MYL2

Summary

MYL2 (myosin light chain 2, HGNC:7583) is a protein-coding gene on chromosome 12q24.11, encoding Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (P10916). Contractile protein that plays a role in heart development and function.

This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy.

Source: NCBI Gene 4633 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertrophic cardiomyopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 507 total — 3 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 99
• Druggable target: yes
• MANE Select transcript: NM_000432

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7583
Approved symbol	MYL2
Name	myosin light chain 2
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Aliases	CMH10
Ensembl gene	ENSG00000111245
Ensembl biotype	protein_coding
OMIM	160781
Entrez	4633

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 25 protein_coding, 1 retained_intron

ENST00000228841, ENST00000546404, ENST00000548438, ENST00000549029, ENST00000663220, ENST00000713800, ENST00000713801, ENST00000713803, ENST00000713804, ENST00000713805, ENST00000713806, ENST00000713826, ENST00000713827, ENST00000713828, ENST00000713829, ENST00000713830, ENST00000713831, ENST00000880458, ENST00000880459, ENST00000880460, ENST00000880461, ENST00000880462, ENST00000966752, ENST00000966753, ENST00000966754, ENST00000966755

RefSeq mRNA: 3 — MANE Select: NM_000432 NM_000432, NM_001406745, NM_001406916

CCDS: CCDS31901

Canonical transcript exons

ENST00000228841 — 7 exons

Exon	Start	End
ENSE00000755126	110913096	110913144
ENSE00000755127	110913246	110913324
ENSE00001295320	110919104	110919193
ENSE00001403466	110920527	110920579
ENSE00002417824	110915715	110915790
ENSE00003655617	110914186	110914290
ENSE00003896317	110910845	110911175

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 99.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 27.9791 / max 6290.3966, expressed in 89 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133279	27.8241	89
133275	0.0688	20
133278	0.0420	16
133280	0.0225	14
133276	0.0217	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.99	gold quality
diaphragm	UBERON:0001103	99.97	gold quality
apex of heart	UBERON:0002098	99.97	gold quality
biceps brachii	UBERON:0001507	99.96	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.96	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.96	gold quality
tibialis anterior	UBERON:0001385	99.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.95	gold quality
gluteal muscle	UBERON:0002000	99.94	gold quality
skeletal muscle tissue	UBERON:0001134	99.93	gold quality
triceps brachii	UBERON:0001509	99.93	gold quality
deltoid	UBERON:0001476	99.92	gold quality
gastrocnemius	UBERON:0001388	99.91	gold quality
quadriceps femoris	UBERON:0001377	99.90	gold quality
vastus lateralis	UBERON:0001379	99.89	gold quality
left ventricle myocardium	UBERON:0006566	99.89	gold quality
body of tongue	UBERON:0011876	99.89	gold quality
cardiac ventricle	UBERON:0002082	99.80	gold quality
heart left ventricle	UBERON:0002084	99.79	gold quality
vena cava	UBERON:0004087	99.46	gold quality
muscle organ	UBERON:0001630	98.41	gold quality
muscle of leg	UBERON:0001383	97.82	gold quality
heart	UBERON:0000948	94.85	gold quality
right atrium auricular region	UBERON:0006631	94.20	gold quality
muscle tissue	UBERON:0002385	94.06	gold quality
cardiac atrium	UBERON:0002081	92.81	gold quality
tongue	UBERON:0001723	91.73	gold quality
myocardium	UBERON:0002349	87.30	gold quality
pharyngeal mucosa	UBERON:0000355	87.24	gold quality
superior surface of tongue	UBERON:0007371	84.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, HESX1, HEY2, JUN, JUNB, MEF2A, MYOD1, NFATC4, NFKB2, NKX2-5, NR2F2, PPARA, RLF, SP4, SRF, TBX5, USF1, ZHX2

miRNA regulators (miRDB)

22 targeting MYL2, 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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-1261	98.62	68.10	896
HSA-MIR-376B-5P	98.46	66.40	606
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-876-5P	97.99	68.49	1345
HSA-MIR-3167	96.81	67.09	1236
HSA-MIR-1266-3P	96.23	66.36	778
HSA-MIR-3165	96.18	66.22	473

Literature-anchored findings (GeneRIF, showing 40)

• mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations (PMID:11748309)
• diphosphorylated MRLC and Rho-kinase accumulated and colocalized at the contractile ring and the midbody in dividing cells (PMID:12185584)
• MLC2 phosphorylation is regulated by both ROCK and MLC kinase and plays an important role in platelet biogenesis by controlling proplatelet formation and fragmentation. (PMID:17244674)
• DLC1 negatively regulates Rho/ROCK/MLC2 (PMID:18648664)
• Following down-regulation of MR-1, the phosphorylations of MLC2, focal adhesion kinase (FAK), and Akt were dramatically decreased (PMID:18948272)
• Profound cellular changes observed in Tg-D166V myocardium when placed in vivo could trigger a series of pathological responses and result in poor prognosis for D166V-positive patients. (PMID:18987303)
• These results indicate that diphosphorylation of regulatory light chain of myosin IIA by Rho-kinase in lamella is responsible for the cell to spread properly. (PMID:19254691)
• Data show that VE-cadherin signals to Rho-kinase-dependent myosin light-chain 2 phosphorylation, leading to actomyosin contractility, which regulates the distribution of VE-cadherin at cell-cell junctions and sprouting. (PMID:19345098)
• Oxidative stress related to asphyxia induces nitration of cardiac MLC2 protein and thus increases its degradation. This and a large decrease in MLC2 phosphorylation contribute to the development of systolic dysfunction. (PMID:20386496)
• Differential phosphorylation of myosin light chain (Thr)18 and (Ser)19 have functional implications in platelets (PMID:20670370)
• MYL2 was down-expressed in heart failure tissues, and findings suggested that MYL2 may play a role in the development and progression of chronic heart failure. (PMID:21259275)
• This is the first report of mutations in TPM1, MY L3, and MYL2 associated with primary, non-hypertrophied restrictive cardiomyopathy. (PMID:21823217)
• results suggest that the A13T mutation triggers a hypertrophic response through changes in cardiac sarcomere organization and myosin cross-bridge function leading to abnormal remodelling of the heart. (PMID:22091967)
• These data demonstrate that smMLCK is a specific and efficient kinase for the in vitro phosphorylation of MYL2, cardiac, and smooth muscle myosin. (PMID:22120626)
• MLC2 isoforms localisation is dependent on cell cycle in HeLa cells. (PMID:22425609)
• AMPK mediates spindle pole-associated pMRLC(ser19) to control spindle orientation via regulation of actin cortex-astral microtubule attachments (PMID:22688514)
• NDRG1 inhibited an important regulatory pathway mediated by ROCK1/pMLC2 pathway that modulates stress fiber assembly. (PMID:23188716)
• study concludes the mutations in the last exon of MYL2 are responsible for a novel autosomal recessive lethal myosinopathy due to defects changing the C-terminal tail of the ventricular form of the myosin regulatory light chain (PMID:23365102)
• Newly implicated variants (MYL2, C12orf51 and OAS1) were found to be significantly associated with 1-h plasma glucose as predisposing risk factors for type 2 diabetes. (PMID:23575436)
• Ostf1b could constitutively activate the Rho kinase 1 (ROCK1) and myosin light chain 2 (MLC2) signalling pathway that promotes cell migration, epithelial mesenchymal transition (EMT) and cytoskeletal dynamics through stress fibre formation. (PMID:23732111)
• Results suggest that Aurora B, but not Rho/MLCK (myosin-light-chain kinase) signaling, is essential for the localization of 2P-MRLC (myosin regulatory light chains) to the midzone in dividing HeLa cells. (PMID:23951055)
• an interplay between phosphorylation and glycosylation of MLC2, which might be involved in the development of muscle atrophy and associated changes (PMID:24184274)
• Four novel body mass index-associated loci near the KCNQ1(rs2237892), ALDH2/MYL2 (rs671, rs12229654), ITIH4 (rs2535633) and NT5C2 (rs11191580) genes are identified in East Asian-ancestry populations. (PMID:24861553)
• Data suggest a mutation in MYL2 (amino acid substitution D94A; novel mutation in familial dilated cardiomyopathy) does affect conformation (reduced alpha-helical content) and function (reduced binding of myosin heavy chain; increased ATPase) of MYL2. (PMID:25825243)
• FLNb enhances invasion of cancer cells through phosphorylation of MRLC and FAK. (PMID:25925610)
• This review focuses on the regulatory functions of MLC-2 in the embryonic and adult heart, with an emphasis on phosphorylation-driven actions of MLC-2v in adult cardiac muscle. (PMID:26074085)
• Myosin regulatory light chain phosphorylation enhances cardiac beta-myosin in vitro motility under load. (PMID:26116789)
• The results show that the MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers. However, the presence of an additional risk factor for hypertrophy, particularly hypertension, adds to the development of HCM. (PMID:26497160)
• the MYL2 gene on chromosome 12 is associated with serum HDL-C levels in Korean men. The association was much stronger in male obese subjects and smokers than that in leaner nonsmoking male subjects. (PMID:26763873)
• Our study provides the first evidence that miR-223 can regulate pulmonary artery smooth muscle cells proliferation, migration, and actomyosin reorganization through its novel targets, RhoB and MLC2, resulting in vascular remodeling and the development of pulmonary arterial hypertension. (PMID:27121468)
• differential regulation of PKA and cell stiffness in unconfined versus confined cells is abrogated by dual, but not individual, inhibition of Piezo1 and myosin II. (PMID:27160899)
• These results indicate shear stress induced vascular smooth muscle cell contraction was mediated by cell surface glycocalyx via a ROCK-MLC phosphatase (MLCP) pathway, providing evidence of the glycocalyx mechanotransduction in myogenic response. (PMID:28191820)
• This exome-wide association study indicated that C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 polymorphisms are linked to blood Pb levels in the Korean population. (PMID:28212632)
• Two siblings with hypertrophic cardiomyopathy had the pathogenic variant p.Ala13Thr variant in MYL2. (PMID:28223422)
• Mutation in myosin regulatory light chain gene is associated with defective myosin motor function that ultimately result in pathological hypertrophic remodeling. (PMID:28467684)
• Lipolysis-stimulated lipoprotein receptors (LSRs) localized to bicellular junctions in association with myosin regulatory light chain 2 (MRLC2) at low cell densities and to tricellular contacts when myosin phosphatase target subunit 1 (MYPT1) localized to the bicellular regions. (PMID:28493278)
• Structural dynamics-based approach reveals that the E56G mutation in human ventricular essential light chain affects the structure of the actin-myosin complex in the presence of ATP. The mutation increases the population in the S structural state (increasing the duty ratio), and changes the structure of the W state, so that it more closely resembles the S state. (PMID:28700929)
• NKX2-5 and MLC2v double-positive cells possess ventricular-like properties. The results demonstrate that the NKX2-5(eGFP/w) and MLC2v(mCherry/w) hPSCs provide a powerful model system to capture region-specific cardiac differentiation from early to late stages. Our study would facilitate subtype-specific cardiac development and functional analysis using the hPSC-derived sources. (PMID:29175323)
• R58Q of myosin regulatory light chain promotes an OFF state of the thick filaments that reduces the number of myosin head domains that are available for actin interaction and ATP utilization. (PMID:29452157)
• The hypocontractile activity of D94A MYL-2 mutant resulted in the rightward shift of the force-pCa dependence and decreased actin-activated myosin ATPase activity. (PMID:29463717)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	myl2b	ENSDARG00000053424
danio_rerio	myl2a	ENSDARG00000104722
mus_musculus	Myl2	ENSMUSG00000013936
rattus_norvegicus	Myl2	ENSRNOG00000030848
caenorhabditis_elegans		WBGENE00003369
caenorhabditis_elegans		WBGENE00003370

Paralogs (7): MYL9 (ENSG00000101335), MYL12A (ENSG00000101608), MYL10 (ENSG00000106436), MYL7 (ENSG00000106631), MYL12B (ENSG00000118680), MYL11 (ENSG00000180209), MYL5 (ENSG00000215375)

Protein

Protein identifiers

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform — P10916 (reviewed: P10916)

Alternative names: Cardiac myosin light chain 2, Myosin light chain 2, slow skeletal/ventricular muscle isoform, Ventricular myosin light chain 2

All UniProt accessions (6): P10916, A0A590UJU8, A0A590UK07, A0AAQ5BH12, G3V1V8, Q6IB42

UniProt curated annotations — full annotation on UniProt →

Function. Contractile protein that plays a role in heart development and function. Following phosphorylation, plays a role in cross-bridge cycling kinetics and cardiac muscle contraction by increasing myosin lever arm stiffness and promoting myosin head diffusion; as a consequence of the increase in maximum contraction force and calcium sensitivity of contraction force. These events altogether slow down myosin kinetics and prolong duty cycle resulting in accumulated myosins being cooperatively recruited to actin binding sites to sustain thin filament activation as a means to fine-tune myofilament calcium sensitivity to force. During cardiogenesis plays an early role in cardiac contractility by promoting cardiac myofibril assembly.

Subunit / interactions. Myosin is a hexamer of 2 heavy chains and 4 light chains. Interacts with MYOC.

Subcellular location. Cytoplasm. Myofibril. Sarcomere. A band.

Tissue specificity. Highly expressed in type I muscle fibers.

Post-translational modifications. N-terminus is methylated by METTL11A/NTM1. Phosphorylated by MYLK3 and MYLK2; promotes cardiac muscle contraction and function. Dephosphorylated by PPP1CB complexed to PPP1R12B. The phosphorylated form in adult is expressed as gradients across the heart from endocardium (low phosphorylation) to epicardium (high phosphorylation); regulates cardiac torsion and workload distribution.

Disease relevance. Cardiomyopathy, familial hypertrophic, 10 (CMH10) [MIM:608758] A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. Rarely, patients present a variant of familial hypertrophic cardiomyopathy, characterized by mid-left ventricular chamber thickening. The disease is caused by variants affecting the gene represented in this entry. Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy (MFM12) [MIM:619424] A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM12 is an autosomal recessive, severe form characterized by progressive myopathy with onset shortly after birth, tremor or clonus at birth, and cardiomyopathy usually leading to death by 6 months of age. Skeletal and cardiac muscle tissues show fiber-type disproportion with small type I and normal sized type II fibers, and myofibrillar disorganization. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. This chain binds calcium.

RefSeq proteins (3): NP_000423, NP_001393674, NP_001393845 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR050403	Myosin_RLC	Family

Pfam: PF13499

UniProt features (21 total): sequence variant 7, modified residue 5, binding site 4, domain 3, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8ACT	ELECTRON MICROSCOPY	3.6
8G4L	ELECTRON MICROSCOPY	6.4
5TBY	ELECTRON MICROSCOPY	20

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10916-F1	84.10	0.56

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 (4): 37; 39; 41; 48

Post-translational modifications (5): 14, 15, 19, 52, 2

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: 419 (showing top): BIOCARTA_RHO_PATHWAY, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, MORF_RAGE, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_GROWTH, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, KEGG_TIGHT_JUNCTION, GOBP_CARDIAC_MYOFIBRIL_ASSEMBLY, MEF2_02, MODULE_16, GGGTGGRR_PAX4_03, GNF2_MYL3

GO Biological Process (13): regulation of the force of heart contraction (GO:0002026), regulation of striated muscle contraction (GO:0006942), heart development (GO:0007507), post-embryonic development (GO:0009791), negative regulation of cell growth (GO:0030308), muscle cell fate specification (GO:0042694), cardiac myofibril assembly (GO:0055003), ventricular cardiac muscle tissue morphogenesis (GO:0055010), heart contraction (GO:0060047), cardiac muscle contraction (GO:0060048), positive regulation of the force of heart contraction (GO:0098735), heart morphogenesis (GO:0003007), muscle cell development (GO:0055001)

GO Molecular Function (6): actin monomer binding (GO:0003785), calcium ion binding (GO:0005509), structural constituent of muscle (GO:0008307), myosin heavy chain binding (GO:0032036), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), myosin complex (GO:0016459), myofibril (GO:0030016), sarcomere (GO:0030017), A band (GO:0031672), cardiac myofibril (GO:0097512), actin cytoskeleton (GO:0015629)

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	4
striated muscle contraction	2
myofibril	2
regulation of heart contraction	1
regulation of biological quality	1
regulation of muscle contraction	1
animal organ development	1
circulatory system development	1
multicellular organism development	1
multicellular organismal process	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
cell fate specification	1
muscle cell fate commitment	1
myofibril assembly	1
cardiac muscle cell development	1
cardiac ventricle morphogenesis	1
ventricular cardiac muscle tissue development	1
cardiac muscle tissue morphogenesis	1
heart process	1
blood circulation	1
heart contraction	1
regulation of the force of heart contraction	1
heart development	1
animal organ morphogenesis	1
muscle cell differentiation	1
cell development	1
actin binding	1
metal ion binding	1
structural molecule activity	1
myosin binding	1
binding	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membraneless organelle	1
actin cytoskeleton	1
protein-containing complex	1

Protein interactions and networks

STRING

3050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYL2	MYH7	P12883	936
MYL2	MYBPC3	Q14896	892
MYL2	ACTC1	P04270	889
MYL2	TNNT2	P45379	877
MYL2	TNNI3	P19429	872
MYL2	MYH6	P13533	859
MYL2	MYOD1	P15172	837
MYL2	NKX2-5	P52952	799
MYL2	RHOA	P06749	792
MYL2	CSRP3	P50461	792
MYL2	ROCK2	O75116	791
MYL2	MYLK3	Q32MK0	791
MYL2	TPM1	P09493	788
MYL2	PRKAG2	Q9UGJ0	766
MYL2	MYLK2	Q9H1R3	748

IntAct

32 interactions, top by confidence:

A	B	Type	Score
MYL2	MYOC	psi-mi:“MI:0915”(physical association)	0.620
MYOC	MYL2	psi-mi:“MI:0915”(physical association)	0.620
MYL2	MYOC	psi-mi:“MI:0403”(colocalization)	0.620
MYL2	USP6	psi-mi:“MI:0915”(physical association)	0.610
USP6	MYL2	psi-mi:“MI:0407”(direct interaction)	0.610
USP6	MYL2	psi-mi:“MI:0915”(physical association)	0.610
USP6	MYL2	psi-mi:“MI:0403”(colocalization)	0.610
IRX6	MYL2	psi-mi:“MI:0915”(physical association)	0.560
MYL2	IRX6	psi-mi:“MI:0915”(physical association)	0.560
MYL2	PSORS1C2	psi-mi:“MI:0915”(physical association)	0.560
MYL2	MYL5	psi-mi:“MI:0914”(association)	0.530
MYL2	ZNF529	psi-mi:“MI:0915”(physical association)	0.490
MYL2	HMGN2	psi-mi:“MI:0915”(physical association)	0.400
GJB5	MYL2	psi-mi:“MI:0915”(physical association)	0.370
NHP2	MYL2	psi-mi:“MI:0915”(physical association)	0.370
BCKDK	AIP	psi-mi:“MI:0914”(association)	0.350
MYL2	AMY1A	psi-mi:“MI:0914”(association)	0.350
MFGE8	MYH7B	psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
TTC4	MYH7B	psi-mi:“MI:0914”(association)	0.350
PSORS1C2	MYL2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): MYL5 (Affinity Capture-MS), MYO5B (Affinity Capture-MS), MYO19 (Affinity Capture-MS), ASPM (Affinity Capture-MS), MYO5A (Affinity Capture-MS), IL36G (Affinity Capture-MS), MYL2 (Affinity Capture-Western), PKM (Affinity Capture-Western), PKM (Affinity Capture-MS), MYL2 (Biochemical Activity), MYL2 (Biochemical Activity), MYL2 (Affinity Capture-Western), PKM (Reconstituted Complex), ZNF529 (Two-hybrid), MYL2 (Proximity Label-MS)

ESM2 similar proteins: A4IF97, B7SNI3, F1SSF9, O14950, O93409, P02608, P02609, P02610, P02611, P02612, P04112, P04113, P04466, P05944, P05963, P07461, P08051, P08052, P08733, P10916, P13543, P13832, P13833, P15845, P18666, P19105, P19625, P19626, P24032, P24732, P24844, P29269, P40423, P41691, P51667, P97457, Q01449, Q02045, Q09510, Q0P571

Diamond homologs: A2WN93, A2WNH1, A2Y609, A3E3H0, A3E4D8, A3E4F9, A4IF97, A4UHC0, A8CEP3, A8I1Q0, B7SNI3, F1SSF9, O14950, O93409, O94739, P02597, P02598, P02608, P02609, P02610, P02611, P02612, P02613, P04112, P04113, P04353, P04464, P04466, P05419, P05944, P05963, P07461, P08051, P08052, P08733, P0DH95, P0DH96, P10916, P11120, P13543

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MYLK	“up-regulates activity”	MYL2	phosphorylation
NKX2-5	“up-regulates quantity by expression”	MYL2	“transcriptional regulation”
CDC42BPA	“up-regulates activity”	MYL2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	10
Uncertain significance	259
Likely benign	150
Benign	33

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1202626	NM_000432.4(MYL2):c.473T>C (p.Ile158Thr)	Pathogenic
14067	NM_000432.4(MYL2):c.173G>A (p.Arg58Gln)	Pathogenic
417460	NC_000012.12:g.(?110910819)(110911175_?)del	Pathogenic
1162324	NM_000432.4(MYL2):c.499T>C (p.Ter167Gln)	Likely pathogenic
1329420	NM_000432.4(MYL2):c.193G>T (p.Glu65Ter)	Likely pathogenic
1339691	NM_000432.4(MYL2):c.141del (p.Asn47fs)	Likely pathogenic
164469	NM_000432.4(MYL2):c.482A>G (p.His161Arg)	Likely pathogenic
1804172	NM_000432.4(MYL2):c.485_487del (p.Gly162del)	Likely pathogenic
181436	NM_000432.4(MYL2):c.496G>T (p.Asp166Tyr)	Likely pathogenic
43479	NM_000432.4(MYL2):c.485G>A (p.Gly162Glu)	Likely pathogenic
532778	NM_000432.4(MYL2):c.173G>T (p.Arg58Leu)	Likely pathogenic
626788	NM_000432.4(MYL2):c.491_495del (p.Glu164fs)	Likely pathogenic
802892	NM_000432.4(MYL2):c.163G>C (p.Ala55Pro)	Likely pathogenic

SpliceAI

1184 predictions. Top by Δscore:

Variant	Effect	Δscore
12:110913097:T:TA	donor_gain	1.0000
12:110913100:T:TA	donor_gain	1.0000
12:110913140:GAACG:G	acceptor_gain	1.0000
12:110913141:AACG:A	acceptor_gain	1.0000
12:110913142:ACG:A	acceptor_gain	1.0000
12:110913143:CG:C	acceptor_gain	1.0000
12:110913143:CGC:C	acceptor_gain	1.0000
12:110913144:GC:G	acceptor_loss	1.0000
12:110913145:C:CC	acceptor_gain	1.0000
12:110913145:CTGCA:C	acceptor_loss	1.0000
12:110913148:C:CT	acceptor_gain	1.0000
12:110913149:A:T	acceptor_gain	1.0000
12:110913244:A:AC	donor_gain	1.0000
12:110913245:C:CA	donor_gain	1.0000
12:110913245:CT:C	donor_gain	1.0000
12:110913245:CTA:C	donor_gain	1.0000
12:110913245:CTAAT:C	donor_gain	1.0000
12:110913248:ATCAG:A	donor_gain	1.0000
12:110913251:AG:A	donor_gain	1.0000
12:110914184:AC:A	donor_gain	1.0000
12:110914185:CC:C	donor_gain	1.0000
12:110914245:T:TA	donor_gain	1.0000
12:110914289:CC:C	acceptor_gain	1.0000
12:110914290:CC:C	acceptor_gain	1.0000
12:110919052:C:CA	donor_gain	1.0000
12:110919099:CCCA:C	donor_loss	1.0000
12:110919100:CCA:C	donor_loss	1.0000
12:110919101:CACCT:C	donor_loss	1.0000
12:110919102:A:AG	donor_loss	1.0000
12:110919102:ACCT:A	donor_gain	1.0000

AlphaMissense

1127 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:110914212:A:G	L83P	1.000
12:110915775:C:G	D37H	1.000
12:110915785:G:C	F33L	1.000
12:110915785:G:T	F33L	1.000
12:110915787:A:G	F33L	1.000
12:110914212:A:T	L83H	0.999
12:110914223:A:C	F79L	0.999
12:110914223:A:T	F79L	0.999
12:110914224:A:C	F79C	0.999
12:110914225:A:G	F79L	0.999
12:110915738:A:G	L49P	0.999
12:110915741:T:A	D48V	0.999
12:110915741:T:C	D48G	0.999
12:110915741:T:G	D48A	0.999
12:110915753:A:T	I44N	0.999
12:110915762:T:A	D41V	0.999
12:110915763:C:G	D41H	0.999
12:110915773:G:C	D37E	0.999
12:110915773:G:T	D37E	0.999
12:110915774:T:A	D37V	0.999
12:110915774:T:G	D37A	0.999
12:110915786:A:G	F33S	0.999
12:110915790:C:G	A32P	0.999
12:110919107:C:A	K30N	0.999
12:110919107:C:G	K30N	0.999
12:110913130:A:G	L123P	0.998
12:110913295:C:G	A102P	0.998
12:110914191:A:G	L90P	0.998
12:110914201:C:A	G87W	0.998
12:110914213:G:A	L83F	0.998

dbSNP variants (sampled 300 via entrez): RS1000171476 (12:110911178 G>C,T), RS1000835312 (12:110919350 T>C), RS1001118295 (12:110915050 T>C), RS1001158656 (12:110914666 A>G), RS1001437310 (12:110920600 CAATA>C), RS1002386724 (12:110919881 T>C), RS1002448666 (12:110920644 C>G,T), RS1002517060 (12:110912987 T>C), RS1002829482 (12:110919514 T>C), RS1002909903 (12:110920453 G>A,C), RS1003184043 (12:110919580 G>A), RS1004689856 (12:110913746 TTTTTGTTTTG>T,TTTTTG,TTTTTGTTTTGTTTTG), RS1005961362 (12:110912973 A>G), RS1006043409 (12:110914086 A>G), RS1006763534 (12:110913521 T>C)

Disease associations

OMIM: gene MIM:160781 | disease phenotypes: MIM:608758, MIM:619424, MIM:192600, MIM:613426

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertrophic cardiomyopathy 10	Definitive	Autosomal dominant
myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy	Moderate	Autosomal recessive
congenital fiber-type disproportion myopathy	Supportive	Autosomal dominant
dilated cardiomyopathy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Definitive	AD
dilated cardiomyopathy	Limited	AD
arrhythmogenic right ventricular cardiomyopathy	No Known Disease Relationship	AD

Mondo (12): hypertrophic cardiomyopathy 10 (MONDO:0012112), hypertrophic cardiomyopathy (MONDO:0005045), myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy (MONDO:0859168), cardiomyopathy (MONDO:0004994), congenital fiber-type disproportion myopathy (MONDO:0009711), congenital heart disease (MONDO:0005453), familial hypertrophic cardiomyopathy (MONDO:0024573), dilated cardiomyopathy (MONDO:0005021), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), hypertrophic cardiomyopathy 1 (MONDO:0008647), congestive heart failure (MONDO:0005009), dilated cardiomyopathy 1S (MONDO:0013262)

Orphanet (9): Rare hypertrophic cardiomyopathy (Orphanet:217569), Rare cardiomyopathy (Orphanet:167848), Congenital fiber-type disproportion myopathy (Orphanet:2020), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Dilated cardiomyopathy (Orphanet:217604), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

99 total (30 of 99 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000276	Long face
HP:0000347	Micrognathia
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000678	Dental crowding
HP:0000767	Pectus excavatum
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001315	Reduced tendon reflexes
HP:0001337	Tremor
HP:0001371	Flexion contracture
HP:0001374	Congenital hip dislocation
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001609	Hoarse voice
HP:0001627	Abnormal heart morphology
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001648	Cor pulmonale
HP:0001653	Mitral regurgitation
HP:0001663	Ventricular fibrillation
HP:0001670	Asymmetric septal hypertrophy

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000954_2	Alcohol consumption	4.000000e-35
GCST001234_1	Gamma glutamyl transpeptidase	9.000000e-58
GCST001237_1	HDL cholesterol	3.000000e-23
GCST001842_1	Drinking behavior	3.000000e-215
GCST001845_4	Coronary heart disease	4.000000e-14
GCST001965_11	Glycemic traits	9.000000e-13
GCST002461_3	Body mass index	5.000000e-09
GCST002732_2	Metabolic syndrome	3.000000e-06
GCST002773_3	Gout	2.000000e-23
GCST004232_26	HDL cholesterol levels	2.000000e-08
GCST004234_14	HDL cholesterol levels	8.000000e-09
GCST004404_7	Alcohol consumption (drinkers vs non-drinkers)	2.000000e-48
GCST005329_1	Coffee consumption	2.000000e-16
GCST005441_8	Alcohol consumption (max-drinks)	2.000000e-12
GCST005878_4	Metabolic syndrome (multivariate analysis)	1.000000e-09
GCST005973_13	White blood cell count	1.000000e-12
GCST005974_4	Neutrophil count	3.000000e-16
GCST007438_4	High density lipoprotein cholesterol levels	1.000000e-08
GCST008972_239	Urate levels	5.000000e-11
GCST010512_25	Serum uric acid levels	2.000000e-08
GCST011141_14	Hypertension	8.000000e-09
GCST011141_18	Hypertension	2.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004315	drinking behavior
EFO:0004340	body mass index
EFO:0000195	metabolic syndrome
EFO:0006782	cups of coffee per day measurement
EFO:0004833	neutrophil count
EFO:0004531	urate measurement
EFO:0004761	uric acid measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
C563538	Cardiomyopathy, Dilated, 1s (supp.)
C563865	Cardiomyopathy, Familial Hypertrophic, 10 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3831286 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	affects expression, decreases expression	4
Ethanol	decreases expression, affects response to substance	2
Triclosan	decreases expression	2
kaempferol	decreases reaction, increases phosphorylation	1
quercitrin	affects expression	1
sodium arsenite	affects methylation	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
xanthohumol	decreases phosphorylation, decreases activity	1
2,7-dihydroxynaphthalene	decreases expression	1
lipopolysaccharide, Escherichia coli O111 B4	decreases reaction, increases phosphorylation	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Calcium	affects abundance, affects reaction	1
Diethylhexyl Phthalate	increases expression	1
Amifostine	decreases reaction, increases phosphorylation	1
Etoposide	decreases expression	1
Lead	affects abundance, affects reaction	1
Lipopolysaccharides	decreases reaction, increases phosphorylation	1
Methapyrilene	decreases methylation	1
Methylnitronitrosoguanidine	increases expression	1
Smoke	increases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1
Particulate Matter	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation