MYO3A

Summary

MYO3A (myosin IIIA, HGNC:7601) is a protein-coding gene on chromosome 10p12.1, encoding Myosin-IIIa (Q8NEV4). Actin-dependent motor protein with a protein kinase activity, playing an essential role in hearing.

The protein encoded by this gene belongs to the myosin superfamily. Myosins are actin-dependent motor proteins and are categorized into conventional myosins (class II) and unconventional myosins (classes I and III through XV) based on their variable C-terminal cargo-binding domains. Class III myosins, such as this one, have a kinase domain N-terminal to the conserved N-terminal motor domains and are expressed in photoreceptors. The protein encoded by this gene plays an important role in hearing in humans. Three different recessive, loss of function mutations in the encoded protein have been shown to cause nonsyndromic progressive hearing loss. Expression of this gene is highly restricted, with the strongest expression in retina and cochlea.

Source: NCBI Gene 53904 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,003 total — 39 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_017433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7601
Approved symbol	MYO3A
Name	myosin IIIA
Location	10p12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000095777
Ensembl biotype	protein_coding
OMIM	606808
Entrez	53904

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000376301, ENST00000376302, ENST00000477691, ENST00000478093, ENST00000543632, ENST00000642197, ENST00000642920, ENST00000644253, ENST00000645292, ENST00000647478, ENST00000916508, ENST00000916509, ENST00000916510

RefSeq mRNA: 2 — MANE Select: NM_017433 NM_001368265, NM_017433

CCDS: CCDS7148, CCDS91223

Canonical transcript exons

ENST00000642920 — 35 exons

Exon	Start	End
ENSE00000638292	26147430	26147559
ENSE00000694864	26143448	26143601
ENSE00000694865	26145446	26145534
ENSE00000694895	26153850	26153929
ENSE00000694920	26154746	26154823
ENSE00000694964	26157310	26157515
ENSE00000694969	26166067	26166178
ENSE00000694973	26168712	26168874
ENSE00000694978	26170416	26170539
ENSE00000816165	26068768	26068884
ENSE00000816166	26070111	26070215
ENSE00000816167	26070318	26070401
ENSE00000816168	26088203	26088405
ENSE00000816169	26096381	26096479
ENSE00000816170	26096568	26096682
ENSE00000816173	26128391	26128538
ENSE00000926037	25954874	25955008
ENSE00000926038	25996490	25996594
ENSE00000926039	25997159	25997258
ENSE00000926040	26016820	26016896
ENSE00000926041	26201265	26201305
ENSE00000926042	26202964	26203107
ENSE00000985367	26021503	26021648
ENSE00000985368	26024022	26024087
ENSE00000985369	26026377	26026532
ENSE00000985370	26066975	26067074
ENSE00000985372	26173663	26174557
ENSE00000985373	26176701	26176845
ENSE00000985374	26193205	26193311
ENSE00000993614	26125398	26125608
ENSE00001177755	25952094	25952278
ENSE00001227247	25935744	25935830
ENSE00001227374	26120676	26120802
ENSE00001227424	25934229	25934328
ENSE00003841991	26211843	26212532

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 86.75.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9050 / max 108.6835, expressed in 324 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104382	0.5937	281
104384	0.1474	77
104383	0.0956	40
104381	0.0361	10
104385	0.0322	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	86.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.03	gold quality
sperm	CL:0000019	80.85	silver quality
ventricular zone	UBERON:0003053	80.74	gold quality
right testis	UBERON:0004534	77.57	gold quality
left testis	UBERON:0004533	77.05	gold quality
buccal mucosa cell	CL:0002336	75.09	silver quality
testis	UBERON:0000473	75.05	gold quality
ganglionic eminence	UBERON:0004023	74.70	gold quality
colonic epithelium	UBERON:0000397	72.12	gold quality
popliteal artery	UBERON:0002250	70.02	gold quality
tibial artery	UBERON:0007610	69.98	gold quality
pancreatic ductal cell	CL:0002079	69.27	silver quality
pancreas	UBERON:0001264	68.39	gold quality
nucleus accumbens	UBERON:0001882	67.02	gold quality
oviduct epithelium	UBERON:0004804	65.44	silver quality
lower esophagus mucosa	UBERON:0035834	65.41	gold quality
cardiac muscle of right atrium	UBERON:0003379	64.44	gold quality
left ventricle myocardium	UBERON:0006566	63.80	gold quality
putamen	UBERON:0001874	63.51	gold quality
myocardium	UBERON:0002349	63.19	gold quality
caudate nucleus	UBERON:0001873	62.82	gold quality
bone marrow cell	CL:0002092	62.43	gold quality
aorta	UBERON:0000947	60.44	gold quality
ileal mucosa	UBERON:0000331	60.22	silver quality
body of pancreas	UBERON:0001150	59.67	gold quality
secondary oocyte	CL:0000655	59.59	gold quality
mucosa of paranasal sinus	UBERON:0005030	59.55	gold quality
tibia	UBERON:0000979	57.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.44
E-MTAB-5061	yes	6.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting MYO3A, 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-3064-3P	100.00	70.09	1254
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-1289	97.46	65.37	655
HSA-MIR-6824-5P	97.41	68.43	583
HSA-MIR-6802-3P	97.29	65.42	613

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 20)

• mutation in humans causes progressive nonsyndromic hearing loss DFNB30 (PMID:12032315)
• class III myosin is an actin-based motor protein having a protein kinase activity (PMID:12672820)
• myosin IIIA can spend a majority of its ATP hydrolysis cycling time on actin (PMID:17012748)
• the actomyosin-ADP state may be important for the ability of myosin III to function as a cellular transporter and actin cross-linker in the actin bundles of sensory cells (PMID:17074769)
• A model in which the activity and concentration of myosin IIIA localized to the tips of actin bundles mediates the morphology of the tips in sensory cells. (PMID:18229949)
• behavioral inhibition-associated SNPs appear to be associated with differences in MYO3A- but not GAD2 lymphoblastoid-mRNA expression levels (PMID:19229853)
• Results suggest that Myo3A motor activity is regulated through a mechanism involving concentration-dependent autophosphorylation. (PMID:20826793)
• The differential regulation of the kinase and motor activities allows for MYO3A to precisely self-regulate its concentration in the actin bundle-based structures of cells. (PMID:24214986)
• Data suggest that, in enterocytes, MYO3A autophosphorylation of kinase domain at Thr184/Thr188 regulates kinase activity, translocation of MYO3A to tips of microvilli, and stability of actin cytoskeleton. (PMID:25402663)
• The structures of Myo3 in complex with Espin1 not only elucidate the mechanism of the binding, but also reveal a Myo3-induced release of Espin1 auto-inhibition mechanism. (PMID:26785147)
• Study reports an amino acid substitution in MYO3A motor-head domain disrupting its ATPase activity that can cause autosomal dominant progressive hereditary hearing loss. Also, these results uncovered a novel interaction between MYO3A and PCDH15 shedding new light on the function of myosin IIIA at stereocilia tips. (PMID:26841241)
• A homozygous mutation, MYO3A:c.1841C>T (p.S614F), was identified to be responsible for non-syndromic congenital deafness in two members of a Kazakh family in China. (PMID:27063751)
• MYO3A is more efficient than MYO3B at increasing formation and elongation of stable microvilli on the surface of cultured epithelial cells. (PMID:27582493)
• Characterization of a novel MYO3A missense mutation associated with a dominant form of late onset hearing loss. (PMID:29880844)
• A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family. (PMID:32519820)
• Whole exome sequencing reveals pathogenic variants in MYO3A, MYO15A and COL9A3 and differential frequencies in ancestral alleles in hearing impairment genes among individuals from Cameroon. (PMID:33078831)
• Frequency and origin of the c.2090T>G p.(Leu697Trp) MYO3A variant associated with autosomal dominant hearing loss. (PMID:33953343)
• Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment. (PMID:34423747)
• Deafness mutation in the MYO3A motor domain impairs actin protrusion elongation mechanism. (PMID:34788109)
• The dynamics of actin protrusions can be controlled by tip-localized myosin motors. (PMID:38042485)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	myo3a	ENSDARG00000010186
mus_musculus	Myo3a	ENSMUSG00000025716
rattus_norvegicus	Myo3a	ENSRNOG00000018478

Paralogs (44): MYH13 (ENSG00000006788), MYO16 (ENSG00000041515), MYO9A (ENSG00000066933), MYO3B (ENSG00000071909), MYH7B (ENSG00000078814), MYO15A (ENSG00000091536), MYH7 (ENSG00000092054), MYO9B (ENSG00000099331), MYH9 (ENSG00000100345), MYH14 (ENSG00000105357), MYH1 (ENSG00000109061), MYH3 (ENSG00000109063), MYH2 (ENSG00000125414), MYO1B (ENSG00000128641), MYO5C (ENSG00000128833), CGNL1 (ENSG00000128849), MYH8 (ENSG00000133020), MYH10 (ENSG00000133026), MYH11 (ENSG00000133392), MYO18B (ENSG00000133454), CCDC102A (ENSG00000135736), MYO1G (ENSG00000136286), MYO7A (ENSG00000137474), MYO1F (ENSG00000142347), CGN (ENSG00000143375), TMF1 (ENSG00000144747), MYH15 (ENSG00000144821), MYO10 (ENSG00000145555), CCDC102B (ENSG00000150636), MYO1E (ENSG00000157483), CCDC158 (ENSG00000163749), MYO1A (ENSG00000166866), MYO5B (ENSG00000167306), MYO7B (ENSG00000169994), MYO1H (ENSG00000174527), MYO1D (ENSG00000176658), MYO18A (ENSG00000196535), MYO6 (ENSG00000196586), MYO5A (ENSG00000197535), MYH6 (ENSG00000197616)

Protein

Protein identifiers

Myosin-IIIa — Q8NEV4 (reviewed: Q8NEV4)

All UniProt accessions (4): A0A2R8Y4D5, A0A2R8Y5M1, Q8NEV4, F5H0U9

UniProt curated annotations — full annotation on UniProt →

Function. Actin-dependent motor protein with a protein kinase activity, playing an essential role in hearing. Probably also plays a role in vision. Required for normal cochlear hair bundle development and hearing. Plays an important role in the early steps of cochlear hair bundle morphogenesis. Influences the number and lengths of stereocilia to be produced and limits the growth of microvilli within the forming auditory hair bundles thereby contributing to the architecture of the hair bundle, including its staircase pattern. Involved in the elongation of actin in stereocilia tips by transporting the actin regulatory factor ESPN to the plus ends of actin filaments.

Subunit / interactions. Interacts with MORN4. Interacts (via C-terminus) with ESPN and ESPNL.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Filopodium tip. Stereocilium.

Tissue specificity. Strongest expression in retina, retinal pigment epithelial cells, cochlea and pancreas.

Disease relevance. Deafness, autosomal recessive, 30 (DFNB30) [MIM:607101] A form of non-syndromic deafness characterized by bilateral progressive hearing loss, which first affects the high frequencies. Hearing loss begins in the second decade, and by age 50 is severe in high and middle frequencies and moderate at low frequencies. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal dominant, 90 (DFNA90) [MIM:620722] A form of non-syndromic, sensorineural hearing loss. Sensorineural hearing loss 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. DFNA90 is characterized by bilateral progressive hearing loss that affects all frequencies. The disease is caused by variants affecting the gene represented in this entry.

Similarity. In the C-terminal section; belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family. In the N-terminal section; belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NEV4-1	1	yes
Q8NEV4-2	2

RefSeq proteins (2): NP_001355194, NP_059129* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR000719	Prot_kinase_dom	Domain
IPR001609	Myosin_head_motor_dom-like	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036083	MYSc_Myo3	Domain
IPR036961	Kinesin_motor_dom_sf	Homologous_superfamily
IPR052409	Myosin-III_kinase_activity	Family

Pfam: PF00063, PF00069, PF00612

Catalyzed reactions (Rhea), 3 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (48 total): sequence variant 21, sequence conflict 7, domain 5, region of interest 4, compositionally biased region 3, binding site 2, splice variant 2, helix 2, chain 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6JLE	X-RAY DIFFRACTION	1.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEV4-F1	68.26	0.34

Functional residue map

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

Catalytic / active sites (1): 150 (proton acceptor)

Ligand- & substrate-binding residues (2): 27–35; 50

Function

Pathways and Gene Ontology

Reactome pathways

4 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
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 128 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_EAR_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_FILOPODIUM_ASSEMBLY, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOMF_CYTOSKELETAL_MOTOR_ACTIVITY, GOBP_EAR_MORPHOGENESIS, GOBP_COCHLEA_DEVELOPMENT, GOBP_SENSORY_PERCEPTION

GO Biological Process (7): visual perception (GO:0007601), sensory perception of sound (GO:0007605), regulation of actin filament length (GO:0030832), protein autophosphorylation (GO:0046777), positive regulation of filopodium assembly (GO:0051491), cochlea morphogenesis (GO:0090103), protein phosphorylation (GO:0006468)

GO Molecular Function (15): microfilament motor activity (GO:0000146), actin binding (GO:0003779), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), calmodulin binding (GO:0005516), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ADP binding (GO:0043531), plus-end directed microfilament motor activity (GO:0060002), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), cytoskeletal motor activity (GO:0003774), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (11): photoreceptor inner segment (GO:0001917), cytoplasm (GO:0005737), myosin complex (GO:0016459), filopodium (GO:0030175), filamentous actin (GO:0031941), stereocilium tip (GO:0032426), filopodium tip (GO:0032433), cytoskeleton (GO:0005856), stereocilium (GO:0032420), cell projection (GO:0042995), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory processing of sound	2
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
ATP-dependent activity	2
protein kinase activity	2
adenyl ribonucleotide binding	2
protein-containing complex	2
actin-based cell projection	2
sensory perception of light stimulus	1
sensory perception of mechanical stimulus	1
regulation of cellular component size	1
regulation of actin cytoskeleton organization	1
protein phosphorylation	1
filopodium assembly	1
regulation of filopodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cochlea development	1
phosphorylation	1
protein modification process	1
cytoskeletal motor activity	1
polypeptide conformation or assembly isomerase activity	1
cytoskeletal protein binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
anion binding	1
microfilament motor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
actin cytoskeleton	1
actin filament	1
stereocilium	1

Protein interactions and networks

STRING

2186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYO3A	ESPN	B1AK53	749
MYO3A	LOXHD1	Q8IVV2	742
MYO3A	MORN4	Q8NDC4	731
MYO3A	WHRN	Q9P202	688
MYO3A	ESPNL	Q6ZVH7	675
MYO3A	TMC1	Q8TDI8	665
MYO3A	STRC	Q7RTU9	635
MYO3A	PCDH15	Q96QU1	632
MYO3A	CDH23	Q9H251	620
MYO3A	E9PNW1	E9PNW1	618
MYO3A	EPS8	Q12929	614
MYO3A	OTOF	Q9HC10	601
MYO3A	EPS8L2	Q9H6S3	599
MYO3A	GIPC3	Q8TF64	593
MYO3A	LHFPL5	Q8TAF8	588

IntAct

10 interactions, top by confidence:

A	B	Type	Score
MORN4	MYO3A	psi-mi:“MI:0403”(colocalization)	0.460
MYO3A	MORN4	psi-mi:“MI:0915”(physical association)	0.460
MYO3A	CANX	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
MYL12B	EFCAB7	psi-mi:“MI:0914”(association)	0.350
TNNC1	MYO1B	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MYO3A	MYZAP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (17): MYO3A (Affinity Capture-MS), MYO3A (Affinity Capture-MS), MYO3A (Two-hybrid), MYO3A (Proximity Label-MS), MYO3A (Affinity Capture-MS), MYO3A (Affinity Capture-MS), MYO3A (Affinity Capture-MS), MYO3A (Affinity Capture-MS), MYO3A (Affinity Capture-MS), YWHAZ (Cross-Linking-MS (XL-MS)), MYO3A (Affinity Capture-MS), MYO3A (Cross-Linking-MS (XL-MS)), RPL27A (Cross-Linking-MS (XL-MS)), WDR91 (Cross-Linking-MS (XL-MS)), MYO3A (Proximity Label-MS)

ESM2 similar proteins: A0MP03, A2AQP0, A5PF48, A7E2Y1, B0I1T2, D3ZJP6, E7F9L8, F1PRN2, F4IUG9, F4JM19, F8VQB6, O00159, O88329, O94832, P08799, P10568, P79114, P91443, P97479, Q01989, Q03479, Q0WPU1, Q13402, Q17LW0, Q17R14, Q1EG27, Q23978, Q23979, Q27966, Q29P71, Q5SUA5, Q5SYD0, Q5ZLA6, Q5ZMC2, Q622K8, Q63355, Q63357, Q6GPA1, Q6PIF6, Q8K3H5

Diamond homologs: A0A8I5ZNK2, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, B0LT89, F1LP90, F1NBT0, G5EEN4, G5EFU0, G5EGQ3, H2L099, O00506, O14047, O14305, O23304, O24527, O54748, O61122, O61125, O75011, O75914, O88506, O88643, O95747, O95819, O96013, P08458, P35465, P83510, Q03497, Q08E52, Q0IHQ8, Q12851, Q13043, Q13153

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MYO3A	“down-regulates activity”	MYO3A	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1003 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	31
Uncertain significance	515
Likely benign	190
Benign	118

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071291	NM_017433.5(MYO3A):c.4298C>G (p.Ser1433Ter)	Pathogenic
1185653	NM_017433.5(MYO3A):c.3737_3738del (p.Glu1246fs)	Pathogenic
1323315	NM_017433.5(MYO3A):c.4587-1G>A	Pathogenic
1460150	NC_000010.10:g.(?26462572)(26463506_?)del	Pathogenic
1687422	NM_017433.5(MYO3A):c.892C>T (p.Gln298Ter)	Pathogenic
2189377	NM_017433.5(MYO3A):c.4483C>T (p.Arg1495Ter)	Pathogenic
2192717	NM_017433.5(MYO3A):c.3154C>T (p.Arg1052Ter)	Pathogenic
2707261	NM_017433.5(MYO3A):c.133C>T (p.Gln45Ter)	Pathogenic
2843851	NM_017433.5(MYO3A):c.3225C>G (p.Tyr1075Ter)	Pathogenic
284395	NM_017433.5(MYO3A):c.3447_3448del (p.Arg1150fs)	Pathogenic
2868467	NC_000010.11:g.26016820del	Pathogenic
2921297	NM_017433.5(MYO3A):c.716T>C (p.Leu239Pro)	Pathogenic
2996525	NM_017433.5(MYO3A):c.3876del (p.Arg1292fs)	Pathogenic
2998455	NM_017433.5(MYO3A):c.743dup (p.Leu250fs)	Pathogenic
3010518	NM_017433.5(MYO3A):c.4341_4344del (p.Asn1447fs)	Pathogenic
3026306	NM_017433.5(MYO3A):c.4545+2T>G	Pathogenic
3244994	NC_000010.10:g.(?26285399)(26286207_?)del	Pathogenic
3375082	NM_017433.5(MYO3A):c.4583_4586del (p.Asp1528fs)	Pathogenic
3392534	NM_017433.5(MYO3A):c.3126T>G (p.Tyr1042Ter)	Pathogenic
3601435	NM_017433.5(MYO3A):c.268A>T (p.Lys90Ter)	Pathogenic
3609195	NM_017433.5(MYO3A):c.2950C>T (p.Arg984Ter)	Pathogenic
3626297	NM_017433.5(MYO3A):c.4478dup (p.Arg1494fs)	Pathogenic
3631478	NM_017433.5(MYO3A):c.2224C>T (p.Gln742Ter)	Pathogenic
3697693	NM_017433.5(MYO3A):c.58dup (p.Thr20fs)	Pathogenic
3712750	NM_017433.5(MYO3A):c.4634dup (p.Leu1545fs)	Pathogenic
3776003	NM_017433.5(MYO3A):c.2482G>T (p.Gly828Ter)	Pathogenic
4014	NM_017433.5(MYO3A):c.3129T>G (p.Tyr1043Ter)	Pathogenic
4015	NM_017433.5(MYO3A):c.1777-12G>A	Pathogenic
4016	NM_017433.5(MYO3A):c.732-2A>G	Pathogenic
4689703	NC_000010.10:g.(26459469_26462591)_(26463487_26465629)del	Pathogenic

SpliceAI

5518 predictions. Top by Δscore:

Variant	Effect	Δscore
10:25952089:TCCA:T	acceptor_loss	1.0000
10:25952090:CCA:C	acceptor_loss	1.0000
10:25952091:CA:C	acceptor_loss	1.0000
10:25952092:AGGTT:A	acceptor_loss	1.0000
10:25952093:G:GA	acceptor_loss	1.0000
10:25952274:TTCAC:T	donor_gain	1.0000
10:25952276:CAC:C	donor_gain	1.0000
10:25952276:CACGT:C	donor_loss	1.0000
10:25952277:AC:A	donor_gain	1.0000
10:25952277:ACGT:A	donor_loss	1.0000
10:25952278:CGTA:C	donor_loss	1.0000
10:25952279:G:GA	donor_loss	1.0000
10:25952279:G:GG	donor_gain	1.0000
10:25952280:TA:T	donor_loss	1.0000
10:25952281:AA:A	donor_loss	1.0000
10:25954865:T:A	acceptor_gain	1.0000
10:25954871:TAGG:T	acceptor_loss	1.0000
10:25954872:A:AG	acceptor_gain	1.0000
10:25954872:A:C	acceptor_loss	1.0000
10:25954873:G:GG	acceptor_gain	1.0000
10:25954873:GGAT:G	acceptor_gain	1.0000
10:25955005:TGAGG:T	donor_loss	1.0000
10:25955006:GAG:G	donor_gain	1.0000
10:25955007:AGGTA:A	donor_loss	1.0000
10:25955009:G:GC	donor_loss	1.0000
10:25955009:G:GG	donor_gain	1.0000
10:25955010:T:A	donor_loss	1.0000
10:25997153:TTCTA:T	acceptor_loss	1.0000
10:25997154:TCTA:T	acceptor_loss	1.0000
10:25997155:CTAG:C	acceptor_loss	1.0000

AlphaMissense

10705 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:25997196:G:T	R149I	1.000
10:26016870:G:A	G187R	1.000
10:26016870:G:C	G187R	1.000
10:26016882:T:A	W191R	1.000
10:26016882:T:C	W191R	1.000
10:26021557:T:A	W214R	1.000
10:26021557:T:C	W214R	1.000
10:25952171:T:A	W21R	0.999
10:25952171:T:C	W21R	0.999
10:25952198:G:A	G30R	0.999
10:25952198:G:C	G30R	0.999
10:25952256:T:A	V49D	0.999
10:25952260:A:C	K50N	0.999
10:25952260:A:T	K50N	0.999
10:25954994:T:A	W97R	0.999
10:25954994:T:C	W97R	0.999
10:25997192:C:G	H148D	0.999
10:25997196:G:C	R149T	0.999
10:25997197:A:C	R149S	0.999
10:25997197:A:T	R149S	0.999
10:25997198:G:C	D150H	0.999
10:25997199:A:C	D150A	0.999
10:25997199:A:G	D150G	0.999
10:25997199:A:T	D150V	0.999
10:25997200:T:A	D150E	0.999
10:25997200:T:G	D150E	0.999
10:25997205:A:T	K152I	0.999
10:25997206:A:C	K152N	0.999
10:25997206:A:T	K152N	0.999
10:25997215:C:A	N155K	0.999

dbSNP variants (sampled 300 via entrez): RS1000010578 (10:25939228 C>T), RS1000011922 (10:26027235 T>C), RS1000012492 (10:26003987 A>T), RS1000016772 (10:26082838 A>C), RS1000022702 (10:26071384 C>A,T), RS1000029713 (10:26174832 C>T), RS1000032268 (10:25935719 A>G), RS1000038621 (10:26211695 C>G), RS1000064730 (10:26004324 G>A), RS1000065454 (10:26068368 C>G), RS1000073870 (10:25965639 G>C), RS1000078439 (10:26189994 C>T), RS1000088633 (10:26074869 T>G), RS1000088778 (10:26167737 C>T), RS1000094688 (10:26104640 T>A,C)

