1.0000
11:720061:G:GG	acceptor_gain	1.0000
11:720061:GC:G	acceptor_gain	1.0000
11:720061:GCA:G	acceptor_gain	1.0000
11:720061:GCAC:G	acceptor_gain	1.0000
11:720061:GCACC:G	acceptor_gain	1.0000
11:720219:CACAG:C	donor_loss	1.0000
11:720222:AGGTG:A	donor_loss	1.0000
11:720223:GG:G	donor_loss	1.0000
11:720714:G:GT	donor_gain	1.0000
11:720744:G:GT	donor_gain	1.0000
11:720744:GAG:G	donor_loss	1.0000
11:720745:AG:A	donor_loss	1.0000
11:720746:GG:G	donor_loss	1.0000
11:720747:G:C	donor_loss	1.0000
11:720748:T:G	donor_loss	1.0000
11:720890:A:G	donor_gain	1.0000
11:720907:G:GT	donor_gain	1.0000
11:720907:GAA:G	donor_gain	1.0000

AlphaMissense

4699 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:710482:T:A	V54D	0.999
11:720066:T:C	L57P	0.999
11:720177:T:C	L94P	0.998
11:720727:T:C	F153S	0.998
11:720062:C:G	H56D	0.997
11:720064:C:A	H56Q	0.997
11:720064:C:G	H56Q	0.997
11:721973:G:C	K322N	0.997
11:721973:G:T	K322N	0.997
11:722536:T:A	W399R	0.997
11:722536:T:C	W399R	0.997
11:724776:T:C	F503L	0.997
11:724778:C:A	F503L	0.997
11:724778:C:G	F503L	0.997
11:710475:T:G	Y52D	0.996
11:720204:T:C	L103P	0.996
11:720676:T:C	L136P	0.996
11:720682:T:C	L138P	0.996
11:721572:T:C	L259P	0.996
11:724801:T:C	L511P	0.996
11:720068:G:C	A58P	0.995
11:720158:T:A	W88R	0.995
11:720158:T:C	W88R	0.995
11:721971:A:G	K322E	0.995
11:722134:T:C	L343P	0.995
11:724807:T:A	V513E	0.995
11:720063:A:G	H56R	0.994
11:720848:G:C	D166H	0.994
11:721975:T:C	L323P	0.994
11:724783:C:A	A505D	0.994

dbSNP variants (sampled 300 via entrez): RS1000129172 (11:720310 C>T), RS1000174405 (11:727612 C>T), RS1000302540 (11:720827 C>T), RS1000432945 (11:717887 T>C), RS1000472372 (11:704914 G>A,T), RS1000479424 (11:708044 C>T), RS1000496655 (11:705578 G>A), RS1000689247 (11:717336 C>T), RS1000741404 (11:717099 C>G), RS1000937765 (11:713836 G>A), RS1000979782 (11:708809 C>T), RS1001011538 (11:726811 G>A,C,T), RS1001104751 (11:704725 G>A,C,T), RS1001194261 (11:727466 G>A,C), RS1001215309 (11:717354 A>G)

Disease associations

OMIM: gene MIM:614988 | disease phenotypes: MIM:617637, MIM:156000, MIM:218040

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive 106	Strong	Autosomal recessive
nonsyndromic genetic hearing loss	Moderate	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
nonsyndromic genetic hearing loss	Moderate	AR

Mondo (5): hearing loss, autosomal recessive 106 (MONDO:0033198), Meniere disease (MONDO:0007972), Costello syndrome (MONDO:0009026), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (2): Costello syndrome (Orphanet:3071), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90013442_17	Keratoconus	1.000000e-26

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D008575	Meniere Disease	C09.218.568.217.500
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases mutagenesis	7
Valproic Acid	decreases expression, increases methylation, affects cotreatment, increases expression	5
sodium arsenite	increases abundance, increases expression, decreases expression	3
Acetaminophen	decreases expression, affects response to substance	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
bisphenol A	increases abundance, decreases expression, affects cotreatment, affects expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
bisphenol S	increases expression, increases methylation	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	increases expression	2
FR900359	decreases phosphorylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
titanium dioxide	decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression, increases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
cupric chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1RF	Abcam HeLa EPS8L2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT03664674	PHASE3	COMPLETED	Phase 3 Study of OTO-104 in Subjects With Unilateral Meniere’s Disease
NCT04677972	PHASE3	COMPLETED	SPI-1005 for the Treatment of Meniere’s Disease
NCT05851508	PHASE3	RECRUITING	The Effecttiveness of Intratympanic Methylprednisolon Injections Compared to Placebo in the Treatment of Vertigo Attacks in Meniere’s Disease
NCT05420350	PHASE2	UNKNOWN	Lamotrigine and Bupropion for Meniere’s Disease
NCT06544434	PHASE2	RECRUITING	Laser Acupuncture for Meniere Disease
NCT04674735	PHASE1	WITHDRAWN	Safety of APSLXR in Patients Presenting Vertigo of Vestibular Origin or Meniere’s Disease
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT04218123	PHASE2/PHASE3	COMPLETED	Assessing the Efficacy of a Serotonin and Norepinephrine Reuptake Inhibitor for Improving Meniere’s Disease Outcomes
NCT04766853	PHASE1/PHASE2	COMPLETED	Verification of the Efficacy/safety of the Intratympanic Drug Delivery for Hearing Loss
NCT04794842	EARLY_PHASE1	UNKNOWN	Comparing Topical Tetracaine Drops to Topical Focal Phenol for Local Anesthesia During Intratympanic Steroid Injection
NCT00599560	Not specified	COMPLETED	Vasopressin and V2 Receptor in Meniere’s Disease
NCT02371798	Not specified	WITHDRAWN	Unilateral Meniere Disease: Can Double Dose Gadolinium and Delayed Imaging Make the Diagnosis?
NCT03520322	Not specified	TERMINATED	A Study of a Mastoid Device in Subjects With Ménière’s Disease
NCT03795675	Not specified	ACTIVE_NOT_RECRUITING	CI Following VS Removal or Labyrinthectomy
NCT04370366	Not specified	RECRUITING	Imaging of Endolymphatic Hydrops at 7T MRI
NCT04569175	Not specified	COMPLETED	Non Enhanced Labyrinth Imaging for the Detection of Endolymphatic Hydrops in Meniere’s Disease NELI Study
NCT04686695	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation Treatment on Meniere Disease
NCT04835688	Not specified	UNKNOWN	Ventilation Tube Insertion for Unilateral Menière’s Disease
NCT04902963	Not specified	COMPLETED	What is the Tympanic Membrane Healing Time After Insertion of a Gelfoam PE Tube?
NCT04935970	Not specified	UNKNOWN	Metabolic Disorders and Vertigo
NCT05322538	Not specified	NOT_YET_RECRUITING	Menier’s Disease - Bone Density Study
NCT05328895	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation for Meniere Disease
NCT05424302	Not specified	RECRUITING	Effect of Peripheral Vestibular Disease Location on Outcomes Following Home-based Virtual Reality Vestibular Therapy
NCT05582148	Not specified	UNKNOWN	Meniere Disease and Hearing Aids
NCT05844657	Not specified	COMPLETED	Comprehensive Evaluation in Patients With Meniere’s Disease
NCT05960786	Not specified	COMPLETED	Treating the Symptoms of Vertigo in a Real-world Setting Using the OtoBand
NCT06278129	Not specified	UNKNOWN	Evaluation of the Diagnostic and Prognostic Efficacy of MRI in Acute Sensorineural Hearing Loss and Ménière’s Disease
NCT06544590	Not specified	COMPLETED	Transcutaneous Auricular Vagus Nerve Stimulation for Meniere Disease
NCT07272473	Not specified	RECRUITING	Effects of Cervical Mobilization on Dizziness, Balance, and Joint Position Sense in Patients With Meniere’s Disease
NCT02812511	Not specified	COMPLETED	Pathophysiology Analysis of Costello Syndrome on Cellular Models
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05361811	Not specified	RECRUITING	Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey