POPDC2

Summary

POPDC2 (popeye domain cAMP effector 2, HGNC:17648) is a protein-coding gene on chromosome 3q13.33, encoding Popeye domain-containing protein 2 (Q9HBU9). Important for the maintenance of cardiac function.

This gene encodes a member of the POP family of proteins which contain three putative transmembrane domains. This membrane associated protein is predominantly expressed in skeletal and cardiac muscle, and may have an important function in these tissues.

Source: NCBI Gene 64091 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiac conduction defect (Strong, GenCC)
• Clinical variants (ClinVar): 70 total — 5 pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_001369919

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17648
Approved symbol	POPDC2
Name	popeye domain cAMP effector 2
Location	3q13.33
Locus type	gene with protein product
Status	Approved
Aliases	POP2
Ensembl gene	ENSG00000121577
Ensembl biotype	protein_coding
OMIM	605823
Entrez	64091

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000264231, ENST00000341124, ENST00000463323, ENST00000468801, ENST00000468916, ENST00000474523, ENST00000476092, ENST00000493094, ENST00000495362, ENST00000866167, ENST00000949666

RefSeq mRNA: 3 — MANE Select: NM_001369919 NM_001308333, NM_001369919, NM_022135

CCDS: CCDS2992, CCDS77797, CCDS93344

Canonical transcript exons

ENST00000493094 — 4 exons

Exon	Start	End
ENSE00001825511	119642056	119642561
ENSE00001899042	119659933	119660589
ENSE00001911634	119648119	119648668
ENSE00003558311	119654505	119654613

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 99.27.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9902 / max 398.0904, expressed in 85 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44035	62.3727	1824
44027	0.5633	66
44029	0.3845	54
44031	0.0217	10
44030	0.0108	5
44028	0.0099	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.27	gold quality
right atrium auricular region	UBERON:0006631	99.13	gold quality
heart left ventricle	UBERON:0002084	99.10	gold quality
cardiac ventricle	UBERON:0002082	99.06	gold quality
cardiac atrium	UBERON:0002081	98.85	gold quality
heart right ventricle	UBERON:0002080	98.21	gold quality
myocardium	UBERON:0002349	96.99	gold quality
left ventricle myocardium	UBERON:0006566	96.99	gold quality
heart	UBERON:0000948	96.66	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.63	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.47	gold quality
gastrocnemius	UBERON:0001388	95.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.48	gold quality
muscle of leg	UBERON:0001383	94.03	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.02	gold quality
lower esophagus	UBERON:0013473	91.94	gold quality
skeletal muscle organ	UBERON:0014892	91.55	gold quality
muscle organ	UBERON:0001630	91.54	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.92	gold quality
gall bladder	UBERON:0002110	89.51	gold quality
vena cava	UBERON:0004087	87.27	gold quality
muscle tissue	UBERON:0002385	86.30	gold quality
left uterine tube	UBERON:0001303	86.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.14	gold quality
smooth muscle tissue	UBERON:0001135	85.58	gold quality
skeletal muscle tissue	UBERON:0001134	85.50	gold quality
triceps brachii	UBERON:0001509	85.05	silver quality
biceps brachii	UBERON:0001507	84.92	silver quality
quadriceps femoris	UBERON:0001377	83.93	silver quality
deltoid	UBERON:0001476	83.89	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting POPDC2, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-1183	98.75	67.10	1116
HSA-MIR-12125	98.59	67.54	1044
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-146B-3P	97.83	65.29	782
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-6894-3P	96.73	65.64	798
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-9900	96.06	65.48	557
HSA-MIR-4765	93.11	66.17	737

Literature-anchored findings (GeneRIF, showing 4)

• recently a novel family of cAMP effector proteins emerged and was termed the Popeye domain containing (POPDC) family, which consists of three members POPDC1, POPDC2 and POPDC3. POPDC proteins are transmembrane proteins, which are abundantly present in striated and smooth muscle cells. POPDC proteins bind cAMP with high affinity comparable to PKA (PMID:28939104)
• POPDC2 a novel susceptibility gene for conduction disorders. (PMID:32535041)
• An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs. (PMID:33261556)
• Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking. (PMID:36624536)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	popdc2	ENSDARG00000069922
mus_musculus	Popdc2	ENSMUSG00000022803
rattus_norvegicus	Popdc2	ENSRNOG00000058752
drosophila_melanogaster	bves	FBGN0031150

Paralogs (2): POPDC1 (ENSG00000112276), POPDC3 (ENSG00000132429)

Protein

Protein identifiers

Popeye domain-containing protein 2 — Q9HBU9 (reviewed: Q9HBU9)

All UniProt accessions (3): C9J3P7, Q9HBU9, H7C5T7

UniProt curated annotations — full annotation on UniProt →

Function. Important for the maintenance of cardiac function. Plays a regulatory function in heart rate dynamics mediated, at least in part, through cAMP-binding and, probably, by increasing cell surface expression of the potassium channel KCNK2 and enhancing current density.

Subcellular location. Membrane. Cell membrane. Sarcolemma.

Tissue specificity. Expressed predominantly in the heart and in the skeletal muscle.

Similarity. Belongs to the popeye family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HBU9-1	1	yes
Q9HBU9-2	2

RefSeq proteins (3): NP_001295262, NP_001356848, NP_071418 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006916	POPDC1-3	Family
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR055272	POPDC1-3_dom	Domain

Pfam: PF04831

UniProt features (13 total): sequence conflict 4, transmembrane region 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1, glycosylation site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBU9-F1	76.07	0.47

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 (1): 361

Glycosylation sites (1): 4

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 86 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GNF2_MYL3, IRF7_01, SRF_C, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_REGULATION_OF_HEART_RATE, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_HEART_PROCESS, YY1_01, MODULE_48, MODULE_95

GO Biological Process (5): regulation of heart rate (GO:0002027), heart development (GO:0007507), skeletal muscle tissue development (GO:0007519), regulation of membrane potential (GO:0042391), striated muscle cell differentiation (GO:0051146)

GO Molecular Function (1): cAMP binding (GO:0030552)

GO Cellular Component (3): membrane (GO:0016020), sarcolemma (GO:0042383), plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of biological quality	2
regulation of heart contraction	1
animal organ development	1
circulatory system development	1
striated muscle tissue development	1
skeletal muscle organ development	1
monoatomic ion transmembrane transport	1
muscle cell differentiation	1
cyclic nucleotide binding	1
adenyl ribonucleotide binding	1
anion binding	1
cellular anatomical structure	1
plasma membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POPDC2	KCNK2	O95069	765
POPDC2	XIRP1	Q702N8	558
POPDC2	TMEM70	Q9BUB7	525
POPDC2	TMEM161A	Q9NX61	520
POPDC2	TMEM38A	Q9H6F2	490
POPDC2	TMEM214	Q6NUQ4	488
POPDC2	ARHGEF25	Q86VW2	476
POPDC2	RHBDD1	Q8TEB9	446
POPDC2	VAMP3	Q15836	435
POPDC2	KLHL31	Q9H511	433
POPDC2	MTUS2	Q5JR59	408
POPDC2	ANO5	Q75V66	402
POPDC2	SUN2	Q9UH99	393
POPDC2	DYRK1A	Q13627	388
POPDC2	CAV3	P56539	379

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ECE1	POPDC2	psi-mi:“MI:0915”(physical association)	0.370
BTG2	POPDC2	psi-mi:“MI:0915”(physical association)	0.370
POPDC2	ANK2	psi-mi:“MI:0914”(association)	0.350
POPDC2	FZD6	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): PIGO (Affinity Capture-MS), DHRS7 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), GHDC (Affinity Capture-MS), ATP11C (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), SOAT1 (Affinity Capture-MS), AAAS (Affinity Capture-MS), ANO6 (Affinity Capture-MS), SLC12A9 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), SLC12A7 (Affinity Capture-MS), ADCY3 (Affinity Capture-MS), C17orf49 (Affinity Capture-MS), VANGL2 (Affinity Capture-MS)

ESM2 similar proteins: A2A6C4, A4QN56, A7MBM2, D2HSA6, E9PY61, O60779, O75387, O95382, P41438, P41440, P42557, P70606, Q0P5V9, Q148L1, Q49LS1, Q49LS3, Q4R877, Q5E9R1, Q5GH56, Q5GH64, Q5GH66, Q5GH72, Q5RF58, Q62866, Q6P6V6, Q6PB70, Q6UX68, Q80ZU9, Q866G7, Q8CGA3, Q8IUH8, Q8IWD5, Q8K0H7, Q8N370, Q8R3N2, Q91WD0, Q92952, Q95KI5, Q96JT2, Q99PL8

Diamond homologs: B1H1G2, B8Q0B2, Q0IH22, Q3BCU4, Q5PQZ7, Q6JWV8, Q8JH92, Q8NE79, Q9DG23, Q9DG25, Q9ES81, Q9ES82, Q9ES83, Q9HBU9, Q9HBV1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	59
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
4277289	POPDC2, 12-BP DEL, NT516	Pathogenic
4277290	POPDC2, ARG263HIS	Pathogenic
4277291	POPDC2, ARG263CYS	Pathogenic
4277292	POPDC2, TRP188TER (rs144241265)	Pathogenic
4277293	POPDC2, 4-BP DEL, NT110	Pathogenic

SpliceAI

1227 predictions. Top by Δscore:

Variant	Effect	Δscore
3:119659928:CTTAC:C	donor_loss	1.0000
3:119659929:TTA:T	donor_loss	1.0000
3:119659930:TAC:T	donor_loss	1.0000
3:119659931:A:AT	donor_loss	1.0000
3:119659931:ACCGG:A	donor_gain	1.0000
3:119659932:C:CT	donor_loss	1.0000
3:119659932:CCGGC:C	donor_gain	1.0000
3:119660731:T:TA	donor_gain	1.0000
3:119642558:GAAG:G	acceptor_gain	0.9900
3:119642560:AGCTG:A	acceptor_gain	0.9900
3:119642561:GCTGT:G	acceptor_gain	0.9900
3:119642562:C:CC	acceptor_gain	0.9900
3:119648411:ATCAC:A	donor_gain	0.9900
3:119648508:G:C	donor_gain	0.9900
3:119659931:A:AC	donor_gain	0.9900
3:119659932:C:CC	donor_gain	0.9900
3:119659932:CCGG:C	donor_gain	0.9900
3:119660693:G:C	donor_gain	0.9900
3:119660708:T:A	donor_gain	0.9900
3:119660709:C:CA	donor_gain	0.9900
3:119642559:AAGC:A	acceptor_loss	0.9800
3:119642559:AAGCT:A	acceptor_gain	0.9800
3:119642561:GCTG:G	acceptor_loss	0.9800
3:119642562:CTGT:C	acceptor_loss	0.9800
3:119642562:CTGTG:C	acceptor_gain	0.9800
3:119642563:T:G	acceptor_loss	0.9800
3:119642564:G:C	acceptor_gain	0.9800
3:119642564:G:GC	acceptor_gain	0.9800
3:119648406:T:TA	donor_gain	0.9800
3:119660732:C:A	donor_gain	0.9800

AlphaMissense

2365 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:119648629:A:G	W214R	0.997
3:119648629:A:T	W214R	0.997
3:119654541:C:A	W188C	0.997
3:119654541:C:G	W188C	0.997
3:119654543:A:G	W188R	0.997
3:119654543:A:T	W188R	0.997
3:119648661:A:G	L203P	0.996
3:119654508:G:C	F199L	0.996
3:119654508:G:T	F199L	0.996
3:119654510:A:G	F199L	0.996
3:119648655:G:T	A205D	0.995
3:119654560:A:G	F182S	0.995
3:119654611:A:T	V165D	0.995
3:119659985:C:G	A147P	0.995
3:119654555:C:G	D184H	0.994
3:119654584:A:G	L174P	0.994
3:119659952:A:G	S158P	0.994
3:119648642:A:C	C209W	0.993
3:119654544:C:A	E187D	0.993
3:119654544:C:G	E187D	0.993
3:119659984:G:T	A147D	0.993
3:119659936:C:A	G163V	0.992
3:119659948:A:G	L159P	0.992
3:119659933:C:G	R164P	0.990
3:119659954:A:G	L157P	0.990
3:119648535:A:G	L245P	0.989
3:119654582:G:C	H175D	0.989
3:119648482:G:T	R263S	0.988
3:119648537:C:A	K244N	0.988
3:119648537:C:G	K244N	0.988

dbSNP variants (sampled 300 via entrez): RS1000026753 (3:119651009 A>G), RS1000097189 (3:119649634 AATGATG>A), RS1000133607 (3:119644383 G>T), RS1000506984 (3:119661087 G>T), RS1000592621 (3:119655600 T>C), RS1000704540 (3:119660734 T>C), RS1000726697 (3:119661442 C>T), RS1000851830 (3:119643262 C>A,T), RS1001079251 (3:119649233 C>A,G,T), RS1001151382 (3:119647740 G>A), RS1001258345 (3:119660663 T>C,G), RS1001421053 (3:119645294 G>A), RS1001543377 (3:119642912 G>A), RS1001585580 (3:119662272 A>C), RS1001780767 (3:119651133 C>T)

Disease associations

OMIM: gene MIM:605823 | disease phenotypes: MIM:621367

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiac conduction defect	Strong	Autosomal recessive

Mondo (2): cardiac conduction disease with or without cardiomyopathy 2 (MONDO:0700389), cardiac conduction defect (MONDO:0100042)

Orphanet (0):

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001639	Hypertrophic cardiomyopathy
HP:0001685	Myocardial fibrosis
HP:0001688	Sinus bradycardia
HP:0001695	Cardiac arrest
HP:0001962	Palpitations
HP:0003560	Muscular dystrophy
HP:0003621	Juvenile onset
HP:0004749	Atrial flutter
HP:0004756	Ventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0005144	Ventricular septal hypertrophy
HP:0006682	Premature ventricular contraction
HP:0011462	Young adult onset
HP:0011705	First degree atrioventricular block
HP:0011706	Second degree atrioventricular block
HP:0011707	Mobitz I atrioventricular block
HP:0012723	Sinoatrial block
HP:0012819	Myocarditis
HP:0025169	Left ventricular systolic dysfunction
HP:0031317	Fatty replacement of ventricular myocardial tissue
HP:0031676	Monomorphic ventricular tachycardia
HP:0034305	2:1 atrioventricular block
HP:0100749	Chest pain

GWAS associations

0 associations (top):

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
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	increases expression	1
dimethylselenide	decreases expression, increases expression, increases oxidation	1
benzo(e)pyrene	decreases methylation	1
gallium nitrate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
jinfukang	decreases expression, affects cotreatment	1
(+)-JQ1 compound	affects expression, increases reaction	1
Arsenic Trioxide	increases expression	1
Panobinostat	affects expression, increases reaction	1
Acetaminophen	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	affects expression	1
Formaldehyde	increases expression	1
Lipopolysaccharides	affects response to substance, affects cotreatment, increases expression	1
Methapyrilene	decreases methylation	1
Quercetin	increases expression	1
Rotenone	decreases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Isotretinoin	decreases expression	1
Reactive Oxygen Species	increases oxidation, decreases expression, increases expression	1
Thapsigargin	decreases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01609738	Not specified	COMPLETED	Left Ventricular Septum Pacing in Patients by Transvenous Approach Through the Inter-ventricular Septum
NCT02881671	Not specified	UNKNOWN	Identification of Genetic Basis of Atrioventricular Conduction Defects: From Congenital Forms to Degenerative Forms
NCT03024047	Not specified	UNKNOWN	Cohort Description of Younger With AV-block
NCT03947021	Not specified	UNKNOWN	Developing Methods for Reconstructing Electrical Heart Activity
NCT04776642	Not specified	RECRUITING	Biobank for Arrhythmia and Conduction Disorders: TowArd Pathophysiology Based Treatment
NCT06278844	Not specified	RECRUITING	Exercise Capacity Improvement by Conduction System Pacing in heArt Failure patieNts Without Compelling CRT inDication
NCT06371846	Not specified	UNKNOWN	Comparative Study of the Surface Electrocardiogram Signals During the Implantation of Conduction System Pacing Devices
NCT06620237	Not specified	ACTIVE_NOT_RECRUITING	BIO|MASTER.CSP Study
NCT06857201	Not specified	WITHDRAWN	RAFT-TAVR PACE: LBBAP vs. RVP Post-TAVR in Patients Requiring PPI
NCT07201363	Not specified	RECRUITING	Biomarkers of Inflammation and Fibrosis in Conduction Disorders After TAVI