MYLK3

protein-coding

myosin light chain kinase 3, the group of Myosin light chain kinase family

Gene summary

Phosphorylation of cardiac myosin heavy chains (see MYH7B, MIM 609928) and light chains (see MYL2, MIM 160781) by a kinase, such as MYLK3, potentiates the force and rate of cross-bridge recruitment in cardiac myocytes (Chan et al., 2008 [PubMed 18202317]).[supplied by OMIM, Jul 2008]

MANE transcript

NM_182493.3

Inheritance

AR, AD

ClinVar variants

P:2U:618B:278

Top phenotype

Primary dilated cardiomyopathy

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr16:46,702,282-46,790,407

External References & Databases

Ensembl (ENSG00000140795)

Transcript & Mutation Effects

hg38 • Region Span ~88.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dilated cardiomyopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

dilated cardiomyopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

dilated cardiomyopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: Ambry Genetics

dilated cardiomyopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

MYLK3 was evaluated for autosomal dominant dilated cardiomyopathy (DCM) using SOP v10 on 26/06/2025. Human genetic evidence supporting this gene-disease relation includes case-level data and segregation data. At least three variants, all proven loss of function (haploinsufficiency), have been reported in humans with DCM, and two were shown to segregate with DCM in affected family members (Tobita et al 2017 PMID: 29235529, Hodatsu et al 2019 PMID: 30690923). There is also evidence of recessive DCM caused by bi-allelic loss-of-function and missense variants, although this evidence was not scored (Al-Hassnan et al 2020 PMID: 32870709 ). This gene-disease relationship is also supported by experimental evidence, including expression data and animal models. MYLK3 is exclusively expressed in the mammalian heart (Seguchi et al 2007 PMID: 17885681, Chan et al 2008 PMID: 18202317), where its major function is to phosphorylate MCL2 (encoded by MYL2) (Seguchi et al 2007 PMID: 17885681). MYLK3 has been shown to be essential for normal sarcomere assembly (Chan et al 2008 PMID: 18202317, Seguchi et al 2007 PMID: 17885681). There are multiple animal models including heterozygous knock-out mice and zebrafish and transgenic mouse models for MYLK3 loss-of-function variants previously reported in affected individuals. Zebrafish knock-down studies showed DCM-like phenotypes, with abnormal histology, enlarged cardiac dimensions and thinned ventricular walls in knock-downs vs wild-type (Seguchi et al 2007 PMID: 17885681). Heterozygous knock-out mice showed significant reduction in contractility and increase in left ventricular chamber dimensions both at systole and diastole in vs wild-type. Hemodynamic measurements also showed decrease in end-systolic pressure, LV dilatation and decrease in LV contractility (Tougas et al 2019 PMID: 31244672). A mouse knock-in model of a human splice variant (confirmed to cause haploinsufficiency) showed obvious LV dilatation with reduced LV contraction in homozygous mice, and LV dilatation with mildly reduced LV contraction in heterozygote mice vs wild-type (Hitsumoto et al 2023 PMID: 37128901). While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 07/11/2025 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYLK3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 1010

not specifiedTotal: 151

Primary dilated cardiomyopathyTotal: 2

MYLK3-related disorderTotal: 2

MYLK3-associated cardiomyopathyTotal: 1

Primary familial dilated cardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182493.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	235 clinvar	10 clinvar	250
missense			549 clinvar	30 clinvar	3 clinvar	582
nonsense		1 clinvar	19 clinvar			20
start loss			2 clinvar			2
frameshift			27 clinvar			27
splice donor/acceptor (+/-2bp)		1 clinvar	16 clinvar			17
Total	0	2	618	265	13	898

Highest pathogenic variant AF is 0.0000068406566

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182493.3	RefSeq	NP_872299.2	13	MANE Select
ENST00000394809.9	Ensembl	ENSP00000378288.4	13	MANE Select
NM_001308301.1	RefSeq	NP_001295230.1	10	Standard
ENST00000536476.5	Ensembl	ENSP00000439297.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mylk3	Danio rerio	Structure: whole organism Quality: edematous abnormal

Gene / Model

Organism

Observed Phenotype

mylk3

Danio rerio

Structure: whole organism

Quality: edematous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
Gastric acid secretion - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)

Biological Process

regulation of vascular permeability involved in acute inflammatory response
protein phosphorylation
sarcomere organization
sarcomerogenesis
cardiac myofibril assembly

Molecular Function

calmodulin-dependent protein kinase activity
myosin light chain kinase activity
ATP binding

Cellular Component

cytoplasm
cytosol
actin cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394809
Coding exons: 13
Length: 83429
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125748
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.502	447	478	0.935	0.0000268	5305
Missense (PolyPhen)		116	153.03	0.75803		1937
Synonymous	-0.506	215	206	1.04	0.0000134	1688
Loss of Function	2.83	16	33.7	0.474	0.00000166	394

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00089	0.00087	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.000068	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Kinase that phosphorylates MYL2 in vitro. Promotes sarcomere formation in cardiomyocytes and increases cardiomyocyte contractility (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.142

Intolerance Scores

LoFtool: 0.585
RVIS EVS: -1.26
RVIS percentile EVS: 5.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.271

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium