MYH3

Summary

MYH3 (myosin heavy chain 3, HGNC:7573) is a protein-coding gene on chromosome 17p13.1, encoding Myosin-3 (P11055). Muscle contraction.

Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome.

Source: NCBI Gene 4621 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Freeman-Sheldon syndrome (Definitive, GenCC) — +9 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,907 total — 59 pathogenic, 61 likely-pathogenic
• Phenotypes (HPO): 173
• MANE Select transcript: NM_002470

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7573
Approved symbol	MYH3
Name	myosin heavy chain 3
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	MYHC-EMB, MYHSE1, HEMHC, SMHCE
Ensembl gene	ENSG00000109063
Ensembl biotype	protein_coding
OMIM	160720
Entrez	4621

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 retained_intron, 2 protein_coding

ENST00000577963, ENST00000579489, ENST00000579928, ENST00000582580, ENST00000583535, ENST00000961194

RefSeq mRNA: 1 — MANE Select: NM_002470 NM_002470

CCDS: CCDS11157

Canonical transcript exons

ENST00000583535 — 41 exons

Exon	Start	End
ENSE00000687635	10629842	10629937
ENSE00000687636	10630092	10630196
ENSE00000687640	10631611	10631736
ENSE00000687647	10632476	10632784
ENSE00000687651	10633591	10633715
ENSE00000687654	10634017	10634182
ENSE00000687657	10634840	10635023
ENSE00000687662	10635735	10635853
ENSE00000687665	10637809	10637935
ENSE00000687670	10638873	10638963
ENSE00000687672	10639044	10639189
ENSE00000687674	10639298	10639474
ENSE00000687676	10639560	10639802
ENSE00000687680	10640333	10640469
ENSE00000687687	10641085	10641202
ENSE00000687691	10642240	10642310
ENSE00000687693	10644351	10644500
ENSE00000687694	10644584	10644702
ENSE00000687696	10645929	10646032
ENSE00000687708	10652420	10652563
ENSE00000855385	10642417	10642723
ENSE00001732611	10645707	10645845
ENSE00002324877	10640563	10640686
ENSE00002325190	10631813	10632016
ENSE00002335447	10647182	10647280
ENSE00002336218	10648557	10648649
ENSE00002347452	10647363	10647426
ENSE00002351565	10630288	10630458
ENSE00002359155	10638043	10638432
ENSE00002377543	10635367	10635563
ENSE00002386512	10641285	10641372
ENSE00002393489	10639996	10640251
ENSE00002425762	10642826	10642996
ENSE00002429136	10651512	10651668
ENSE00002684351	10628532	10628679
ENSE00002693367	10656090	10656148
ENSE00002728342	10657289	10657309
ENSE00003469227	10649577	10649685
ENSE00003526272	10654861	10655072
ENSE00003572434	10650374	10650401
ENSE00003680786	10629597	10629734

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 91.12.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.7390 / max 2050.2331, expressed in 104 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164611	3.5052	97
164605	0.0506	14
164602	0.0411	13
164610	0.0288	15
164609	0.0251	10
164612	0.0251	12
164603	0.0237	7
164608	0.0217	6
164604	0.0177	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	91.12	gold quality
right testis	UBERON:0004534	90.16	gold quality
testis	UBERON:0000473	87.62	gold quality
sperm	CL:0000019	87.25	silver quality
hindlimb stylopod muscle	UBERON:0004252	85.48	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.87	gold quality
male germ cell	CL:0000015	84.08	silver quality
gastrocnemius	UBERON:0001388	83.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.44	gold quality
muscle of leg	UBERON:0001383	82.59	gold quality
seminal vesicle	UBERON:0000998	80.49	gold quality
sural nerve	UBERON:0015488	79.35	gold quality
gluteal muscle	UBERON:0002000	78.91	gold quality
muscle organ	UBERON:0001630	77.96	gold quality
tibialis anterior	UBERON:0001385	77.00	silver quality
right lobe of liver	UBERON:0001114	76.14	gold quality
popliteal artery	UBERON:0002250	75.94	gold quality
tibial artery	UBERON:0007610	75.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.73	gold quality
muscle layer of sigmoid colon	UBERON:0035805	75.52	gold quality
body of uterus	UBERON:0009853	75.19	gold quality
right lobe of thyroid gland	UBERON:0001119	74.60	gold quality
mucosa of transverse colon	UBERON:0004991	74.24	gold quality
ectocervix	UBERON:0012249	74.24	gold quality
granulocyte	CL:0000094	74.14	gold quality
aorta	UBERON:0000947	74.04	gold quality
left lobe of thyroid gland	UBERON:0001120	73.88	gold quality
left uterine tube	UBERON:0001303	73.72	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.34	gold quality
skin of leg	UBERON:0001511	73.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3

miRNA regulators (miRDB)

13 targeting MYH3, 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-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-873-5P	98.84	66.90	1348

Literature-anchored findings (GeneRIF, showing 24)

• show that mutations in the embryonic myosin heavy chain 3 gene cause Freeman-Sheldon syndrome, one of the most severe multiple congenital contracture syndromes, and nearly 1/3 of all cases of Sheldon-Hall syndrome, the most common distal arthrogryposis (PMID:16642020)
• This article reports novel MYH3 mutations associated with distal arthrogryposis and demonstrates myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations. (PMID:18695058)
• Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot. (PMID:19142688)
• Identification of an MYH3 mutation in this family with distal arthrogryposis type 1 broadens the phenotype associated with MYH3 mutations to include distal arthrogryposis types 1, 2A (Freeman-Sheldon syndrome), and 2B (Sheldon-Hall syndrome). (PMID:21531865)
• eMYH plays a crucial role in important processes in the early developing heart and, hence, is a candidate causative gene for atrial septal defects and cardiomyopathy. (PMID:21862559)
• Molecular genetic investigations revealed pathogenic mutations in MYH3, TPM2, and TNNI2 in one sporadic and 19 familial cases of distal arthrogryposis. (PMID:22519952)
• The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle (PMID:25740846)
• The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3. (PMID:25957469)
• developmental p.Thr178Ile MYH3 myopathy is associated with a combined pathomechanism of insufficient dosage of functional embryonic MyHC and production of mutant protein (PMID:26544689)
• MYH3 mutations are associated with Freeman-Sheldon Syndrome. (PMID:26945064)
• our patient is the first reported case of a child with classical FSS, caused by a common MYH3 mutation, who has an unaffected mother with molecularly proven somatic mosaicism, who is also a likely gonadal mosaic. This case emphasizes the importance of parental genetic testing, when a clinically apparent de novo diagnosis is suspected in a child. (PMID:26996280)
• Protein-altering variants of MYH3 were identified in two families with symptoms related to autosomal dominant spondylocarpotarsal synostosis syndrome. (PMID:27381093)
• Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions. (PMID:28205584)
• Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3-related disorders. (PMID:29314551)
• Although some MYH3 variants cause dominant Spondylocarpotarsal synostosis syndrome, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. (PMID:29805041)
• A novel truncating mutation in MYH3 causes spondylocarpotarsal synostosis syndrome with basilar invagination. (PMID:30228365)
• two heterozygous variations of the MYH3 gene probably underlie the disease in the pedigrees (PMID:31030430)
• Identification of a novel pathogenic mutation of the MYH3 gene in a family with distal arthrogryposis type 2B. (PMID:31746383)
• Report a case-control study investigating the role of MYH3 among non-syndromic atrial septal defect patients in contributing to septal development. The non-synonymous c. 3574G>A (p.Ala1192Thr) [p = 0.001, OR = 2.30 (1.36-3.87)] located within the tail domain indicated a highly conserved protein region. (PMID:32315303)
• Identification of a novel pathogenic variant in the MYH3 gene in a five-generation family with CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A). (PMID:32767732)
• Recessive MYH3 variants cause ““Contractures, pterygia, and variable skeletal fusions syndrome 1B”” mimicking Escobar variant multiple pterygium syndrome. (PMID:32902138)
• METTL3 achieves lipopolysaccharide-induced myocardial injury via m[6]A-dependent stabilization of Myh3 mRNA. (PMID:37245538)
• Functional assessment of a novel biallelic MYH3 variation causing CPSKF1B (contractures, pterygia, and spondylocarpotarsal fusion syndrome1B). (PMID:38444278)
• Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis. (PMID:38856159)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Myh3	ENSMUSG00000020908
rattus_norvegicus	Myh3	ENSRNOG00000046276

Paralogs (44): MYH13 (ENSG00000006788), MYO16 (ENSG00000041515), MYO9A (ENSG00000066933), MYO3B (ENSG00000071909), MYH7B (ENSG00000078814), MYO15A (ENSG00000091536), MYH7 (ENSG00000092054), MYO3A (ENSG00000095777), MYO9B (ENSG00000099331), MYH9 (ENSG00000100345), MYH14 (ENSG00000105357), MYH1 (ENSG00000109061), 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-3 — P11055 (reviewed: P11055)

Alternative names: Muscle embryonic myosin heavy chain, Myosin heavy chain 3, Myosin heavy chain, fast skeletal muscle, embryonic, SMHCE

All UniProt accessions (1): P11055

UniProt curated annotations — full annotation on UniProt →

Function. Muscle contraction.

Subunit / interactions. Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2).

Subcellular location. Cytoplasm. Myofibril.

Tissue specificity. Expressed in fetal bone, thymus, placenta, heart, brain, and liver.

Disease relevance. Arthrogryposis, distal, 2A (DA2A) [MIM:193700] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA2A is characterized by contractures of the hands and feet, oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice, puckered lips, and a H-shaped dimple of the chin. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis, distal, 2B3 (DA2B3) [MIM:618436] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. Distal arthrogryposis type 2 is characterized by contractures of the hands and feet, and a distinctive face characterized by prominent nasolabial folds, small mouth and downslanting palpebral fissures. DA2B3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (CPSFS1A) [MIM:178110] An autosomal dominant disease characterized by contractures of proximal and distal joints, pterygia involving the neck, axillae, elbows, and/or knees, as well as variable vertebral, carpal, and tarsal fusions and short stature. Progression of vertebral fusions has been observed, and inter- and intrafamilial variability has been reported. The disease is caused by variants affecting the gene represented in this entry. Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B (CPSFS1B) [MIM:618469] An autosomal recessive disease characterized by contractures affecting proximal and distal joints, vertebral fusions and scoliosis, carpal and tarsal fusions as well as webbing of the skin (pterygium) involving the neck, elbows, fingers, and/or knees. Other features include facial dysmorphism, short neck, and absent finger flexion creases. Inter- and intrafamilial variability has been observed. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils. Limited proteolysis of myosin heavy chain produces 1 light meromyosin (LMM) and 1 heavy meromyosin (HMM). HMM can be further cleaved into 2 globular subfragments (S1) and 1 rod-shaped subfragment (S2).

Similarity. Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.

RefSeq proteins (1): NP_002461* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001609	Myosin_head_motor_dom-like	Domain
IPR002928	Myosin_tail	Domain
IPR004009	SH3_Myosin	Domain
IPR008989	Myosin_S1_N	Homologous_superfamily
IPR014751	XRCC4-like_C	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036000	MYSc_Myh3	Domain
IPR036961	Kinesin_motor_dom_sf	Homologous_superfamily

Pfam: PF00063, PF01576, PF02736

UniProt features (43 total): sequence variant 28, sequence conflict 6, domain 3, region of interest 2, chain 1, coiled-coil region 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11055-F1	74.35	0.09

Functional residue map

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

Ligand- & substrate-binding residues (1): 179–186

Post-translational modifications (1): 130

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction
R-HSA-397014	Muscle contraction

MSigDB gene sets: 493 (showing top): GOBP_BODY_MORPHOGENESIS, GCANCTGNY_MYOD_Q6, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, KEGG_TIGHT_JUNCTION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, MODULE_329, GOBP_SARCOMERE_ORGANIZATION, GOBP_SKELETAL_MUSCLE_CONTRACTION, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, CEBPB_01, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, KEGG_VIRAL_MYOCARDITIS, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS

GO Biological Process (9): skeletal muscle contraction (GO:0003009), muscle contraction (GO:0006936), muscle organ development (GO:0007517), actin filament-based movement (GO:0030048), muscle filament sliding (GO:0030049), embryonic limb morphogenesis (GO:0030326), sarcomere organization (GO:0045214), ATP metabolic process (GO:0046034), face morphogenesis (GO:0060325)

GO Molecular Function (9): microfilament motor activity (GO:0000146), calmodulin binding (GO:0005516), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), myosin phosphatase activity (GO:0017018), actin filament binding (GO:0051015), nucleotide binding (GO:0000166), cytoskeletal motor activity (GO:0003774), actin binding (GO:0003779)

GO Cellular Component (10): cytoplasm (GO:0005737), cytosol (GO:0005829), muscle myosin complex (GO:0005859), myosin II complex (GO:0016460), sarcomere (GO:0030017), myosin filament (GO:0032982), extracellular exosome (GO:0070062), myosin complex (GO:0016459), myofibril (GO:0030016), contractile muscle fiber (GO:0043292)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
ATP-dependent activity	2
cytoplasm	2
contractile muscle fiber	2
myosin complex	2
supramolecular fiber	2
striated muscle contraction	1
musculoskeletal movement	1
muscle system process	1
animal organ development	1
muscle structure development	1
actin filament-based process	1
muscle contraction	1
actin-myosin filament sliding	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
myofibril assembly	1
actomyosin structure organization	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
anatomical structure morphogenesis	1
head morphogenesis	1
face development	1
cytoskeletal motor activity	1
polypeptide conformation or assembly isomerase activity	1
protein binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein serine/threonine phosphatase activity	1
actin binding	1
protein-containing complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
cytoskeletal protein binding	1
intracellular anatomical structure	1
myosin II complex	1
myofibril	1
extracellular vesicle	1

Protein interactions and networks

STRING

1688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYH3	TNNI2	P48788	923
MYH3	TNNT3	P45378	886
MYH3	MUTYH	Q9UIF7	769
MYH3	TPM2	P06468	768
MYH3	MYOG	P15173	765
MYH3	FBN2	P35556	742
MYH3	MYOD1	P15172	715
MYH3	ACTA1	P02568	700
MYH3	MYL11	Q96A32	683
MYH3	PAX7	P23759	656
MYH3	MYF5	P13349	640
MYH3	ACTN2	P35609	635
MYH3	MSTN	O14793	620
MYH3	ANKRD2	Q9GZV1	605
MYH3	MYBPC1	Q00872	593

IntAct

48 interactions, top by confidence:

A	B	Type	Score
PRKAG2	PRKAB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
YWHAZ	LMNA	psi-mi:“MI:0914”(association)	0.560
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
TAF6L	SUPT3H	psi-mi:“MI:0914”(association)	0.530
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
CDCA8	DCLK1	psi-mi:“MI:0914”(association)	0.350
HIF1A	MYL1	psi-mi:“MI:0914”(association)	0.350
SIX1	EYA4	psi-mi:“MI:0914”(association)	0.350
TLE3	ATP2A1	psi-mi:“MI:0914”(association)	0.350
TMEM260	MYH3	psi-mi:“MI:0914”(association)	0.350
CFTR	MYH7B	psi-mi:“MI:0914”(association)	0.350
ABTB2	IFT56	psi-mi:“MI:0914”(association)	0.350
KRT40	ANKRD36	psi-mi:“MI:0914”(association)	0.350
AKAP17A	NOS1AP	psi-mi:“MI:0914”(association)	0.350
TLE3	COL1A1	psi-mi:“MI:0914”(association)	0.350
ASAH2	MYH3	psi-mi:“MI:0914”(association)	0.350
MYH3	MYH6	psi-mi:“MI:0914”(association)	0.350
C5orf24	MYH7B	psi-mi:“MI:0914”(association)	0.350

BioGRID (59): MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), ACTN2 (Co-fractionation), MYH3 (Co-fractionation), TPM2 (Co-fractionation), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH3 (Affinity Capture-MS)

