PLEKHM2

protein-coding

pleckstrin homology and RUN domain containing M2, the group of Pleckstrin homology domain containing

Gene summary

This gene encodes a protein that binds the plus-end directed microtubule motor protein kinesin, together with the lysosomal GTPase Arl8, and is required for lysosomes to distribute away from the microtubule-organizing center. The encoded protein belongs to the multisubunit BLOC-one-related complex that regulates lysosome positioning. It binds a Salmonella effector protein called Salmonella induced filament A and is a critical host determinant in Salmonella pathogenesis. It has a domain architecture consisting of an N-terminal RPIP8, UNC-14, and NESCA (RUN) domain that binds kinesin-1 as well as the lysosomal GTPase Arl8, and a C-terminal pleckstrin homology domain that binds the Salmonella induced filament A effector protein. Naturally occurring mutations in this gene lead to abnormal localization of lysosomes, impaired autophagy flux and are associated with recessive dilated cardiomyopathy and left ventricular noncompaction. [provided by RefSeq, Feb 2017]

MANE transcript

NM_015164.4

Inheritance

ClinVar variants

P:3U:487B:269

Top phenotype

Dilated Cardiomyopathy, Recessive

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr1:15,684,320-15,734,769

External References & Databases

Ensembl (ENSG00000116786)

Transcript & Mutation Effects

hg38 • Region Span ~50.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial dilated cardiomyopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016333

Submitter: G2P

dilated cardiomyopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

dilated cardiomyopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: ClinGen

PLEKHM2 (pleckstrin homology domain-containing family M member 2) was originally evaluated for DCM by the ClinGen DCM GCEP on 10/09/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 11/15/2025. As a result, the classification changed. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. Human genetic evidence supporting this gene-disease relationship includes three case-level data. At least three variants were reported in association with human DCM. PLEKHM2 c.1932_1933delGA (p.Lys645Alafs*12) was reported in relation to autosomal recessive dilated cardiomyopathy (DCM) in a large consanguineous Bedouin family in the homozygous state in three related individuals (Muhammad et al., 2015, PMID 26464484). The role of this protein is primarily related to lysosomal trafficking (Rosa-Ferreira & Munro, 2011, PMID 22172677; Khatter et al., 2015, PMID 25908847; Almacellas et al., 2020, PMID 32573315). The authors of this case-level and segregation data also present experimental evidence supporting this gene-disease assertion, including expression studies using western blot which demonstrated that the PLEKHM2 protein is expressed in fibroblasts of two of the relatives with DCM from the aforementioned pedigree. The patient-derived iPSC-cardiomyocytes showed low expression levels of genes encoding contractile functional proteins (Korover et al., 2023, PMID: 37349842). PLEKHM2 c.2756del (p.Gly919Ala_fs*34) and c.1986G>A (p.Ser662Ser=) were found in a 21-year-old Caucasian patient in compound heterozygous state (trans). The Westen blot using the patient’s heart did not express PLEKHM2 protein. PLEKHM2 c.2923-2A>G was found in an individual with DCM (Helio et al., 2023, PMID: 37795486). However, the pathogenicity of this variant remains unclear. In summary, there is moderate evidence to support this gene-disease relationship. More evidence is needed to establish the relationship of PLEKHM2 with AR DCM definitively. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 11/15/2024 (SOP Version 10).

dilated cardiomyopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLEKHM2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 817

not specifiedTotal: 228

Dilated Cardiomyopathy, RecessiveTotal: 43

PLEKHM2-related disorderTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015164.4. 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			7 clinvar	238 clinvar	5 clinvar	250
missense		1 clinvar	449 clinvar	22 clinvar	4 clinvar	476
nonsense			9 clinvar			9
start loss						0
frameshift		1 clinvar	10 clinvar			11
splice donor/acceptor (+/-2bp)		1 clinvar	12 clinvar			13
Total	0	3	487	260	9	759

Highest pathogenic variant AF is 0.0000047944286

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015164.4	RefSeq	NP_055979.2	20	MANE Select
ENST00000375799.8	Ensembl	ENSP00000364956.3	20	MANE Select
NM_001410755.1	RefSeq	NP_001397684.1	19	Standard
ENST00000375793.2	Ensembl	ENSP00000364950.2	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Salmonella infection - Homo sapiens (human)

Biological Process

Golgi organization
lysosome localization
regulation of protein localization
positive regulation of membrane tubulation

Molecular Function

protein binding
kinesin binding

Cellular Component

endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375799
Coding exons: 20
Length: 50438
Individuals with no LoFs: 124661
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 124684
p: 0.0000922

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.00	467	606	0.771	0.0000382	6513
Missense (PolyPhen)		130	188.76	0.68869		2055
Synonymous	-0.0573	270	269	1.00	0.0000192	1985
Loss of Function	4.07	17	47.2	0.360	0.00000233	543

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00023	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000091	0.000088	rare
South Asian	0.000033	0.000033	rare
Other	0.00018	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in the regulation of conventional kinesin activity. Required for maintenance of the Golgi apparatus organization. May play a role in membrane tubulation (PubMed:15905402). May play a role in lysosomes movement and localization at the cell periphery (PubMed:25898167). {ECO:0000269|PubMed:15905402, ECO:0000269|PubMed:25898167}.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.449
RVIS EVS: -0.57
RVIS percentile EVS: 19.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.375

Gene Damage Prediction

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