POPDC3

Summary

POPDC3 (popeye domain cAMP effector 3, HGNC:17649) is a protein-coding gene on chromosome 6q21, encoding Popeye domain-containing protein 3 (Q9HBV1). May play a role in the maintenance of heart function mediated, at least in part, through cAMP-binding.

This gene encodes a member of the POP family of proteins containing three putative transmembrane domains. This gene is expressed in cardiac and skeletal muscle and may play an important role in these tissues during development. Alternatively spliced transcript variants have been found.

Source: NCBI Gene 64208 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive limb-girdle muscular dystrophy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 2 total
• Phenotypes (HPO): 10
• MANE Select transcript: NM_022361

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17649
Approved symbol	POPDC3
Name	popeye domain cAMP effector 3
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	POP3, MGC22671, bA355M14.1
Ensembl gene	ENSG00000132429
Ensembl biotype	protein_coding
OMIM	605824
Entrez	64208

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000254765, ENST00000429112, ENST00000474760, ENST00000489134, ENST00000882193, ENST00000882194, ENST00000882195, ENST00000965832, ENST00000965833, ENST00000965834, ENST00000965835, ENST00000965836, ENST00000965837, ENST00000965838, ENST00000965839

RefSeq mRNA: 1 — MANE Select: NM_022361 NM_022361

CCDS: CCDS5052

Canonical transcript exons

ENST00000254765 — 4 exons

Exon	Start	End
ENSE00001229790	105161425	105162160
ENSE00001843961	105157900	105158751
ENSE00001956280	105179833	105180014
ENSE00003601073	105159711	105159819

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 98.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.8199 / max 175.0723, expressed in 1264 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74873	8.1343	1254
74870	0.3369	58
74874	0.1555	54
74871	0.1260	47
74872	0.0671	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.29	gold quality
biceps brachii	UBERON:0001507	98.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.94	gold quality
vastus lateralis	UBERON:0001379	97.92	gold quality
quadriceps femoris	UBERON:0001377	97.59	gold quality
diaphragm	UBERON:0001103	97.52	gold quality
gastrocnemius	UBERON:0001388	97.44	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.28	gold quality
skeletal muscle tissue	UBERON:0001134	97.00	gold quality
skeletal muscle organ	UBERON:0014892	96.97	gold quality
muscle organ	UBERON:0001630	96.96	gold quality
gluteal muscle	UBERON:0002000	96.83	gold quality
muscle of leg	UBERON:0001383	96.80	gold quality
deltoid	UBERON:0001476	95.96	gold quality
triceps brachii	UBERON:0001509	95.71	gold quality
tibialis anterior	UBERON:0001385	95.30	gold quality
heart right ventricle	UBERON:0002080	93.48	gold quality
muscle tissue	UBERON:0002385	93.25	gold quality
heart left ventricle	UBERON:0002084	91.46	gold quality
cardiac ventricle	UBERON:0002082	91.33	gold quality
left ventricle myocardium	UBERON:0006566	91.24	gold quality
apex of heart	UBERON:0002098	89.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.82	gold quality
myocardium	UBERON:0002349	88.74	gold quality
right atrium auricular region	UBERON:0006631	88.51	gold quality
cardiac atrium	UBERON:0002081	88.05	gold quality
heart	UBERON:0000948	87.46	gold quality
stromal cell of endometrium	CL:0002255	86.80	gold quality
sperm	CL:0000019	86.52	gold quality
body of tongue	UBERON:0011876	85.54	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	27.23
E-GEOD-81608	yes	14.07
E-ANND-3	yes	4.48

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting POPDC3, 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-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-561-3P	99.64	70.90	3647

Literature-anchored findings (GeneRIF, showing 8)

• Frequent silencing of POPDC3 is associated with promoter hypermethylation in gastric cancer. (PMID:20627872)
• Reduced expression of Popdc3 may play a significant role in the carcinogenesis and progression of gastric cancer. Popdc3 may be an independent prognostic factor. (PMID:22654436)
• 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)
• Pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. (PMID:31610034)
• The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation. (PMID:34069715)
• Homozygous missense variant in POPDC3 causes recessive limb-girdle muscular dystrophy type 26. (PMID:35075722)
• Progress on the study of Popeye domain-containing 3 (POPDC3) in malignancies and striated muscle function and homeostasis. (PMID:36843357)
• A homozygous loss of function variant in POPDC3: From invalidating exercise intolerance to a limb-girdle muscular dystrophy phenotype. (PMID:37104941)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	popdc3	ENSDARG00000058551
mus_musculus	Popdc3	ENSMUSG00000019848
rattus_norvegicus	Popdc3	ENSRNOG00000047102
drosophila_melanogaster	bves	FBGN0031150

Paralogs (2): POPDC1 (ENSG00000112276), POPDC2 (ENSG00000121577)

Protein

Protein identifiers

Popeye domain-containing protein 3 — Q9HBV1 (reviewed: Q9HBV1)

All UniProt accessions (2): Q9HBV1, Q5T554

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the maintenance of heart function mediated, at least in part, through cAMP-binding. May play a role in the regulation of KCNK2/TREK-1-mediated current amplitude.

Subcellular location. Membrane.

Tissue specificity. Expressed predominantly in skeletal muscle (at protein level). Also detected in heart.

Disease relevance. Muscular dystrophy, limb-girdle, autosomal recessive 26 (LGMDR26) [MIM:618848] An autosomal recessive muscular disorder characterized by adult onset of weakness and atrophy of proximal limb muscles, elevated serum creatine kinase levels, and dystrophic findings on muscle biopsy. There is no cardiac or respiratory involvement. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the popeye family.

RefSeq proteins (1): NP_071756* (*=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 (10 total): sequence variant 4, transmembrane region 3, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBV1-F1	81.87	0.54

Functional residue map

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

Glycosylation sites (1): 4

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 122 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, DOANE_BREAST_CANCER_CLASSES_DN, WEI_MYCN_TARGETS_WITH_E_BOX, AMIT_EGF_RESPONSE_480_MCF10A, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT, LIAO_METASTASIS, TGANTCA_AP1_C, TSENG_IRS1_TARGETS_DN, RICKMAN_HEAD_AND_NECK_CANCER_C, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, GOBP_MUSCLE_CELL_DIFFERENTIATION, TAATTA_CHX10_01

GO Biological Process (4): 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 (3): cAMP binding (GO:0030552), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (2): membrane (GO:0016020), sarcolemma (GO:0042383)

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

544 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POPDC3	KCNK2	O95069	541
POPDC3	OR7A10	O76100	480
POPDC3	SLU7	O95391	471
POPDC3	CPNE8	Q86YQ8	462
POPDC3	ARHGEF25	Q86VW2	449
POPDC3	KIF20A	O95235	436
POPDC3	TSPYL2	Q9H2G4	431
POPDC3	MROH9	Q5TGP6	403
POPDC3	OR52R1	Q8NGF1	396
POPDC3	TPK1	Q9H3S4	392
POPDC3	VAMP3	Q15836	385
POPDC3	ROBO1	Q9Y6N7	377
POPDC3	CNTNAP2	Q9UHC6	373
POPDC3	CNTNAP5	Q8WYK1	371
POPDC3	CPVL	Q9H3G5	368

IntAct

3 interactions, top by confidence:

A	B	Type	Score
POPDC3	SCRN1	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (2): SCRN1 (Affinity Capture-MS), SCRN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B7P9G0, B1H1G2, B8Q0B2, O18866, O18867, O95259, P29973, P29974, P70604, Q00194, Q00195, Q03041, Q03720, Q08460, Q0IH22, Q12791, Q16280, Q16281, Q21029, Q28204, Q28279, Q28718, Q28EW0, Q29441, Q3BCU4, Q5PQZ7, Q5U2P1, Q60603, Q62398, Q62927, Q62976, Q63472, Q6JWV8, Q8JH92, Q8NCM2, Q8NE79, Q90805, Q90980, Q90ZC7, Q920E3

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

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1025 predictions. Top by Δscore:

Variant	Effect	Δscore
6:105159708:TA:T	donor_loss	1.0000
6:105159709:A:AG	donor_loss	1.0000
6:105161808:A:AC	donor_gain	1.0000
6:105161809:C:CC	donor_gain	1.0000
6:105163632:G:C	donor_gain	1.0000
6:105163777:CATT:C	acceptor_gain	1.0000
6:105163780:T:TC	acceptor_gain	1.0000
6:105158750:ACCTA:A	acceptor_loss	0.9900
6:105158753:T:C	acceptor_loss	0.9900
6:105159709:A:AC	donor_gain	0.9900
6:105159710:C:CC	donor_gain	0.9900
6:105159820:C:A	acceptor_loss	0.9900
6:105159820:C:CC	acceptor_gain	0.9900
6:105159821:T:A	acceptor_loss	0.9900
6:105161427:T:TA	donor_gain	0.9900
6:105161794:A:AC	donor_gain	0.9900
6:105161795:C:CC	donor_gain	0.9900
6:105161795:CTA:C	donor_gain	0.9900
6:105161846:T:TA	donor_gain	0.9900
6:105161972:AGT:A	donor_gain	0.9900
6:105162157:TTTC:T	acceptor_gain	0.9900
6:105162158:TTCC:T	acceptor_loss	0.9900
6:105162160:CCTA:C	acceptor_gain	0.9900
6:105162160:CCTAT:C	acceptor_loss	0.9900
6:105162161:CTAT:C	acceptor_loss	0.9900
6:105162163:A:C	acceptor_gain	0.9900
6:105163705:T:TA	donor_gain	0.9900
6:105163778:A:C	acceptor_gain	0.9900
6:105163779:T:TC	acceptor_gain	0.9900
6:105163780:T:C	acceptor_gain	0.9900

AlphaMissense

1903 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:105159747:C:A	W186C	0.999
6:105159747:C:G	W186C	0.999
6:105159749:A:G	W186R	0.999
6:105159749:A:T	W186R	0.999
6:105158712:A:G	W212R	0.998
6:105158712:A:T	W212R	0.998
6:105158744:A:G	L201P	0.997
6:105159714:A:C	F197L	0.997
6:105159714:A:T	F197L	0.997
6:105159716:A:G	F197L	0.997
6:105159766:A:G	F180S	0.997
6:105158704:T:A	R214S	0.996
6:105158704:T:G	R214S	0.996
6:105158725:A:C	C207W	0.996
6:105158727:A:G	C207R	0.996
6:105159748:C:G	W186S	0.996
6:105161428:C:A	G161V	0.996
6:105158621:T:A	K242I	0.995
6:105161437:A:T	L158H	0.995
6:105161477:C:G	A145P	0.995
6:105158620:T:A	K242N	0.994
6:105158620:T:G	K242N	0.994
6:105158705:C:G	R214T	0.994
6:105158726:C:T	C207Y	0.994
6:105158738:G:T	A203E	0.994
6:105159757:G:A	S183F	0.994
6:105161446:A:T	L155H	0.994
6:105161672:A:G	W80R	0.994
6:105161672:A:T	W80R	0.994
6:105158618:A:G	L243P	0.993

dbSNP variants (sampled 300 via entrez): RS1000021743 (6:105169712 T>A,C), RS1000131759 (6:105176633 T>G), RS1000166529 (6:105179447 T>G), RS1000231969 (6:105176327 A>G), RS1000294336 (6:105169607 A>C), RS1000669632 (6:105181870 A>G,T), RS1000909117 (6:105169970 T>C), RS1001175886 (6:105175608 G>A,C), RS1001633192 (6:105161304 C>G,T), RS1001693335 (6:105168140 T>G), RS1001801817 (6:105169236 GAC>G), RS1001905948 (6:105163264 T>C), RS1002146259 (6:105173694 T>C), RS1002180297 (6:105177831 A>G), RS1002243581 (6:105173286 G>C)

Disease associations

OMIM: gene MIM:605824 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
muscular dystrophy, limb-girdle, autosomal recessive 26	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal recessive limb-girdle muscular dystrophy	Definitive	AR

Mondo (1): muscular dystrophy, limb-girdle, autosomal recessive 26 (MONDO:0030014)

Orphanet (0):

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002527	Falls
HP:0003557	Increased variability in muscle fiber diameter
HP:0003701	Proximal muscle weakness
HP:0003713	Muscle fiber necrosis
HP:0008981	Calf muscle hypertrophy
HP:0008994	Proximal lower limb muscle weakness
HP:0009046	Difficulty running
HP:0012548	Fatty replacement of skeletal muscle
HP:0030234	Highly elevated creatine kinase

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000175_14	Height	8.000000e-07
GCST000400_1	Menarche (age at onset)	2.000000e-14
GCST001096_6	Multiple sclerosis	8.000000e-06
GCST009391_605	Metabolite levels	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0010505	isocitrate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	5
trichostatin A	increases expression, affects cotreatment, decreases expression	3
Arsenic	affects cotreatment, increases abundance, increases expression	3
Valproic Acid	affects expression, increases expression	3
Temozolomide	affects response to substance, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Tretinoin	increases expression, decreases expression	2
Aflatoxin B1	decreases methylation, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
bisphenol A	increases expression	1
lead acetate	increases expression	1
sodium arsenate	increases abundance, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
sulforaphane	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
diallyl trisulfide	increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC668394	increases expression	1
Sunitinib	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1

Clinical trials (associated diseases)

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