ESM2 similar proteins: A0MP03, A3LYL7, A5DKH0, A5PF48, A6ZMG6, E7F9L8, E9Q634, F1PRN2, F4I460, F4JM19, O00159, O00160, O08638, O88329, O94832, P10568, P10587, P11055, P35748, P35749, P70248, P97479, Q01989, Q04439, Q076A3, Q12965, Q13402, Q17LW0, Q17R14, Q23979, Q27966, Q29P71, Q5SYD0, Q5ZLA6, Q62774, Q62812, Q63355, Q63356, Q63357, Q6BUQ2

Diamond homologs: A2AQP0, A7E2Y1, F1PT61, F4I507, F4I5Q6, F4IVR7, G3UW82, K7U9N8, O08638, O14157, O94477, P02563, P02564, P02565, P02566, P02567, P04461, P05659, P05661, P08799, P08964, P10587, P11055, P12844, P12845, P12847, P12882, P12883, P13533, P13535, P13538, P13539, P13540, P13541, P13542, P14105, P19524, P21271, P24733, P32492

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
“MYOD1/SWI/SNF complex”	“up-regulates quantity by expression”	MYH3	“transcriptional regulation”
TNFSF12	“down-regulates quantity by destabilization”	MYH3	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1907 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	61
Uncertain significance	908
Likely benign	596
Benign	124

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065334	NM_002470.4(MYH3):c.1581+2T>C	Pathogenic
1177399	NM_002470.4(MYH3):c.2501T>C (p.Phe834Ser)	Pathogenic
1299399	NM_002470.4(MYH3):c.2103G>C (p.Glu701Asp)	Pathogenic
1299400	NM_002470.4(MYH3):c.2045C>A (p.Pro682Gln)	Pathogenic
1360675	NM_002470.4(MYH3):c.5692C>T (p.Arg1898Ter)	Pathogenic
1405964	NM_002470.4(MYH3):c.2778_2779del (p.Arg926fs)	Pathogenic
14138	NM_002470.4(MYH3):c.2015G>A (p.Arg672His)	Pathogenic
14139	NM_002470.4(MYH3):c.2014C>T (p.Arg672Cys)	Pathogenic
14140	NM_002470.4(MYH3):c.533C>T (p.Thr178Ile)	Pathogenic
14141	NM_002470.4(MYH3):c.2474T>A (p.Val825Asp)	Pathogenic
14142	NM_002470.4(MYH3):c.2590_2592del (p.Leu864del)	Pathogenic
1466873	NM_002470.4(MYH3):c.3436G>T (p.Glu1146Ter)	Pathogenic
1514894	NM_002470.4(MYH3):c.2170C>T (p.Arg724Ter)	Pathogenic
1517973	NM_002470.4(MYH3):c.430C>T (p.Arg144Ter)	Pathogenic
1945191	NM_002470.4(MYH3):c.129_132del (p.Glu45fs)	Pathogenic
1945413	NM_002470.4(MYH3):c.3619C>T (p.Gln1207Ter)	Pathogenic
1954419	NM_002470.4(MYH3):c.166C>T (p.Gln56Ter)	Pathogenic
2021369	NM_002470.4(MYH3):c.899dup (p.Leu301fs)	Pathogenic
2027262	NM_002470.4(MYH3):c.538del (p.Glu180fs)	Pathogenic
2029328	NM_002470.4(MYH3):c.4378_4379del (p.Lys1460fs)	Pathogenic
2029969	NM_002470.4(MYH3):c.4885C>T (p.Gln1629Ter)	Pathogenic
2031964	NM_002470.4(MYH3):c.370del (p.Val124fs)	Pathogenic
203471	NM_002470.4(MYH3):c.3224A>C (p.Gln1075Pro)	Pathogenic
2082234	NM_002470.4(MYH3):c.1216A>T (p.Lys406Ter)	Pathogenic
208736	NM_002470.4(MYH3):c.5605_5659-47del	Pathogenic
2095900	NM_002470.4(MYH3):c.3164_3165del (p.Lys1055fs)	Pathogenic
2127637	NM_002470.4(MYH3):c.1286C>G (p.Ser429Ter)	Pathogenic
2141735	NM_002470.4(MYH3):c.927C>G (p.Tyr309Ter)	Pathogenic
2186647	NM_002470.4(MYH3):c.5006del (p.Lys1669fs)	Pathogenic
2200781	NC_000017.11:g.10639475del	Pathogenic

SpliceAI

4470 predictions. Top by Δscore:

Variant	Effect	Δscore
17:10629592:CTCA:C	donor_loss	1.0000
17:10629593:TCACC:T	donor_loss	1.0000
17:10629594:CA:C	donor_loss	1.0000
17:10629595:A:AC	donor_gain	1.0000
17:10629595:A:T	donor_loss	1.0000
17:10629595:AC:A	donor_gain	1.0000
17:10629596:C:CC	donor_gain	1.0000
17:10629596:C:CG	donor_loss	1.0000
17:10629596:CC:C	donor_gain	1.0000
17:10629596:CCCTG:C	donor_gain	1.0000
17:10629732:ATCCT:A	acceptor_loss	1.0000
17:10629733:TC:T	acceptor_gain	1.0000
17:10629734:CC:C	acceptor_gain	1.0000
17:10629734:CCTAA:C	acceptor_loss	1.0000
17:10629735:C:CC	acceptor_gain	1.0000
17:10629836:A:AC	donor_gain	1.0000
17:10629837:C:CC	donor_gain	1.0000
17:10629840:A:AC	donor_gain	1.0000
17:10629840:ACAG:A	donor_gain	1.0000
17:10629841:C:CC	donor_gain	1.0000
17:10629841:CAG:C	donor_gain	1.0000
17:10629841:CAGC:C	donor_gain	1.0000
17:10629934:CACT:C	acceptor_gain	1.0000
17:10630087:CTTA:C	donor_loss	1.0000
17:10630088:TTAC:T	donor_loss	1.0000
17:10630089:TAC:T	donor_loss	1.0000
17:10630090:A:AC	donor_gain	1.0000
17:10630091:C:CC	donor_gain	1.0000
17:10630091:C:CG	donor_loss	1.0000
17:10630192:CGGAT:C	acceptor_gain	1.0000

AlphaMissense

12906 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:10640573:C:T	G760E	1.000
17:10641125:C:A	G709W	1.000
17:10641125:C:G	G709R	1.000
17:10641125:C:T	G709R	1.000
17:10641136:A:C	I705S	1.000
17:10641136:A:T	I705N	1.000
17:10641139:C:G	R704P	1.000
17:10641145:C:T	G702D	1.000
17:10641146:C:A	G702C	1.000
17:10641146:C:G	G702R	1.000
17:10641157:C:A	G698V	1.000
17:10641157:C:T	G698D	1.000
17:10641158:C:A	G698C	1.000
17:10641158:C:G	G698R	1.000
17:10641159:G:C	N697K	1.000
17:10641159:G:T	N697K	1.000
17:10641169:A:G	L694P	1.000
17:10641313:A:C	C673W	1.000
17:10641314:C:T	C673Y	1.000
17:10641315:A:G	C673R	1.000
17:10641322:A:C	F670L	1.000
17:10641322:A:T	F670L	1.000
17:10641324:A:G	F670L	1.000
17:10641356:A:G	L659P	1.000
17:10641365:A:G	L656P	1.000
17:10642525:A:G	W594R	1.000
17:10642525:A:T	W594R	1.000
17:10642647:A:G	L553P	1.000
17:10642701:A:G	L535P	1.000
17:10642836:A:G	L524P	1.000

dbSNP variants (sampled 300 via entrez): RS1000092200 (17:10660922 T>C,G), RS1000249557 (17:10656722 C>T), RS1000270582 (17:10654749 T>C,G), RS1000320224 (17:10628981 A>G,T), RS1000375331 (17:10665306 C>A), RS1000400754 (17:10651751 T>G), RS1000464800 (17:10666403 G>A,T), RS1000532751 (17:10657629 A>G), RS1000534948 (17:10670992 T>A,C), RS1000560652 (17:10632841 C>T), RS1000595907 (17:10665053 T>C), RS1000647331 (17:10675597 C>A,T), RS1000730592 (17:10659353 T>C), RS1000790077 (17:10638549 A>C,G), RS1000866525 (17:10675303 G>A,C)

Disease associations

OMIM: gene MIM:160720 | disease phenotypes: MIM:193700, MIM:178110, MIM:618469, MIM:618436, MIM:601680, MIM:156000, MIM:108120, MIM:617468, MIM:272460

GenCC curated gene-disease

Disease	Classification	Inheritance
Freeman-Sheldon syndrome	Definitive	Autosomal dominant
contractures, pterygia, and variable skeletal fusions syndrome 1B	Strong	Autosomal recessive
distal arthrogryposis type 2B1	Strong	Autosomal dominant
arthrogryposis	Strong	Autosomal dominant
contractures, pterygia, and variable skeletal fusions syndrome	Strong	Autosomal recessive
digitotalar dysmorphism	Supportive	Autosomal dominant
Sheldon-hall syndrome	Supportive	Autosomal dominant
autosomal recessive multiple pterygium syndrome	Supportive	Autosomal recessive
spondylocarpotarsal synostosis syndrome	Supportive	Autosomal recessive
contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A	Supportive	Autosomal dominant

Mondo (18): Freeman-Sheldon syndrome (MONDO:0008675), contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (MONDO:0008338), contractures, pterygia, and variable skeletal fusions syndrome 1B (MONDO:0020746), arthrogryposis, distal, type 2B3 (MONDO:0032751), distal arthrogryposis type 2B1 (MONDO:0020820), Meniere disease (MONDO:0007972), distal arthrogryposis (MONDO:0019942), prostate cancer (MONDO:0008315), arthrogryposis multiplex congenita (MONDO:0015168), spondylocarpotarsal synostosis syndrome (MONDO:0010094), arthrogryposis syndrome (MONDO:0015225), cleft lip/palate (MONDO:0016044), arthrogryposis, distal, type 1A (MONDO:0007157), digitotalar dysmorphism (MONDO:0015240), Sheldon-hall syndrome (MONDO:0011128)

Orphanet (11): Freeman-Sheldon syndrome (Orphanet:2053), Autosomal dominant multiple pterygium syndrome (Orphanet:65743), Sheldon-Hall syndrome (Orphanet:1147), Distal arthrogryposis (Orphanet:97120), Familial prostate cancer (Orphanet:1331), Arthrogryposis multiplex congenita (Orphanet:1037), Spondylocarpotarsal synostosis (Orphanet:3275), Arthrogryposis syndrome (Orphanet:109007), Cleft lip/palate (Orphanet:199306), Distal arthrogryposis type 1 (Orphanet:1146), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

173 total (30 of 173 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000041	Chordee
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000135	Hypogonadism
HP:0000157	Abnormality of the tongue
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000205	Pursed lips
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000298	Mask-like facies
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000325	Triangular face
HP:0000343	Long philtrum
HP:0000346	Whistling appearance
HP:0000347	Micrognathia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002183_2	Relative hand skill in reading disability	8.000000e-06
GCST006309_8	Post bronchodilator percent predicted FEV1 in smoking	6.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009902	handedness
EFO:0004314	forced expiratory volume

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D001176	Arthrogryposis	C05.550.150; C05.651.102; C05.660.077; C16.131.621.077
D008575	Meniere Disease	C09.218.568.217.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C565097	Digitotalar Dysmorphism (supp.)
C535483	Freeman-Sheldon syndrome (supp.)
C566739	Multiple Pterygium Syndrome, Autosomal Dominant (supp.)
C535780	Spondylocarpotarsal synostosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	affects expression, decreases reaction	1
arsenite	decreases reaction, affects binding	1
mono-(2-ethylhexyl)phthalate	increases methylation	1
ferrous chloride	decreases expression	1
CGP 52608	increases reaction, affects binding	1
monomethylarsonous acid	increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
incobotulinumtoxinA	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Benztropine	increases expression	1
Cannabidiol	increases expression	1
Clozapine	increases expression	1
Ivermectin	decreases expression	1
Nickel	affects expression, decreases reaction	1
Quercetin	increases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

310 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
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function