PPA2

protein-coding

inorganic pyrophosphatase 2

Gene summary

The protein encoded by this gene is localized to the mitochondrion, is highly similar to members of the inorganic pyrophosphatase (PPase) family, and contains the signature sequence essential for the catalytic activity of PPase. PPases catalyze the hydrolysis of pyrophosphate to inorganic phosphate, which is important for the phosphate metabolism of cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_176869.3

Inheritance

ClinVar variants

P:27U:136B:87

Top phenotype

Sudden cardiac failure, alcohol induced

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr4:105,369,077-105,474,067

External References & Databases

Ensembl (ENSG00000138777)

Transcript & Mutation Effects

hg38 • Region Span ~105.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sudden cardiac failure, infantileSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014973

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

sudden cardiac failure, infantileDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014973

Submitter: G2P

sudden cardiac failure, infantileDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014973

Submitter: Ambry Genetics

sudden cardiac failure, infantileSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014973

Submitter: Labcorp Genetics (formerly Invitae)

dilated cardiomyopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: ClinGen

PPA2 was evaluated for autosomal recessive (AR) dilated cardiomyopathy. PPA2 is a nuclear gene related to mitochondrial function. PPA2 plays roles in mtDNA maintenance, oxidative phosphorylation, generation of ATP, ROS homeostasis, and mitochondrial membrane potential (Phoon et. al, 2020, PMID: 31705601). At the time of this review, dilated cardiomyopathy is the only condition that has been associated with this gene. Human genetic evidence for this gene-disease relationship contains case-level data. At least 9 variants (including missense, nonsense, and frameshift variants) have been reported in humans with DCM in 4 separate publications (Vasilescu et. al, 2018, PMID: 30384889; Zhao et. al, 2021, PMID: 33826954; Guimier et. al, 2021, PMID: 34400813; Manzanilla-Romero et. al, 2023; PMID: 37269378). All cases reported in the literature were infant onset, often in the presence of viral illness, or in teenage/young adulthood in the presence of alcohol consumption. Several cases presented with sudden cardiac death, with limited phenotype information available on autopsy or due to the patient’s young age and were not scored for DCM (Kennedy et. al, 2016, PMID: 27523597; Guimier et. al, 2016, PMID: 27523598; Sanford et. al, 2020, PMID: 33028643; Guimer et. al, 2021, PMID: 34400813; Genthe et. al, 2023, PMID: 37869221; Graham et. al, 2023, PMID: 37249496; González et. al, 2024, PMID: 38582264). In addition, this gene-disease assertion is supported by expression studies and functional alteration. Expression of PPA2 in human heart tissue was demonstrated by northern blot (Curbo et. al, 2006, PMID: 16300924). Decreased expression of PPA2 was demonstrated in western blot of patient homogenates (Kennedy et. al, 2016, PMID: 27523597). In addition, functional alterations were shown in both patient and non-patient cells. Increased oxygen consumption rates were found in PPA2-deficient fibroblasts (Kennedy et. al, 2016, PMID: 27523597). Additionally, yeast PPA2 knockouts showed increased diamide sensitivity, suggesting reduced levels of antioxidants (Kennedy et. al, 2016, PMID: 27523597). In summary, there is strong evidence to support the relationship between PPA2 and AR DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 05/16/2025 (SOP Version 10).

sudden cardiac failure, infantileSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014973

Submitter: PanelApp Australia

sudden cardiac failure, alcohol-inducedSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014974

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Sudden cardiac failure, alcohol inducedAR

Manifestation: Cardiovascular

Intervention: General

Rationale: Individuals have been reported as suffering sudden cardiac failure after ingesting small amounts of alcohol, and awareness may allow avoidance of triggering agents as well as early diagnosis allowing preventive measures (eg, ICD)

Refs: 27523597; 27523598

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPA2 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 331

Inborn genetic diseasesTotal: 45

not specifiedTotal: 30

Sudden cardiac failure, infantileTotal: 26

Sudden cardiac failure, alcohol-inducedTotal: 16

PPA2-related disorderTotal: 15

Cardiovascular phenotypeTotal: 2

sudden cardiac failureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_176869.3. 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			3 clinvar	72 clinvar	1 clinvar	76
missense	3 clinvar	16 clinvar	116 clinvar	14 clinvar		149
nonsense	2 clinvar	3 clinvar	4 clinvar			9
start loss			1 clinvar			1
frameshift			6 clinvar			6
splice donor/acceptor (+/-2bp)		3 clinvar	6 clinvar			9
Total	5	22	136	86	1	250

Highest pathogenic variant AF is 0.0010266774

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_176869.3	RefSeq	NP_789845.1	12	MANE Select
ENST00000341695.10	Ensembl	ENSP00000343885.5	12	MANE Select
NM_006903.4	RefSeq	NP_008834.3	11	Standard
NM_176866.2	RefSeq	NP_789842.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxidative phosphorylation - Homo sapiens (human)
tRNA Aminoacylation
Translation
Metabolism of proteins
Pyrophosphate hydrolysis

Biological Process

tRNA aminoacylation for protein translation
protein dephosphorylation
phosphate-containing compound metabolic process
regulation of mitochondrial membrane potential
diphosphate metabolic process

Molecular Function

magnesium ion binding
inorganic diphosphatase activity
protein serine/threonine phosphatase activity

Cellular Component

mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341695
Coding exons: 12
Length: 105005
Individuals with no LoFs: 125717
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125748
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.435	159	175	0.908	0.00000865	2184
Missense (PolyPhen)		61	75.552	0.80739		945
Synonymous	0.318	57	60.1	0.948	0.00000293	588
Loss of Function	0.621	17	20.0	0.850	9.36e-7	255

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00018	rare
Latino/Admixed American	0.000062	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00015	rare
South Asian	0.00018	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hydrolyzes inorganic pyrophosphate (PubMed:27523597). This activity is essential for correct regulation of mitochondrial membrane potential, and mitochondrial organization and function (PubMed:27523598). {ECO:0000269|PubMed:27523597, ECO:0000269|PubMed:27523598}.;
Disease: DISEASE: Sudden cardiac failure, infantile (SCFI) [MIM:617222]: A disease characterized by sudden death within the first 2 years of life due to unexpected cardiac arrest. Some patients manifest hypertrophic cardiomyopathy, lipid accumulation in myocardium, degeneration of mitochondrial cristae, metabolic acidosis, and elevated plasma lactate levels. SCFI transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:27523597, ECO:0000269|PubMed:27523598}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.145

Intolerance Scores

LoFtool: 0.940
RVIS EVS: 0
RVIS percentile EVS: 53.73

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.597

Gene Damage Prediction

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