MYPN

protein-coding

myopalladin, the group of I-set domain containing

Gene summary

Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

MANE transcript

NM_032578.4

Inheritance

AD, AR

ClinVar variants

P:91U:970B:590

Top phenotype

Cardiomyopathy, dilated, 1KK; Cardiomyopathy, familial hypertrophic, 22; Cardiomyopathy, dilated, 1KK

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr10:68,087,897-68,212,017

External References & Databases

Ensembl (ENSG00000138347)

Transcript & Mutation Effects

hg38 • Region Span ~124.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypertrophic cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

MYPN was first reported in relation to autosomal dominant hypertrophic cardiomyopathy in 2001 (Bang et al., PMID: 11309420). Nine variants (8 missense, 1 nonsense) that have been reported in nine probands in two publications (PMIDs: 22286171, 20801532) are included in this curation; however, none of the variants were able to be scored given their frequencies in gnomAD and the lack of screening for variants in other sarcomeric HCM genes. The mechanism of pathogenicity is unknown. This gene-disease association is supported by expression studies and an animal model (PMIDs: 11309420, 22286171). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the HCM GCEP on 04/29/2020. It was reevaluated on 06/14/2023 by the HCVD GCEP. As a result of this reevaluation, the classification changed from limited to disputed due to the lack of genetic evidence.

familial isolated restrictive cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019150

Submitter: Orphanet

dilated cardiomyopathy 1KKLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014100

Submitter: Labcorp Genetics (formerly Invitae)

childhood-onset nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015738

Submitter: Orphanet

hypertrophic cardiomyopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: PanelApp Australia

MYPN-related myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015023

Submitter: G2P

cap myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015753

Submitter: Orphanet

familial hypertrophic cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

MYPN-related myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015023

Submitter: PanelApp Australia

dilated cardiomyopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

familial dilated cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

MYPN-related myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015023

Submitter: Labcorp Genetics (formerly Invitae)

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

dilated cardiomyopathy 1KKLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014100

Submitter: ClinGen

MYPN was originally evaluated for DCM by the ClinGen DCM GCEP on 23 July 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 5th March 2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. MYPN was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2008 (Dubosq-Bidot et al., 2008, PMID 18006477). Human genetic evidence supporting this gene-disease relationship includes case-level data. Variants (50 missense, 2 frameshift) in this gene have been reported in at least 56 probands in 21 publications. However, variants in this gene segregated with disease in only one family (3 additional family members) and a case-control study (Mazzarotto et al., 2020, PMID 31983221) found no enrichment of MYPN rare variants in two DCM cohorts compared to controls. This gene-disease assertion is supported by one animal model (mouse; Filomena et al., 2021, PMID 34558411), expression studies and protein interaction studies. MYPN has also been curated by the hereditary cardiovascular disease Gene Curation Expert Panel for hypertrophic cardiomyopathy (Disputed, June 14, 2023) and by the congenital myopathies Gene Curation Expert Panel for nemaline myopathy 11 (Definitive, June 17, 2020). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of MYPN with autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 5th March 2025 (SOP Version 10).

MYPN-related myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015023

Submitter: ClinGen

MYPN was reported in relation to autosomal recessive MYPN-related myopathy in 2017 (Miyatake et al., PMID: 28017374). At least 8 unique variants (nonsense, frameshift, splice-site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands in 3 publications (PMIDs: 28017374, 28220527, 31133047). The mechanism for disease is homozygous loss of function. This gene-disease association is supported by animal models and expression studies. In summary, MYPN is definitively associated with autosomal recessive MYPN-related myopathy.

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated, 1KK; Cardiomyopathy, familial hypertrophic, 22; Cardiomyopathy, dilated, 1KKAD

Manifestation: Cardiovascular; Neurologic

Intervention: Cardiovascular

Rationale: Surveillance (eg, including echocardiogram and electrocardiogram) and preventive measures related to cardiac manifestations may allow early diagnosis and management, which may reduce morbidity and mortality

Refs: 18006477; 22286171; 22892539; 28017374

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYPN variants in ClinVar

29 Conditions Cataloged

Dilated cardiomyopathy 1KKTotal: 1194

Cardiovascular phenotypeTotal: 1043

not providedTotal: 482

not specifiedTotal: 230

MYPN-related disorderTotal: 173

MYPN-related myopathyTotal: 144

Primary dilated cardiomyopathyTotal: 13

Hypertrophic cardiomyopathyTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032578.4. 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			9 clinvar	489 clinvar	3 clinvar	501
missense		2 clinvar	946 clinvar	92 clinvar	6 clinvar	1046
nonsense	17 clinvar	13 clinvar	3 clinvar			33
start loss			1 clinvar			1
frameshift	28 clinvar	15 clinvar	6 clinvar			49
splice donor/acceptor (+/-2bp)	4 clinvar	12 clinvar	5 clinvar			21
Total	49	42	970	581	9	1651

Highest pathogenic variant AF is 0.000016727381

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032578.4	RefSeq	NP_115967.2	19	MANE Select
ENST00000358913.10	Ensembl	ENSP00000351790.5	19	MANE Select
NM_001256267.2	RefSeq	NP_001243196.1	19	Standard
NM_001256268.2	RefSeq	NP_001243197.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrin-mediated Cell Adhesion

Biological Process

homophilic cell adhesion via plasma membrane adhesion molecules
axon guidance
sarcomere organization
dendrite self-avoidance

Molecular Function

actin binding
protein binding
cytoskeletal protein binding
SH3 domain binding
muscle alpha-actinin binding

Cellular Component

nucleus
plasma membrane
Z disc
axon
I band

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358913
Coding exons: 19
Length: 105863
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.129	716	726	0.986	0.0000422	8620
Missense (PolyPhen)		261	284.24	0.91823		3471
Synonymous	-0.804	292	275	1.06	0.0000170	2669
Loss of Function	4.65	21	59.8	0.351	0.00000347	677

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines. {ECO:0000269|PubMed:11309420}.;
Disease: DISEASE: Cardiomyopathy, dilated 1KK (CMD1KK) [MIM:615248]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:18006477, ECO:0000269|PubMed:22286171, ECO:0000269|PubMed:22892539}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial hypertrophic 22 (CMH22) [MIM:615248]: 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. {ECO:0000269|PubMed:22286171}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial restrictive 4 (RCM4) [MIM:615248]: A heart disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function. {ECO:0000269|PubMed:22286171}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.578
RVIS EVS: 0.81
RVIS percentile EVS: 87.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.559

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High