PLN

Summary

PLN (phospholamban, HGNC:9080) is a protein-coding gene on chromosome 6q22.31, encoding Phospholamban (P26678). Reversibly inhibits the activity of ATP2A2/SERCA2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+).

The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. The encoded protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta-agonists. The encoded protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure, and also familial hypertrophic cardiomyopathy.

Source: NCBI Gene 5350 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intrinsic cardiomyopathy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 58 total — 9 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 23
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002667

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9080
Approved symbol	PLN
Name	phospholamban
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	CMD1P
Ensembl gene	ENSG00000198523
Ensembl biotype	protein_coding
OMIM	172405
Entrez	5350

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000357525, ENST00000875724, ENST00000875725, ENST00000875726, ENST00000875727, ENST00000953960

RefSeq mRNA: 1 — MANE Select: NM_002667 NM_002667

CCDS: CCDS5120

Canonical transcript exons

ENST00000357525 — 2 exons

Exon	Start	End
ENSE00001432691	118558825	118561716
ENSE00001447253	118548296	118548392

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 99.98.

FANTOM5 (CAGE): breadth broad, TPM avg 17.3338 / max 5368.7264, expressed in 303 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69465	11.5950	258
69466	4.7483	189
69467	0.9090	108
69469	0.0393	19
69468	0.0288	14
69470	0.0135	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.98	gold quality
myocardium	UBERON:0002349	99.91	gold quality
left ventricle myocardium	UBERON:0006566	99.89	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.87	gold quality
vena cava	UBERON:0004087	99.81	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.80	gold quality
biceps brachii	UBERON:0001507	99.75	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.73	gold quality
cauda epididymis	UBERON:0004360	99.72	gold quality
triceps brachii	UBERON:0001509	99.68	gold quality
blood vessel layer	UBERON:0004797	99.66	gold quality
vastus lateralis	UBERON:0001379	99.65	gold quality
diaphragm	UBERON:0001103	99.63	gold quality
gluteal muscle	UBERON:0002000	99.61	gold quality
cardiac ventricle	UBERON:0002082	99.58	gold quality
heart left ventricle	UBERON:0002084	99.57	gold quality
saphenous vein	UBERON:0007318	99.50	gold quality
quadriceps femoris	UBERON:0001377	99.39	gold quality
descending thoracic aorta	UBERON:0002345	99.37	gold quality
cardiac atrium	UBERON:0002081	99.35	gold quality
superficial temporal artery	UBERON:0001614	99.33	gold quality
heart	UBERON:0000948	99.28	gold quality
right atrium auricular region	UBERON:0006631	99.27	gold quality
apex of heart	UBERON:0002098	99.25	gold quality
popliteal artery	UBERON:0002250	99.20	gold quality
tibial artery	UBERON:0007610	99.20	gold quality
aorta	UBERON:0000947	99.08	gold quality
right coronary artery	UBERON:0001625	99.08	gold quality
thoracic aorta	UBERON:0001515	98.91	gold quality
ascending aorta	UBERON:0001496	98.87	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	2102.46
E-HCAD-36	yes	1863.79
E-MTAB-8381	yes	1457.21
E-MTAB-8205	yes	399.58
E-HCAD-1	yes	37.07
E-MTAB-8410	yes	35.50
E-HCAD-11	yes	9.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3

miRNA regulators (miRDB)

102 targeting PLN, 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-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AA	99.96	70.64	3753

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• sarcolipin binds to phospholamban and inhibits polymerization (PMID:12032137)
• phosphorylation of phospholamban does not affect its structure and gives it more loose helical packing than if not phosphorylated (PMID:12080135)
• Modeling of the inhibitory interaction of phospholamban with the Ca2+ ATPase. (PMID:12525698)
• report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg –> Cys missense mutation at residue 9 (R9C) in phospholamban (PMID:12610310)
• role in regulating sarco(endo)plasmic reticulum Ca2+-ATPase by binding to transmembrane helices in conjunction with sarcolipin (PMID:12692302)
• Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy. (PMID:12705874)
• SERCA2a and phospholamban bind to S100A1 in the human heart (PMID:12804600)
• The frequency-dependent phosphorylation of Ser16-PLB may favor an increase in Ca2+ transient and force generation in humans. (PMID:14530977)
• This study concludes that phospholamban (PLB) increases the maximal activity (Vmax) of calcium (Ca2+)-ATPase, and that the magnitude of this effect is sensitive to mutation. A region of mutant PLB responsible for this regulatory property is identified. (PMID:15736939)
• The unusual bellflower-like assembly is held together by leucine/isoleucine zipper motifs along the membrane-spanning helices. (PMID:16043693)
• the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice (PMID:16432188)
• Human PLN may play a more inhibitory role than that of other species in Ca2+ cycling. Expression of human PLN in the mouse is compensated by alterations in Ca2+-handling proteins and cardiac remodeling in an effort to normalize cardiac contractility. (PMID:16476846)
• Mutations in the phospholamban gene are not a frequent cause of hypertrophic and idiopathic dilated cardiomyopathy. (PMID:16829191)
• Phospholamban in the human esophagus might be of less importance for regulation of SERCA than in heart. Lower expression of calsequestrin and calreticulin might contribute to increased lower esophageal sphincter pressure in achalasia. (PMID:17009399)
• Gene expression of PLB was studied in children with congenital heart defects. (PMID:17515962)
• A truncation mutant was identified in PLN. (PMID:17655857)
• The structure and dynamics of PLN pentamer was compared in its unphosphorylated and pseudo-phosphorylatd states. (PMID:17766390)
• analysis of phospholamban in oriented lipid bilayers using 15N solid-state NMR spectroscopy (PMID:17905829)
• G147D PPI-1 can attenuate responses of cardiomyocytes to beta-adrenergic agonists by decreasing PLN phosphorylation and therefore may contribute to deteriorated function in heart failure. (PMID:18192322)
• findings suggest that the g.203A>C genetic variant in the human phospholamban promoter may contribute to depressed contractility and accelerate functional deterioration in heart failure (PMID:18241046)
• analysis of how mutations increase phospholamban oligomerization and alter the structure of its regulatory complex (PMID:18708665)
• A weak inhibitor transgene PLN(Arg9Cys) is diminished in its ability to modify the level of sarco(endo)plasmic reticulum ccalcium-ATPase activity, leading to heart failure despite fast sarcoplasmic reticulum calcium ion reuptake. (PMID:19139388)
• Attenuated R amplitudes were identified as an early ECG phenotype in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation. (PMID:19324307)
• PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval (PMID:19587794)
• Data do not support a role for the phospholamban -36A>C alteration in modulating the heart failure phenotype. (PMID:19638213)
• These data demonstrate that alphaKAP exhibits a novel interaction with SERCA2a and may serve to spatially position CaMKII isoforms at the SR and to uniquely modulate the phosphorylation of PLN. (PMID:19671701)
• Three steps in the kinetic reaction with calcium-dependent ATPase (SERCA) are affected by the presence of PLB: binding of the first calcium ion, a subsequent conformational change in SERCA, and binding of the second calcium ion. (PMID:19708671)
• Study conclude that PLN is enriched in the ER due to COP I-mediated transport that is dependent on its intact di-arginine motif and that the N-terminal di-arginine motif may act as a general ER retrieval sequence. (PMID:20634894)
• In this study, they investigated the effects of PLB phosphorylation and mutation on the interaction between a PLB oligomer and SERCA in the context of 2D crystals. (PMID:21108950)
• Mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels. (PMID:21167350)
• Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A. (PMID:21282613)
• PLN gene mutations were not found to be associated with HCM in the study group. (PMID:21332051)
• both topology and function of PLN are shaped by the interactions with lipids, which fine-tune the regulation of SERCA (PMID:21576492)
• PLN generates canonical ion channel fluctuations with two conductance levels and a moderate cation selectivity (PMID:21687864)
• 1,014 patients with heart failure screened for mutations in PLN gene; identified 4 unrelated patients with PLN mutations, 3 in same amino acid residue (R9); conclude mutations in PLN gene are rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology; Arg9 and Leu39 residues are leading location of mutations described to date (PMID:22137083)
• human PLN-R14Del is misrouted to the sarcolemma, in the absence of endogenous PLN, and alters NKA activity, leading to cardiac remodeling. (PMID:22155237)
• TOAC spin labels placed on the WT-PLB transmembrane domain showed highly restricted motion with more than 100ns rotational correlation time (tau(c)); whereas the loop, and the cytoplasmic regions each consists of two distinct motional dynamics (PMID:22172806)
• Characterizing phospholamban to sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) protein binding interactions in human cardiac sarcoplasmic reticulum vesicles using chemical cross-linking. (PMID:22247554)
• Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy. (PMID:22427649)
• The researchers found evidence of an association between the phospholamban R14del and the presence of dilated or arrhythmogenic cardiomyopathies in a group of patients. (PMID:22820313)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pln2	ENSDARG00000097256
mus_musculus	Pln	ENSMUSG00000038583
rattus_norvegicus	Pln	ENSRNOG00000079579

Protein

Protein identifiers

Phospholamban — P26678 (reviewed: P26678)

All UniProt accessions (2): P26678, Q5R352

UniProt curated annotations — full annotation on UniProt →

Function. Reversibly inhibits the activity of ATP2A2/SERCA2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). Binds preferentially to the ATP-bound E1 conformational form of ATP2A2 which predominates at low Ca(2+) concentrations during the diastolic phase of the cardiac cycle. Inhibits ATP2A2 Ca(2+) affinity by disrupting its allosteric activation by ATP. Modulates the contractility of the heart muscle in response to physiological stimuli via its effects on ATP2A2. Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in the heart muscle. The degree of ATP2A2 inhibition depends on the oligomeric state of PLN. ATP2A2 inhibition is alleviated by PLN phosphorylation. Also inhibits the activity of ATP2A3/SERCA3. Controls intracellular Ca(2+) levels in elongated spermatids and may play a role in germ cell differentiation. In the thalamic reticular nucleus of the brain, plays a role in the regulation of sleep patterns and executive functioning.

Subunit / interactions. Homopentamer. Can also form heterooligomers with other sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) regulators ARLN, ERLN, SLN and STRIT1/DWORF. Monomer. Interacts with HAX1. Interacts as a monomer with ATP2A2; the interaction decreases ATP2A2 Ca(2+) affinity. Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2. Interacts with S100A1 in a Ca(2+)-dependent manner.

Subcellular location. Endoplasmic reticulum membrane. Sarcoplasmic reticulum membrane. Mitochondrion membrane. Membrane.

Tissue specificity. Heart muscle (at protein level).

Post-translational modifications. Phosphorylation by PKA abolishes the inhibition of ATP2A2-mediated calcium uptake. Phosphorylated at Thr-17 by CaMK2, and in response to beta-adrenergic stimulation. Phosphorylation by DMPK may stimulate sarcoplasmic reticulum calcium uptake in cardiomyocytes. Palmitoylated by ZDHHC16, promoting formation of the homopentamer. In elongated spermatids, proteolytically cleaved by SPPL2C which modulates intracellular Ca(2+) homeostasis.

Disease relevance. Cardiomyopathy, dilated, 1P (CMD1P) [MIM:609909] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, familial hypertrophic, 18 (CMH18) [MIM:613874] 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. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. For practical reasons, PLN activity is most often studied with ATP2A1 instead of ATP2A2.

Similarity. Belongs to the phospholamban family.

RefSeq proteins (1): NP_002658* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005984	PLB	Family

Pfam: PF04272

UniProt features (19 total): sequence variant 4, mutagenesis site 4, modified residue 3, helix 2, chain 1, topological domain 1, strand 1, transmembrane region 1, region of interest 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6Y40	X-RAY DIFFRACTION	1.75
7E0Z	X-RAY DIFFRACTION	2.16
7E12	X-RAY DIFFRACTION	2.8
7E11	X-RAY DIFFRACTION	3.43
1PLP	SOLUTION NMR
1ZLL	SOLUTION NMR
2HYN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26678-F1	81.81	0.39

Functional residue map

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

Post-translational modifications (4): 1, 16, 17, 36

Mutagenesis-validated functional residues (4):

Position	Phenotype
13	abolishes phosphorylation by pka.
14	abolishes phosphorylation by pka.
16	abolishes phosphorylation by pka.
17	no effect on phosphorylation by pka.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5578775	Ion homeostasis
R-HSA-936837	Ion transport by P-type ATPases

MSigDB gene sets: 309 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_CIRCADIAN_RHYTHM, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_COGNITION, GOBP_RESPONSE_TO_ZINC_ION, GOBP_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_VESICLE_ORGANIZATION, GCANCTGNY_MYOD_Q6, GOBP_ASSOCIATIVE_LEARNING, GOBP_NEGATIVE_REGULATION_OF_ATP_DEPENDENT_ACTIVITY

GO Biological Process (36): acrosome assembly (GO:0001675), regulation of the force of heart contraction (GO:0002026), calcium ion transport (GO:0006816), intracellular calcium ion homeostasis (GO:0006874), Notch signaling pathway (GO:0007219), blood circulation (GO:0008015), regulation of heart contraction (GO:0008016), visual learning (GO:0008542), response to zinc ion (GO:0010043), negative regulation of heart rate (GO:0010459), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), response to insulin (GO:0032868), response to testosterone (GO:0033574), locomotor rhythm (GO:0045475), muscle cell cellular homeostasis (GO:0046716), cardiac muscle tissue development (GO:0048738), circadian sleep/wake cycle, sleep (GO:0050802), regulation of cytosolic calcium ion concentration (GO:0051480), regulation of calcium ion transport (GO:0051924), negative regulation of calcium ion transport (GO:0051926), relaxation of cardiac muscle (GO:0055119), regulation of cardiac muscle cell contraction (GO:0086004), adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process (GO:0086023), regulation of cardiac muscle cell membrane potential (GO:0086036), regulation of the force of heart contraction by cardiac conduction (GO:0086092), negative regulation of calcium ion import (GO:0090281), regulation of ATPase-coupled calcium transmembrane transporter activity (GO:1901894), negative regulation of ATPase-coupled calcium transmembrane transporter activity (GO:1901895), regulation of relaxation of cardiac muscle (GO:1901897), negative regulation of calcium ion import into sarcoplasmic reticulum (GO:1902081), heart process (GO:0003015), spermatogenesis (GO:0007283), regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), negative regulation of heart contraction (GO:0045822), regulation of calcium ion import (GO:0090279), regulation of relaxation of muscle (GO:1901077)

GO Molecular Function (8): enzyme inhibitor activity (GO:0004857), ATPase inhibitor activity (GO:0042030), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), transmembrane transporter binding (GO:0044325), ATPase binding (GO:0051117), transporter inhibitor activity (GO:0141110), protein binding (GO:0005515)

GO Cellular Component (12): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), mitochondrial membrane (GO:0031966), vesicle (GO:0031982), sarcoplasmic reticulum membrane (GO:0033017), perinuclear region of cytoplasm (GO:0048471), calcium ion-transporting ATPase complex (GO:0090534), phospholamban complex (GO:1990629), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cardiac conduction	1
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
molecular function inhibitor activity	3
cytoplasm	3
calcium ion transport	2
protein binding	2
intracellular membrane-bounded organelle	2
organelle membrane	2
cellular anatomical structure	2
developmental process involved in reproduction	1
spermatid development	1
cellular component assembly involved in morphogenesis	1
cellular process involved in reproduction in multicellular organism	1
secretory granule organization	1
organelle assembly	1
regulation of heart contraction	1
regulation of biological quality	1
metal ion transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
cell surface receptor signaling pathway	1
circulatory system process	1
heart contraction	1
regulation of blood circulation	1
visual behavior	1
associative learning	1
response to metal ion	1
regulation of heart rate	1
negative regulation of heart contraction	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
response to peptide hormone	1
response to lipid	1
response to ketone	1
locomotory behavior	1
circadian behavior	1
cellular homeostasis	1
heart development	1
striated muscle tissue development	1
circadian sleep/wake cycle process	1
sleep	1
circadian sleep/wake cycle	1

Protein interactions and networks

STRING

802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLN	SLN	O00631	970
PLN	ATP2A2	P16614	898
PLN	SLC8A1	P32418	815
PLN	ATP2A3	Q93084	798
PLN	TRAM2	Q15035	763
PLN	ATP2A1	O14983	752
PLN	TLX2	O43763	702
PLN	RYR2	Q92736	701
PLN	CASQ2	O14958	515
PLN	NPPA	P01160	493
PLN	MYH6	P13533	479
PLN	ATP2B4	P23634	478
PLN	ACTC1	P04270	476
PLN	SCN5A	Q14524	466
PLN	FRMD5	Q7Z6J6	462

IntAct

190 interactions, top by confidence:

A	B	Type	Score
PLN	EDA	psi-mi:“MI:0915”(physical association)	0.890
EDA	PLN	psi-mi:“MI:0915”(physical association)	0.890
PLN	BCL2L13	psi-mi:“MI:0915”(physical association)	0.720
PLN	LDLRAD1	psi-mi:“MI:0915”(physical association)	0.670
PLN	CREB3	psi-mi:“MI:0915”(physical association)	0.560
PLN	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
PLN	CPLX4	psi-mi:“MI:0915”(physical association)	0.560
PLN	MGST3	psi-mi:“MI:0915”(physical association)	0.560
PLN	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
PLN	GJA8	psi-mi:“MI:0915”(physical association)	0.560
PLN	SPACA1	psi-mi:“MI:0915”(physical association)	0.560
PLN	MTIF3	psi-mi:“MI:0915”(physical association)	0.560
PLN	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
PLN	SLC30A8	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (88): PLN (Two-hybrid), BCL2L13 (Two-hybrid), CREB3 (Two-hybrid), CREB3L1 (Two-hybrid), EDA (Two-hybrid), DMPK (Affinity Capture-Western), PLN (Affinity Capture-Western), PLN (Biochemical Activity), PLN (Affinity Capture-Western), PLN (Affinity Capture-Western), PLN (Two-hybrid), PLN (Two-hybrid), PLN (Two-hybrid), PLN (Two-hybrid), PLN (Two-hybrid)

ESM2 similar proteins: A0A131KVX9, A4IFH6, B1IRV8, B1LFB6, F7V996, O00631, O24817, O27226, O31445, O55654, O78456, P02947, P0CK21, P0CK22, P0DSW1, P0DSW2, P10302, P16754, P18024, P24616, P26677, P26678, P37305, P38458, P41663, P49485, P61012, P61013, P61014, P61015, P61016, P76136, P77494, Q06SD4, Q0THS6, Q1RBS2, Q2V2P6, Q320T9, Q38623, Q3V0X1

Diamond homologs: A4IFH6, P26677, P26678, P61012, P61013, P61014, P61015, P61016

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
DMPK	up-regulates	PLN	phosphorylation
PRKG1	“up-regulates activity”	PLN	phosphorylation
PRKACA	“up-regulates activity”	PLN	phosphorylation
PLN	“down-regulates activity”	ATP2A2	binding
AKT	“down-regulates activity”	PLN	phosphorylation
AKT1	“down-regulates activity”	PLN	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	1
Uncertain significance	40
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1072579	NM_002667.5(PLN):c.9dup (p.Val4fs)	Pathogenic
13636	NM_002667.5(PLN):c.25C>T (p.Arg9Cys)	Pathogenic
1453340	NM_002667.5(PLN):c.95_98del (p.Phe32fs)	Pathogenic
1977709	NM_002667.5(PLN):c.105_106del (p.Phe35fs)	Pathogenic
239214	NM_002667.4(PLN):c.-97-?_*1344+?del	Pathogenic
3706363	NM_002667.5(PLN):c.4G>T (p.Glu2Ter)	Pathogenic
44580	NM_002667.5(PLN):c.37AGA[1] (p.Arg14del)	Pathogenic
657898	NC_000006.12:g.(?118548061)(118559090_?)del	Pathogenic
940239	NM_002667.5(PLN):c.26_29dup (p.Ala11fs)	Pathogenic
3720713	NM_002667.5(PLN):c.26G>T (p.Arg9Leu)	Likely pathogenic

SpliceAI

358 predictions. Top by Δscore:

Variant	Effect	Δscore
6:118548391:AG:A	donor_loss	0.9900
6:118548393:G:T	donor_loss	0.9900
6:118558818:A:AG	acceptor_gain	0.9900
6:118558819:TTCCA:T	acceptor_loss	0.9900
6:118558820:TCCA:T	acceptor_loss	0.9900
6:118558821:CCA:C	acceptor_loss	0.9900
6:118558822:CA:C	acceptor_loss	0.9900
6:118558823:A:AG	acceptor_gain	0.9900
6:118558823:AG:A	acceptor_gain	0.9900
6:118558823:AGG:A	acceptor_loss	0.9900
6:118558824:G:GA	acceptor_gain	0.9900
6:118558824:GG:G	acceptor_gain	0.9900
6:118558824:GGCT:G	acceptor_gain	0.9900
6:118548393:G:GG	donor_gain	0.9800
6:118558816:A:AG	acceptor_gain	0.9800
6:118558817:C:G	acceptor_gain	0.9800
6:118558824:GGC:G	acceptor_gain	0.9800
6:118558824:GGCTA:G	acceptor_gain	0.9800
6:118548390:AAGGT:A	donor_gain	0.9700
6:118548391:AGGTA:A	donor_gain	0.9700
6:118548392:GGTAA:G	donor_gain	0.9700
6:118548393:G:GA	donor_gain	0.9700
6:118548394:T:A	donor_gain	0.9700
6:118558819:T:G	acceptor_gain	0.9700
6:118548388:CCAAG:C	donor_gain	0.9600
6:118548389:CAAGG:C	donor_gain	0.9600
6:118554999:T:TG	acceptor_gain	0.9400
6:118548395:A:C	donor_gain	0.9300
6:118551421:C:CT	acceptor_gain	0.9300
6:118551422:T:TT	acceptor_gain	0.9300

AlphaMissense

332 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:118559042:T:C	C41R	0.985
6:118559040:T:A	I40K	0.983
6:118559040:T:G	I40R	0.971
6:118559046:T:G	L42R	0.953
6:118559052:T:G	L44R	0.951
6:118559046:T:C	L42P	0.949
6:118559031:T:C	L37P	0.948
6:118559027:T:C	C36R	0.944
6:118559046:T:A	L42H	0.942
6:118559013:T:C	L31P	0.935
6:118558953:C:A	A11D	0.932
6:118559031:T:A	L37H	0.914
6:118559057:T:C	C46R	0.912
6:118559024:T:C	F35L	0.909
6:118559026:C:A	F35L	0.909
6:118559026:C:G	F35L	0.909
6:118559052:T:C	L44P	0.903
6:118559023:T:A	N34K	0.902
6:118559023:T:G	N34K	0.902
6:118558952:G:C	A11P	0.885
6:118559031:T:G	L37R	0.885
6:118559052:T:A	L44Q	0.876
6:118559004:T:C	L28P	0.874
6:118558962:G:T	R14I	0.845
6:118559044:T:G	C41W	0.842
6:118558965:C:A	A15D	0.835
6:118559025:T:C	F35S	0.835
6:118559034:T:C	I38T	0.832
6:118558963:A:C	R14S	0.829
6:118558963:A:T	R14S	0.829

dbSNP variants (sampled 300 via entrez): RS1000049083 (6:118555808 C>T), RS1000100235 (6:118561617 A>G), RS1000116025 (6:118557151 A>C), RS1000400508 (6:118555544 A>G), RS1000520331 (6:118553172 C>T), RS1000837151 (6:118549939 T>C), RS1000982173 (6:118558680 G>A), RS1001152567 (6:118558459 T>C), RS1001200058 (6:118550459 AG>A), RS1001655702 (6:118556123 G>A), RS1001693862 (6:118550168 A>G), RS1001771653 (6:118561848 A>G), RS1001771767 (6:118555943 C>T), RS1002126923 (6:118555249 G>A), RS1002179200 (6:118555375 C>T)

Disease associations

OMIM: gene MIM:172405 | disease phenotypes: MIM:609909, MIM:613874, MIM:609040

GenCC curated gene-disease

Disease	Classification	Inheritance
dilated cardiomyopathy 1P	Definitive	Autosomal dominant
hypertrophic cardiomyopathy 18	Strong	Autosomal dominant
intrinsic cardiomyopathy	Strong	Autosomal dominant
arrhythmogenic right ventricular cardiomyopathy	Moderate	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
arrhythmogenic right ventricular cardiomyopathy	Moderate	AD
intrinsic cardiomyopathy	Definitive	AD

Mondo (10): dilated cardiomyopathy 1P (MONDO:0012362), hypertrophic cardiomyopathy 18 (MONDO:0013475), cardiomyopathy (MONDO:0004994), dilated cardiomyopathy (MONDO:0005021), intrinsic cardiomyopathy (MONDO:0000591), cardiac arrest (MONDO:0000745), hypertrophic cardiomyopathy (MONDO:0005045), arrhythmogenic right ventricular dysplasia 9 (MONDO:0012180), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), (MONDO:0015470)

Orphanet (4): Familial isolated dilated cardiomyopathy (Orphanet:154), Rare cardiomyopathy (Orphanet:167848), Dilated cardiomyopathy (Orphanet:217604), Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001712	Left ventricular hypertrophy
HP:0001727	Thromboembolic stroke
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0003596	Middle age onset
HP:0004308	Ventricular arrhythmia
HP:0004757	Paroxysmal atrial fibrillation
HP:0005110	Atrial fibrillation
HP:0006673	Reduced systolic function
HP:0011462	Young adult onset
HP:0011675	Arrhythmia
HP:0012378	Fatigue
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0100578	Lipoatrophy
HP:0100749	Chest pain

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000363_13	QT interval	5.000000e-22
GCST000364_12	QT interval	2.000000e-17
GCST000364_8	QT interval	2.000000e-24
GCST000441_1	Cardiac structure and function	1.000000e-09
GCST000444_2	QT interval	2.000000e-29
GCST001746_15	QT interval	2.000000e-06
GCST002500_55	QT interval	3.000000e-18
GCST002500_56	QT interval	1.000000e-22
GCST002500_57	QT interval	2.000000e-67
GCST002500_58	QT interval	8.000000e-16
GCST002500_59	QT interval	1.000000e-08
GCST003598_10	QRS duration	5.000000e-19
GCST003598_37	QRS duration	1.000000e-18
GCST003818_50	Resting heart rate	3.000000e-55
GCST003844_31	QRS duration	8.000000e-29
GCST003870_9	QRS complex (Sokolow-Lyon)	1.000000e-09
GCST004297_5	Atrial fibrillation	1.000000e-08
GCST006414_118	Atrial fibrillation	2.000000e-22
GCST010919_19	QT interval	5.000000e-74
GCST012099_6	Hypertrophic cardiomyopathy (sarcomere negative)	6.000000e-10
GCST012101_6	Hypertrophic cardiomyopathy	3.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004298	cardiovascular measurement
EFO:0005054	QRS complex
EFO:0007742	QRS amplitude

MeSH disease descriptors (7)

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
D006323	Heart Arrest	C14.280.383
C563808	Arrhythmogenic Right Ventricular Dysplasia, Familial, 9 (supp.)
C563690	Cardiomyopathy, Dilated, 1p (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression, affects expression	2
Nickel	decreases expression	2
psilocin	increases response to substance, increases phosphorylation	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
manganese chloride	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Chir 99021	affects cotreatment, decreases expression, affects binding, increases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, decreases expression	1
Dasatinib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Ascorbic Acid	affects binding, affects cotreatment, increases expression	1
Cadmium	decreases expression	1
Copper	affects cotreatment, increases expression	1
Cycloheximide	decreases expression, decreases reaction	1
Diethylhexyl Phthalate	increases expression	1
Dobutamine	affects response to substance	1
Hydrocortisone	affects cotreatment, decreases expression	1
Manganese	decreases expression	1
Psilocybin	increases phosphorylation, increases response to substance	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	1
Tretinoin	increases expression	1
Trichloroethylene	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

16 cell lines: 16 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7DY	SCVIi031-A	Induced pluripotent stem cell	Male
CVCL_B7DZ	SCVIi030-A	Induced pluripotent stem cell	Female
CVCL_B7SI	SCVIi049-A	Induced pluripotent stem cell	Male
CVCL_B7SJ	SCVIi050-A	Induced pluripotent stem cell	Male
CVCL_C0EU	UPITTi002-A-1	Induced pluripotent stem cell	Male
CVCL_C0FZ	ISMMSi044-A	Induced pluripotent stem cell	Male
CVCL_C0G0	ISMMSi045-A	Induced pluripotent stem cell	Male
CVCL_C0G1	ISMMSi046-A	Induced pluripotent stem cell	Female
CVCL_C0G2	ISMMSi047-A	Induced pluripotent stem cell	Male
CVCL_C0G3	ISMMSi048-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT03593317	PHASE2	RECRUITING	Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD
NCT03685149	PHASE2	COMPLETED	Pilot Randomized Trial With Flecainide in ARVC Patients
NCT06174220	PHASE2	RECRUITING	Targeted Therapy With Glycogen Synthase Kinase-3 Inhibition for Arrhythmogenic Cardiomyopathy