POPDC3

protein-coding

popeye domain containing 3

Gene summary

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. [provided by RefSeq, Nov 2008]

MANE transcript

NM_022361.5

Inheritance

ClinVar variants

P:6U:36B:5

Top phenotype

Muscular dystrophy, limb-girdle, autosomal recessive 26

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr6:105,157,900-105,180,014

External References & Databases

Ensembl (ENSG00000132429)

Transcript & Mutation Effects

hg38 • Region Span ~22.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

muscular dystrophy, limb-girdle, autosomal recessive 26LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030014

Submitter: Ambry Genetics

muscular dystrophy, limb-girdle, autosomal recessive 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030014

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive limb-girdle muscular dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

*POPDC3* (Popeye Domain-Containing Protein 3) was first reported in relation to autosomal recessive limb-girdle muscular dystrophy (LGMD) in 2019 (Vissing et al., PMID: 31610034). *POPDC3* is a Popeye domain-containing protein that is abundantly expressed in heart and skeletal muscle. Autosomal recessive LGMD (MONDO:0015152) is characterized by adult-onset weakness primarily affecting the proximal muscles of the lower limbs. Seven homozygous probands from seven families have been described in five publications (PMID: 31610034, 35842834, 35075722, 37104941, 41026953; 9.8 pts). Co-segregation with the LGMD phenotype was observed in affected siblings in two families. Reported variants include two unique splice variants, one stop-gained variant, and four unique missense variants (9.8 pts). Three of the missense variants were shown to impair regulation of TREK-1 current in Xenopus oocytes, but the significance of this effect with respect to the disease mechanism is considered unclear. The mechanism for disease is though to be biallelic loss of function, but the exact pathogenic mechanisms are not yet known. This gene-disease association is also supported by experimental evidence (1.5 pts). POPDC3 is uniquely expressed in skeletal and cardiac muscle, providing evidence towards an association with this muscle-affecting disorder (PMID: 10882522), and co-IP studies have demonstrated a direct interaction between POPDC3 and *BVES* (*POPDC1*), which is definitively associated with autosomal recessive LGMD (PMID: 36624536). In addition, a zebrafish knock-out mutant model demonstrated ventral tail curvature and dystrophic changes in myofibers (PMID: 31610034), although a significant phenotype was not observed by early adulthood in homozygous knock-out mice (C57BL/6N-Popdc3tm1.1(KOMP)Vlcg/MbpMmucd; https://www.mmrrc.org/catalog/sds.php?mmrrc_id=49150). In summary, there is definitive evidence (11.3 pts) to support the relationship between *POPDC3* and autosomal recessive LGMD. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the MDM GCEP in May 2023. It was reevaluated in February 2025. As a result of this reevaluation, the classification was upgraded from Moderate to Definitive with the addition of an additional case and protein interaction data (PMID: 36624536, 41026953).

muscular dystrophy, limb-girdle, autosomal recessive 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030014

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Muscular dystrophy, limb-girdle, autosomal recessive 26AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31610034

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POPDC3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 31

Muscular dystrophy, limb-girdle, autosomal recessive 26Total: 7

not providedTotal: 5

POPDC3-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022361.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				1 clinvar	2 clinvar	3
missense	4 clinvar		33 clinvar	1 clinvar	1 clinvar	39
nonsense		1 clinvar				1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar		3 clinvar			4
Total	5	1	36	2	3	47

Highest pathogenic variant AF is 0.000028502209

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022361.5	RefSeq	NP_071756.2	3	MANE Select
ENST00000254765.4	Ensembl	ENSP00000254765.3	3	MANE Select
ENST00000429112.1	Ensembl	ENSP00000414409.1	2	Standard
ENST00000882193.1	Ensembl	ENSP00000552252.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

heart development
skeletal muscle tissue development
biological_process
regulation of membrane potential
striated muscle cell differentiation

Molecular Function

molecular_function
cAMP binding

Cellular Component

membrane
integral component of membrane
sarcolemma

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000254765
Coding exons: 3
Length: 21716
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125739
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.666	133	156	0.850	0.00000791	1898
Missense (PolyPhen)		50	62.902	0.79488		754
Synonymous	-0.431	61	56.9	1.07	0.00000274	568
Loss of Function	1.81	5	11.7	0.429	6.43e-7	136

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in the maintenance of heart function mediated, at least in part, through cAMP-binding. {ECO:0000250|UniProtKB:Q9ES81, ECO:0000269|PubMed:10882522}.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.636
RVIS EVS: 0.24
RVIS percentile EVS: 69.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.324

Gene Damage Prediction

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