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): 49 total — 5 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 10 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 23
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.42 (intermediate), LOEUF 1.70 (unconstrained)
• 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: 9 — 9 protein_coding

MANE Select: ENST00000357525

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000357525, ENST00000875724, ENST00000875725, ENST00000875726, ENST00000875727, ENST00000953960, ENST00001098559, ENST00001122238, ENST00001136380

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.

Highest expression (Bgee): heart right ventricle, myocardium, ventricle myocardium, cardiac muscle of right atrium, vena cava.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PLN is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 10 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

10 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	1.0e-07	+0.15	6:118325837:A:G
Artery Aorta	eqtl	9.7e-07	+0.20	6:118335796:C:T
Muscle Skeletal	eqtl	3.9e-05	+0.11	6:118540479:G:A
Adipose Subcutaneous	eqtl	8.8e-05	+0.13	6:118334218:G:A
Skin Sun Exposed Lower leg	eqtl	9.7e-04	+0.14	6:118329307:C:A
Heart Left Ventricle	eqtl	2.8e-03	+0.09	6:118701790:C:A
Heart Atrial Appendage	eqtl	7.7e-03	+0.10	6:118699032:G:A
Kidney Cortex	eqtl	1.8e-02	+0.55	6:118739987:T:C
Colon Sigmoid	eqtl	2.6e-02	-0.30	6:118017773:T:C
Colon Transverse	eqtl	2.7e-02	-0.20	6:119339127:C:T

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

showing 100 of 286 tissues 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
body of tongue	UBERON:0011876	98.84	gold quality
coronary artery	UBERON:0001621	98.64	gold quality
left coronary artery	UBERON:0001626	98.58	gold quality
urethra	UBERON:0000057	98.51	gold quality
skeletal muscle tissue	UBERON:0001134	98.50	gold quality
nipple	UBERON:0002030	98.44	gold quality
muscle tissue	UBERON:0002385	98.26	gold quality
gall bladder	UBERON:0002110	98.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.20	gold quality
mucosa of stomach	UBERON:0001199	98.17	gold quality
deltoid	UBERON:0001476	98.15	gold quality
muscle organ	UBERON:0001630	97.91	gold quality
muscle of leg	UBERON:0001383	97.38	gold quality
gastrocnemius	UBERON:0001388	97.30	gold quality
myometrium	UBERON:0001296	97.11	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.06	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.81	gold quality
lower esophagus	UBERON:0013473	96.70	gold quality
seminal vesicle	UBERON:0000998	96.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.60	gold quality
tibialis anterior	UBERON:0001385	96.59	gold quality
body of uterus	UBERON:0009853	96.08	gold quality
left uterine tube	UBERON:0001303	95.69	gold quality
synovial joint	UBERON:0002217	95.43	gold quality
corpus epididymis	UBERON:0004359	95.29	gold quality
pericardium	UBERON:0002407	94.77	gold quality
smooth muscle tissue	UBERON:0001135	93.91	gold quality
caput epididymis	UBERON:0004358	92.73	gold quality
calcaneal tendon	UBERON:0003701	92.69	gold quality
penis	UBERON:0000989	92.50	gold quality
fundus of stomach	UBERON:0001160	92.10	gold quality
sigmoid colon	UBERON:0001159	91.73	gold quality
tongue	UBERON:0001723	91.50	gold quality
choroid plexus epithelium	UBERON:0003911	91.11	gold quality
urinary bladder	UBERON:0001255	90.66	gold quality
pylorus	UBERON:0001166	90.49	gold quality
trabecular bone tissue	UBERON:0002483	89.89	gold quality
visceral pleura	UBERON:0002401	89.75	gold quality
colonic epithelium	UBERON:0000397	89.34	gold quality
skin of hip	UBERON:0001554	89.33	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.58	gold quality
parietal pleura	UBERON:0002400	88.47	gold quality
tendon	UBERON:0000043	88.17	gold quality
large intestine	UBERON:0000059	87.93	gold quality
pleura	UBERON:0000977	87.90	gold quality
colon	UBERON:0001155	87.76	gold quality
lower lobe of lung	UBERON:0008949	87.35	gold quality
pharyngeal mucosa	UBERON:0000355	87.23	gold quality
rectum	UBERON:0001052	87.23	gold quality
intestine	UBERON:0000160	86.87	gold quality
endocervix	UBERON:0000458	86.85	gold quality
caecum	UBERON:0001153	86.72	gold quality
prostate gland	UBERON:0002367	86.64	gold quality
esophagus	UBERON:0001043	86.38	gold quality
superior surface of tongue	UBERON:0007371	86.11	gold quality
transverse colon	UBERON:0001157	85.95	gold quality
mucosa of urinary bladder	UBERON:0001259	85.87	gold quality
jejunum	UBERON:0002115	85.14	gold quality
sperm	CL:0000019	84.84	gold quality
vermiform appendix	UBERON:0001154	84.03	gold quality
small intestine	UBERON:0002108	83.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.55	gold quality
male germ cell	CL:0000015	83.34	gold quality
peritoneum	UBERON:0002358	83.20	gold quality
omental fat pad	UBERON:0010414	83.17	gold quality
ectocervix	UBERON:0012249	83.12	gold quality
adipose tissue	UBERON:0001013	82.59	gold quality
tibial nerve	UBERON:0001323	82.57	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.45	gold quality
connective tissue	UBERON:0002384	82.43	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Heart muscle	tissue	1463.0	high
Skeletal muscle	tissue	474.8	high
Tongue	tissue	215.0
Smooth muscle	tissue	119.9	medium
Gallbladder	tissue	86.4	not detected
Endometrium 1	tissue	64.8	not detected
Esophagus	tissue	41.2	not detected
Adipose tissue	tissue	37.7	not detected
Urinary bladder	tissue	35.8	not detected
Seminal vesicle	tissue	34.9	not detected
Colon	tissue	33.7	low
Prostate	tissue	32.9	not detected
Cervix	tissue	24.9	not detected
Rectum	tissue	23.0	not detected
Epididymis	tissue	20.6	not detected
Small intestine	tissue	20.3	not detected
Fallopian tube	tissue	20.3	not detected
Substantia nigra	tissue	18.1
Vagina	tissue	15.5	not detected
Spinal cord	tissue	14.8
Kidney	tissue	14.0	medium
Ovary	tissue	12.9	not detected
Duodenum	tissue	12.8	not detected
Superior colliculi	tissue	11.9
Adrenal gland	tissue	11.7	not detected
Appendix	tissue	11.6	not detected
Medulla oblongata	tissue	9.5
Lung	tissue	9.4	not detected
Midbrain	tissue	9.2
Thalamus	tissue	9.1
Cerebral cortex	tissue	9.0	low
Retrosplenial and cingulate cortex	tissue	9.0
Periaqueductal gray	tissue	8.8
Pons	tissue	8.6
Septum	tissue	8.6
Basal ganglia	tissue	8.5	not detected
Hippocampal formation	tissue	8.5
Entorhinal cortex	tissue	8.5
Olfactory bulb	tissue	8.1
Motor cortex	tissue	7.5
Retrosplenial cortex	tissue	7.5
Temporal cortex	tissue	7.5
Prefrontal cortex	tissue	7.2
Insular cortex	tissue	7.2
Putamen	tissue	7.0
Corpus callosum	tissue	6.8
Somatosensory cortex	tissue	6.6
Occipital cortex	tissue	6.4
Ventral forebrain	tissue	6.2
Cerebellum	tissue	5.8	not detected
Amygdala	tissue	5.7
Hypothalamus	tissue	5.4
Breast	tissue	5.3	not detected
Stomach 1	tissue	5.0	not detected
Choroid plexus	tissue	4.5
Postcentral gyrus	tissue	3.7
Thyroid gland	tissue	3.6	not detected
Nucleus accumbens	tissue	3.5
Hippocampus	tissue	3.3	not detected
Testis	tissue	3.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (340.5), Dorsal spinal cord (14.8), Ventral spinal cord (9.3), Nucleus basalis of Meynert (7.0), White matter (6.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3

miRNA regulators (miRDB)

Targeting PLN by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 102 miRNAs:

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

gnomAD constraint: pLI 0.417, LOEUF 1.7, missense Z -0.418 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000357525 — one region, missense o/e 0.94. 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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97622) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 24 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal myocardial fiber physiology	3
increased cardiac muscle contractility	3
impaired skeletal muscle contractility	2
abnormal cardiac muscle contractility	2
abnormal skeletal muscle fiber type ratio	2
skeletal muscle atrophy	2
muscle weakness	1
myopathy	1
abnormal muscle physiology	1
increased heart weight	1
abnormal soleus morphology	1
abnormal skeletal muscle fiber morphology	1
impaired muscle relaxation	1
oxidative stress	1
abnormal cardiac muscle relaxation	1
atrial fibrillation	1
centrally nucleated skeletal muscle fibers	1
skeletal muscle fibrosis	1
skeletal muscle endomysial fibrosis	1
decreased soleus weight	1
abnormal heart left ventricle pressure	1
impaired exercise endurance	1
decreased muscle cell calcium uptake	1
increased creatine kinase activity	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Canis lupus familiaris	P61012	100.0%	Diamond
Sus scrofa	P61013	100.0%	Diamond
Oryctolagus cuniculus	P61015	100.0%	Diamond
Bos taurus	A4IFH6	96.2%	Diamond
Gallus gallus	P26677	82.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CEP85L	protein-coding	387119
SLC35F1	protein-coding	222553
MCM9	protein-coding	254394
ASF1A	protein-coding	25842

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 by resolution:

PDB	Title	Method	Resolution (Å)
6Y40	14-3-3 Sigma in complex with phosphorylated PLN peptide	X-RAY DIFFRACTION	1.75
7E0Z	Crystal structure of PKAc-PLN complex	X-RAY DIFFRACTION	2.16
7E12	Crystal structure of PKAc-A11E complex	X-RAY DIFFRACTION	2.8
7E11	Crystal structure of PKAc-PLN R9C complex	X-RAY DIFFRACTION	3.43
1PLP	SOLUTION STRUCTURE OF THE CYTOPLASMIC DOMAIN OF PHOSPHOLAMBAN	SOLUTION NMR
1ZLL	NMR Structure of Unphosphorylated Human Phospholamban Pentamer	SOLUTION NMR
2HYN	Complete ensemble of NMR structures of unphosphorylated human phospholamban pentamer	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

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)

Type	Positions
N-acetylmethionine	1
Phosphoserine	16
Phosphothreonine	17
S-palmitoyl cysteine	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 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-5578775	Ion homeostasis	curated
R-HSA-936837	Ion transport by P-type ATPases	curated
R-HSA-5576891	Cardiac conduction	—
R-HSA-983712	Ion channel transport	—
R-HSA-397014	Muscle contraction	—
R-HSA-382551	Transport of small molecules	—

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 (25): acrosome assembly (GO:0001675), regulation of the force of heart contraction (GO:0002026), calcium ion transport (GO:0006816), intracellular calcium ion homeostasis (GO:0006874), 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), response to insulin (GO:0032868), response to testosterone (GO:0033574), locomotor rhythm (GO:0045475), 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), regulation of cardiac muscle cell membrane potential (GO:0086036), 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), spermatogenesis (GO:0007283)

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 (11): 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), protein-containing complex (GO:0032991)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Cardiac conduction	1
Ion channel transport	1
Muscle contraction	1
Transport of small molecules	1

GO top-level categories

showing 60 of 68 GO namespaces:

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
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
response to peptide hormone	1
response to lipid	1
response to ketone	1
locomotory behavior	1
circadian behavior	1
circadian sleep/wake cycle process	1
sleep	1
circadian sleep/wake cycle	1
intracellular calcium ion homeostasis	1
regulation of metal ion transport	1
negative regulation of monoatomic ion transport	1
regulation of calcium ion transport	1
relaxation of muscle	1
regulation of cardiac muscle contraction	1
cardiac muscle cell contraction	1
regulation of actin filament-based movement	1
regulation of membrane potential	1
negative regulation of calcium ion transport	1
calcium ion import	1
regulation of calcium ion import	1
catalytic activity	1
enzyme regulator activity	1
ATP-dependent activity	1
identical protein binding	1
protein dimerization activity	1
enzyme binding	1
transporter activity	1
transporter regulator activity	1
binding	1
endomembrane system	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum	1
sarcoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 44 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of ATPase-coupled calcium transmembrane transporter activity	BP	direct assay
negative regulation of calcium ion import into sarcoplasmic reticulum	BP	direct assay
negative regulation of calcium ion transport	BP	direct assay
negative regulation of heart rate	BP	mutant phenotype
regulation of ATPase-coupled calcium transmembrane transporter activity	BP	direct assay
regulation of calcium ion transport	BP	direct assay
regulation of cardiac muscle cell contraction	BP	direct assay
regulation of cytosolic calcium ion concentration	BP	direct assay
regulation of heart contraction	BP	mutant phenotype
calcium ion-transporting ATPase complex	CC	direct assay
membrane	CC	direct assay
mitochondrion	CC	high-throughput assay
ATPase inhibitor activity	MF	direct assay
transmembrane transporter binding	MF	physical interaction
transporter inhibitor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 702 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLN	SLN	O00631	951
PLN	ATP2A2	P16614	891
PLN	SLC8A1	P32418	802
PLN	ATP2A3	Q93084	779
PLN	TRAM2	Q15035	755
PLN	ATP2A1	O14983	744
PLN	TLX2	O43763	682
PLN	RYR2	Q92736	600
PLN	MYH6	P13533	494
PLN	CASQ2	O14958	486
PLN	MYH14	Q7Z406	482
PLN	NPPA	P01160	472
PLN	ATP2B1	P20020	449
PLN	TNNT2	P45379	447
PLN	ACTC1	P04270	441

IntAct

Human interaction partners of PLN in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 59 partners by confidence:

Partner	Interaction type	MIscore	Records
EDA	physical association	0.890	12
BCL2L13	physical association	0.720	8
LDLRAD1	physical association	0.670	4
DMPK	phosphorylation reaction	0.560	4
ARL13B	physical association	0.560	3
ASGR2	physical association	0.560	3
ATP6V0E1	physical association	0.560	3
BIK	physical association	0.560	3
CD53	physical association	0.560	3
CLDN7	physical association	0.560	3
CLEC2D	physical association	0.560	3
CPLX4	physical association	0.560	3
CREB3	physical association	0.560	3
CREB3L1	physical association	0.560	3
ELOVL4	physical association	0.560	3
FAM209A	physical association	0.560	3
FKBP8	physical association	0.560	3
FNDC9	physical association	0.560	3
GJA8	physical association	0.560	3
GPR152	physical association	0.560	3
GPR37L1	physical association	0.560	3
GPX8	physical association	0.560	3
HIBADH	physical association	0.560	3
HSD17B13	physical association	0.560	3
KIR2DL3	physical association	0.560	3
LSMEM2	physical association	0.560	3
MFF	physical association	0.560	3
MFSD5	physical association	0.560	3
MGST2	physical association	0.560	3
MGST3	physical association	0.560	3

BioGRID (88 interactions; top human partners by supporting records): ATP2A2 (Affinity Capture-Western; 7 records), EDA (Two-hybrid; 4 records), ATP2A1 (Affinity Capture-Western; 3 records), DMPK (Affinity Capture-Western; 3 records), SLN (Affinity Capture-Western; 3 records), BCL2L13 (Two-hybrid; 2 records), LDLRAD1 (Two-hybrid; 2 records), AQP6 (Two-hybrid), ARL13B (Two-hybrid), ASGR2 (Two-hybrid), ATP6V0E1 (Two-hybrid), ATRX (Synthetic Lethality), BIK (Two-hybrid), C4orf3 (FRET), CD53 (Two-hybrid)

SIGNOR signaling

6 signaling 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

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
ILK-SERCA2A-PLN complex	3	ATP2A2, ILK, PLN
SLN-PLN-SERCA1A complex	3	PLN, SLN, ATP2A1
SLN-PLN-SERCA2A complex	3	ATP2A2, PLN, SLN
SERCA-PLN complex	2	ATP2A2, PLN

Disease & clinical

Genetic variants

Variant evidence for PLN: 49 ClinVar records (6 pathogenic / likely pathogenic); 21 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	37
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (6)

Showing all 6 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
239214	NM_002667.4(PLN):c.-97-?_*1344+?del	Pathogenic	criteria provided, single submitter	1
1453340	NM_002667.5(PLN):c.95_98del (p.Phe32fs)	Pathogenic	criteria provided, single submitter	1
1977709	NM_002667.5(PLN):c.105_106del (p.Phe35fs)	Pathogenic	criteria provided, single submitter	1
3706363	NM_002667.5(PLN):c.4G>T (p.Glu2Ter)	Pathogenic	criteria provided, single submitter	1
3720713	NM_002667.5(PLN):c.26G>T (p.Arg9Leu)	Likely pathogenic	criteria provided, single submitter	1
657898	NC_000006.12:g.(?118548061)(118559090_?)del	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PLN’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 19 predictions of 64):

Position(s)	Effect	Δscore	Sites
6:118548393–118548394	donor_loss	0.9900	5
6:118558823–118558824	acceptor_loss	0.9900	6
6:118548394	donor_gain	0.9600
6:118548392	donor_gain	0.9500
6:118558817	acceptor_gain	0.9500
6:118558819	acceptor_gain	0.9400
6:118548395	donor_gain	0.9300
6:118548392	donor_gain	0.8800
6:118548392	donor_gain	0.8400
6:118548423	donor_gain	0.7500

AlphaMissense

75 missense substitutions predicted likely pathogenic (of 332 scored), across 33 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F35	7	0.774	0.909
R14	5	0.772	0.845
F32	5	0.723	0.778
R13	4	0.697	0.735
L42	3	0.948	0.953
L37	3	0.916	0.948
L44	3	0.910	0.951
C41	3	0.866	0.985
L31	3	0.804	0.935
I38	3	0.800	0.832
N34	3	0.797	0.902
L51	3	0.743	0.763
I12	3	0.706	0.753
I40	2	0.977	0.983
A11	2	0.909	0.932
A15	2	0.803	0.835
L28	2	0.761	0.874
L43	2	0.690	0.808
R9	2	0.689	0.782
L52	2	0.648	0.686

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Squamous Cell Carcinoma (validation)	unfavorable	7.75e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000391
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000762

Disease associations

OMIM: gene MIM:172405 | disease phenotypes: MIM:609909

GenCC curated gene-disease

5 curated gene-disease records:

Disease	Classification	Inheritance	Records
dilated cardiomyopathy 1P	Definitive	Autosomal dominant	3
hypertrophic cardiomyopathy 18	Strong	Autosomal dominant	2
intrinsic cardiomyopathy	Strong	Autosomal dominant
arrhythmogenic right ventricular cardiomyopathy	Moderate	Autosomal dominant	2
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

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

2 validity classifications:

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

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 7 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
Arrhythmogenic right ventricular cardiomyopathy	green
Dilated Cardiomyopathy and conduction defects	green
Dilated and arrhythmogenic cardiomyopathy	green
Hypertrophic cardiomyopathy	green
Paediatric or syndromic cardiomyopathy	green
Sudden unexplained death or survivors of a cardiac event	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (5): dilated cardiomyopathy 1P (MONDO:0012362), hypertrophic cardiomyopathy 18 (MONDO:0013475), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), (MONDO:0015470), intrinsic cardiomyopathy (MONDO:0000591)

Orphanet (1): Familial isolated dilated cardiomyopathy (Orphanet:154)

HPO phenotypes

23 phenotypes (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:

Study	Trait	p-value
GCST010919_19	QT interval	5e-74
GCST002500_33	QT interval	2e-67
GCST003818_20	Resting heart rate	3e-55
GCST000444_2	QT interval	2e-29
GCST003844_32	QRS duration	8e-29
GCST000364_8	QT interval	2e-24
GCST002500_32	QT interval	1e-22
GCST006414_82	Atrial fibrillation	2e-22
GCST000363_13	QT interval	5e-22
GCST003598_37	QRS duration	5e-19
GCST003598_17	QRS duration	1e-18
GCST002500_31	QT interval	3e-18
GCST000364_12	QT interval	2e-17
GCST002500_34	QT interval	8e-16
GCST012101_3	Hypertrophic cardiomyopathy	3e-10
GCST012099_17	Hypertrophic cardiomyopathy (sarcomere negative)	6e-10
GCST000441_1	Cardiac structure and function	1e-9
GCST003870_9	QRS complex (Sokolow-Lyon)	1e-9
GCST002500_35	QT interval	1e-8
GCST004297_5	Atrial fibrillation	1e-8
GCST001746_11	QT interval	2e-6

EFO canonical traits (from GWAS)

4 canonical traits:

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

MeSH disease descriptors

2 disease descriptors:

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
C563690	Cardiomyopathy, Dilated, 1p *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

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 phosphorylation, increases response to substance	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 binding, increases expression, affects cotreatment, decreases 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	increases expression, affects cotreatment	1
Cycloheximide	decreases expression, decreases reaction	1
Diethylhexyl Phthalate	increases expression	1
Dobutamine	affects response to substance	1
Hydrocortisone	decreases expression, affects cotreatment	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 333 trials:

NCT	Phase	Status	Title
NCT00348530	Phase 4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	Phase 4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	Phase 4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	Phase 4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	Phase 4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	Phase 4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	Phase 4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	Phase 4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	Phase 4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	Phase 4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	Phase 4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	Phase 4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	Phase 4	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	Phase 4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	Phase 4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	Phase 4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	Phase 4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05371496	Phase 4	COMPLETED	Cardiac and Metabolic Effects of Semaglutide in Heart Failure With Preserved Ejection Fraction
NCT05718128	Phase 4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	Phase 4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	Phase 3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	Phase 3	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	Phase 3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	Phase 3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	Phase 3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	Phase 3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	Phase 3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	Phase 3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	Phase 3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	Phase 3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	Phase 3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	Phase 3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	Phase 3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	Phase 3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	Phase 3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	Phase 3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	Phase 3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	Phase 3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT03593317	Phase 2	RECRUITING	Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD
NCT03685149	Phase 2	COMPLETED	Pilot Randomized Trial With Flecainide in ARVC Patients
NCT06174220	Phase 2	RECRUITING	Targeted Therapy With Glycogen Synthase Kinase-3 Inhibition for Arrhythmogenic Cardiomyopathy
NCT00185250	Phase 2	COMPLETED	Betaferon/ Betaseron (Interferon Beta-1b) in Patients With Chronic Viral Cardiomyopathy
NCT00490347	Phase 2	COMPLETED	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Feasibility Trial
NCT00694161	Phase 2	COMPLETED	The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy
NCT01102140	Phase 2	TERMINATED	The Impact of Pomegranate Extract on Chronic Cardiomyopathy Complicated by Renal Insufficiency (ImPrOVE): a Pilot Study
NCT01442129	Phase 2	COMPLETED	The Effect of Intramyocardial Injection of Mesenchymal Precursor Cells on Myocardial Function in Patients Undergoing LVAD Implantation
NCT01636570	Phase 2	COMPLETED	Vitamin D3 Supplementation for Heart Failure Patients
NCT01643330	Phase 2	COMPLETED	A Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure
NCT02016365	Phase 2	COMPLETED	Safety and Efficacy Study of Doxycycline/UrsoDeoxyCholicAcid on Disease Progression in ATTR Amyloidosis
NCT02362646	Phase 2	COMPLETED	Safety & Efficacy of Intramyocardial Injection of Mesenchymal Precursor Cells on Myocardial Function in LVAD Recipients
NCT02485938	Phase 2	COMPLETED	HOPE-Duchenne (Halt cardiomyOPathy progrEssion in Duchenne)
NCT02681913	Phase 2	UNKNOWN	Adenosine as an Adjunct to Blood Cardioplegia
NCT04304560	Phase 2	UNKNOWN	Value of SGLT2 Inhibitor (Dapagliflozin) as an Added Therapy in Diabetic Patients With Heart Failure With Reduced Ejection Fraction; Randomized Controlled Clinical Trial
NCT06080074	Phase 2	RECRUITING	Multicenter Trial of ECMO in Children With Severe Cardiac Failure Using the Cardiohelp System
NCT06228924	Phase 1	RECRUITING	Open-label, Dose Escalation Study of Safety and Preliminary Efficacy of TN-401 in Adults With PKP2 Mutation-associated ARVC
NCT00696410	Phase 1	COMPLETED	The Impact of Zinc Supplementation on Left Ventricular Function in Nonischemic Cardiomyopathy
NCT02077010	Phase 1	COMPLETED	Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population
NCT02408432	Phase 1	COMPLETED	Bone Marrow Derived Mesenchymal Stem Cells in Improving Heart Function in Patients With Heart Failure Caused by Anthracyclines
NCT02646540	Phase 1	COMPLETED	AiDing Diuresis wIth Tolvaptan (ADD-IT)
NCT02962661	Phase 1	SUSPENDED	Donor Bone Marrow Derived Mesenchymal Stem Cells in Controlling Heart Failure in Patients With Cardiomyopathy Caused by Anthracyclines