Disease associations

OMIM: gene MIM:606808 | disease phenotypes: MIM:607101, MIM:620722

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 30	Definitive	Autosomal recessive
hearing loss, autosomal dominant 90	Moderate	Autosomal dominant
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	Definitive	AR

Mondo (6): autosomal recessive nonsyndromic hearing loss 30 (MONDO:0011774), hearing loss, autosomal dominant 90 (MONDO:0958232), hearing loss disorder (MONDO:0005365), nonsyndromic genetic hearing loss (MONDO:0019497), sensorineural hearing loss disorder (MONDO:0020678), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (3): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic deafness (Orphanet:96210), Rare non-syndromic genetic deafness (Orphanet:87884)

HPO phenotypes

3 total (4 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000408	Progressive sensorineural hearing impairment
HP:0001730	Progressive hearing impairment
HP:0000407	Sensorineural hearing impairment

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001762_142	Obesity-related traits	4.000000e-07
GCST001762_692	Obesity-related traits	6.000000e-06
GCST001762_807	Obesity-related traits	5.000000e-06
GCST001925_3	PR interval	4.000000e-06
GCST005790_16	Rosacea symptom severity	8.000000e-06
GCST006138_19	Resting-state electroencephalogram vigilance	4.000000e-06
GCST008161_13	Waist circumference adjusted for body mass index	5.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004810	interleukin-6 measurement
EFO:0004462	PR interval
EFO:0009180	rosacea severity measurement
EFO:0004357	electroencephalogram measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C564609	Deafness, Autosomal Recessive (supp.)
C564624	Deafness, Autosomal Recessive 30 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5546 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 112,434 (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
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL535	SUNITINIB	4	79,020
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL513909	BI-2536	2	895
CHEMBL1908397	KW-2449	1	622
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — NinaC subfamily

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM

ChEMBL bioactivities

19 potent at pChembl≥5 of 19 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.54	IC50	28.8	nM	STAUROSPORINE
7.40	IC50	40.2	nM	STAUROSPORINE
7.39	Kd	41	nM	AST-487
7.35	IC50	44.8	nM	STAUROSPORINE
7.17	Kd	67	nM	TAE-684
6.58	Kd	260	nM	LESTAURTINIB
6.30	Kd	500	nM	STAUROSPORINE
6.13	Kd	740	nM	KW-2449
6.08	Kd	830	nM	CHEMBL1241674
6.00	IC50	1000	nM	TP-030n
5.85	Kd	1400	nM	SU-014813
5.72	Kd	1900	nM	AXITINIB
5.55	Kd	2800	nM	FORETINIB
5.51	Kd	3100	nM	SUNITINIB
5.21	Kd	6200	nM	BOSUTINIB
5.20	Kd	6300	nM	BI-2536

PubChem BioAssay actives

18 with measured affinity, of 183 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2198337: Inhibition of human MYO3A using myelin basic protein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0288	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435170: Binding constant for MYO3A kinase domain	kd	0.0410	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625104: Binding constant for MYO3A kinase domain	kd	0.0670	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507639: Binding affinity to MYO3A	kd	0.2600	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625104: Binding constant for MYO3A kinase domain	kd	0.7400	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	625104: Binding constant for MYO3A kinase domain	kd	0.8300	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	625104: Binding constant for MYO3A kinase domain	kd	1.4000	uM
Axitinib	625104: Binding constant for MYO3A kinase domain	kd	1.9000	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625104: Binding constant for MYO3A kinase domain	kd	2.8000	uM
Sunitinib	625104: Binding constant for MYO3A kinase domain	kd	3.1000	uM
Bosutinib	625104: Binding constant for MYO3A kinase domain	kd	6.2000	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	625104: Binding constant for MYO3A kinase domain	kd	6.3000	uM

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
arsenite	increases methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
Amiodarone	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	decreases expression	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Nickel	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

82 unique, capped per target: 82 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1048290	Binding	Inhibition of MYO3A assessed as enzyme activity at 1 uM relative to untreated control	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss