PPA2

Summary

PPA2 (inorganic pyrophosphatase 2, HGNC:28883) is a protein-coding gene on chromosome 4q24, encoding Inorganic pyrophosphatase 2, mitochondrial (Q9H2U2). Hydrolyzes inorganic pyrophosphate. It is a selective cancer dependency (DepMap: 42.0% of cell lines).

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.

Source: NCBI Gene 27068 — RefSeq curated summary.

At a glance

• Gene–disease (curated): sudden cardiac failure, infantile (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 432 total — 5 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 14
• Cancer dependency (DepMap): dependent in 42.0% of screened cell lines
• MANE Select transcript: NM_176869

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28883
Approved symbol	PPA2
Name	inorganic pyrophosphatase 2
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20459
Ensembl gene	ENSG00000138777
Ensembl biotype	protein_coding
OMIM	609988
Entrez	27068

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 21 protein_coding, 5 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000341695, ENST00000348706, ENST00000351450, ENST00000354147, ENST00000432483, ENST00000457404, ENST00000499847, ENST00000502596, ENST00000502610, ENST00000502833, ENST00000503171, ENST00000504028, ENST00000505713, ENST00000506815, ENST00000508518, ENST00000509031, ENST00000509426, ENST00000510015, ENST00000513605, ENST00000513649, ENST00000514209, ENST00000515567, ENST00000899796, ENST00000899797, ENST00000899798, ENST00000899799, ENST00000899800, ENST00000899801, ENST00000899802, ENST00000899803, ENST00000899804, ENST00000899805, ENST00000919900, ENST00000960435

RefSeq mRNA: 4 — MANE Select: NM_176869 NM_006903, NM_176866, NM_176867, NM_176869

CCDS: CCDS34043, CCDS3667, CCDS3668, CCDS3669

Canonical transcript exons

ENST00000341695 — 12 exons

Exon	Start	End
ENSE00001894198	105369077	105369753
ENSE00002064461	105473894	105474062
ENSE00003508841	105453598	105453642
ENSE00003529103	105449350	105449403
ENSE00003592311	105456681	105456745
ENSE00003601027	105437950	105438036
ENSE00003609342	105370837	105370873
ENSE00003611366	105424196	105424322
ENSE00003613040	105446383	105446502
ENSE00003613295	105396249	105396334
ENSE00003687809	105399037	105399164
ENSE00003693060	105386567	105386636

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 95.2180 / max 669.1515, expressed in 1826 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53472	90.3573	1826
53470	2.5701	1190
53471	2.1207	1178
53469	0.1698	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.16	gold quality
parotid gland	UBERON:0001831	98.65	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.04	gold quality
rectum	UBERON:0001052	97.82	gold quality
colonic mucosa	UBERON:0000317	97.72	gold quality
mucosa of transverse colon	UBERON:0004991	97.41	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.35	gold quality
adrenal tissue	UBERON:0018303	97.10	gold quality
jejunal mucosa	UBERON:0000399	97.07	gold quality
right adrenal gland	UBERON:0001233	97.04	gold quality
heart right ventricle	UBERON:0002080	97.00	gold quality
body of pancreas	UBERON:0001150	96.92	gold quality
saliva-secreting gland	UBERON:0001044	96.86	gold quality
left adrenal gland	UBERON:0001234	96.81	gold quality
duodenum	UBERON:0002114	96.78	gold quality
minor salivary gland	UBERON:0001830	96.77	gold quality
right adrenal gland cortex	UBERON:0035827	96.74	gold quality
left adrenal gland cortex	UBERON:0035825	96.67	gold quality
upper leg skin	UBERON:0004262	96.63	gold quality
islet of Langerhans	UBERON:0000006	96.61	gold quality
right atrium auricular region	UBERON:0006631	96.61	gold quality
transverse colon	UBERON:0001157	96.52	gold quality
adult mammalian kidney	UBERON:0000082	96.50	gold quality
adrenal gland	UBERON:0002369	96.50	gold quality
skin of abdomen	UBERON:0001416	96.49	gold quality
triceps brachii	UBERON:0001509	96.46	gold quality
nasal cavity mucosa	UBERON:0001826	96.41	gold quality
cardiac atrium	UBERON:0002081	96.37	gold quality
pancreas	UBERON:0001264	96.36	gold quality
diaphragm	UBERON:0001103	96.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting PPA2, 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-3662	99.99	73.82	5684
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-3198	97.84	65.64	579
HSA-MIR-4309	97.84	65.45	588
HSA-MIR-708-3P	97.50	68.67	1082

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• No pathogenic mutations were identified in the PPA2 gene in patients with mitochondrial DNA depletion syndromes (MDS). (PMID:16300924)
• We think that PP2A can be one of the key components to regulate the fusion of various endocytotic compartments and /or the trafficking along the microtubules. (PMID:19067239)
• Single nucleotide polymorphisms in PPA2 is associated with response to antipsychotic agents in schizophrenia. (PMID:23241943)
• findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized (PMID:27523597)
• data demonstrate that PPA2 is an essential gene in yeast and that biallelic mutations in PPA2 cause a mitochondrial disease leading to sudden cardiac arrest in infants (PMID:27523598)
• Sudden unexpected death in asymptomatic infants due to PPA2 variants. (PMID:31705601)
• Structural and biochemical characterization of inorganic pyrophosphatase from Homo sapiens. (PMID:33036755)
• PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families. (PMID:34400813)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppa2	ENSDARG00000009685
mus_musculus	Ppa2	ENSMUSG00000028013
rattus_norvegicus	Ppa2	ENSRNOG00000012091
drosophila_melanogaster	Nurf-38	FBGN0016687
caenorhabditis_elegans		WBGENE00008149

Paralogs (1): PPA1 (ENSG00000180817)

Protein

Protein identifiers

Inorganic pyrophosphatase 2, mitochondrial — Q9H2U2 (reviewed: Q9H2U2)

Alternative names: Pyrophosphatase SID6-306, Pyrophosphate phospho-hydrolase 2

All UniProt accessions (10): Q9H2U2, A0A0C4DGB9, D6R967, D6RAD3, D6RGI1, D6RGV9, F8W7R6, H0Y8X2, H0Y9D8, H0YAK2

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes inorganic pyrophosphate. This activity is essential for correct regulation of mitochondrial membrane potential, and mitochondrial organization and function.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion.

Tissue specificity. Detected in brain, gastric carcinoma, lung, ovary, skeletal muscle, umbilical cord blood and a cell line derived from kidney proximal tubule epithelium.

Disease relevance. Sudden cardiac failure, alcohol-induced (SCFAI) [MIM:617223] An autosomal recessive disease characterized by sudden death due to unexpected cardiac arrest following ingestion of small amounts of alcohol. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the PPase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9H2U2-1	1	yes
Q9H2U2-2	2
Q9H2U2-3	3
Q9H2U2-4	4
Q9H2U2-6	5

RefSeq proteins (4): NP_008834, NP_789842, NP_789843, NP_789845* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008162	Pyrophosphatase	Family
IPR036649	Pyrophosphatase_sf	Homologous_superfamily

Pfam: PF00719

Enzyme classification (BRENDA):

• EC 3.6.1.1 — inorganic diphosphatase (BRENDA: 104 organisms, 246 substrates, 220 inhibitors, 192 Km, 105 kcat entries)

Substrate kinetics (BRENDA)

25 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DIPHOSPHATE	—	121
MG-DIPHOSPHATE	0.0004–4.2	18
ATP	0.064–4.13	5
MG2+	1.65–4.9	4
TRIPHOSPHATE	0.0167–1.37	4
4-NITROPHENYL PHOSPHATE	69.7	1
ADP	4.43	1
CA-DIPHOSPHATE	0.19	1
CDP	3.12	1
CO-DIPHOSPHATE	0.29	1
CTP	3.61	1
GDP	3.56	1
GTP	3.63	1
GUANOSINE 5’-TETRAPHOSPHATE	0.1554	1
IDP	3.47	1

Catalyzed reactions (Rhea), 1 shown:

• diphosphate + H2O = 2 phosphate + H(+) (RHEA:24576)

UniProt features (30 total): sequence variant 9, modified residue 5, splice variant 5, sequence conflict 5, binding site 4, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2U2-F1	87.39	0.79

Functional residue map

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

Ligand- & substrate-binding residues (4): 164; 169; 169; 201

Post-translational modifications (5): 317, 216, 224, 259, 261

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-379726	Mitochondrial tRNA aminoacylation
R-HSA-71737	Pyrophosphate hydrolysis
R-HSA-1430728	Metabolism
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 151 (showing top): AGGAAGC_MIR5163P, chr4q24, XU_GH1_AUTOCRINE_TARGETS_UP, PAL_PRMT5_TARGETS_UP, AATGGAG_MIR136, ATGTTAA_MIR302C, MODULE_331, MODULE_205, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_REGULATION_OF_MITOCHONDRIAL_MEMBRANE_POTENTIAL, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, MAYBURD_RESPONSE_TO_L663536_DN, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, GOERING_BLOOD_HDL_CHOLESTEROL_QTL_CIS, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (3): phosphate-containing compound metabolic process (GO:0006796), regulation of mitochondrial membrane potential (GO:0051881), diphosphate metabolic process (GO:0071344)

GO Molecular Function (6): magnesium ion binding (GO:0000287), inorganic diphosphate phosphatase activity (GO:0004427), protein serine/threonine phosphatase activity (GO:0004722), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), synapse (GO:0045202), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
tRNA Aminoacylation	1
Metabolism	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metabolic process	1
regulation of membrane potential	1
phosphorus metabolic process	1
oxoacid metabolic process	1
metal ion binding	1
pyrophosphatase activity	1
phosphoprotein phosphatase activity	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cell junction	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3431 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPA2	GPI	P06744	628
PPA2	MARS1	P56192	570
PPA2	AARS1	P49588	550
PPA2	PNP	P00491	547
PPA2	TPI1	P00938	540
PPA2	UQCRFS1	P47985	531
PPA2	YARS1	P54577	531
PPA2	PAPSS1	O43252	530
PPA2	IARS2	Q9NSE4	529
PPA2	PARS2	Q7L3T8	507
PPA2	IARS1	P41252	499
PPA2	FDPS	P14324	498
PPA2	KARS1	Q15046	494
PPA2	AKT1	P31749	493
PPA2	OGDH	Q02218	490

IntAct

43 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
HTT	PPA2	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
ZWINT	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
COMT		psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
KDM4C	SMCHD1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	NUDT19	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
ASS1	TIMM44	psi-mi:“MI:0914”(association)	0.350
SAR1B	UBA6	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SYNC	NDC80	psi-mi:“MI:0914”(association)	0.350
PPA2	CLUH	psi-mi:“MI:0914”(association)	0.350
SYNC	MAP3K7	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
ERBB2	DNM1L	psi-mi:“MI:0914”(association)	0.350
MYC	AP3B1	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
HRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
HRAS	IGHV1-45	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (181): MTIF2 (Affinity Capture-MS), HIST1H1D (Affinity Capture-MS), ACSF2 (Affinity Capture-MS), CLUH (Affinity Capture-MS), ACADVL (Affinity Capture-MS), ACSS1 (Affinity Capture-MS), GLS (Affinity Capture-MS), PNPT1 (Affinity Capture-MS), CLPP (Affinity Capture-MS), PCCB (Affinity Capture-MS), NNT (Affinity Capture-MS), ARPIN (Affinity Capture-MS), LYRM7 (Affinity Capture-MS), NIPSNAP3A (Affinity Capture-MS), MECR (Affinity Capture-MS)

ESM2 similar proteins: A1A535, A2VDN0, A5A6H8, A8E7C5, A9ULX8, B5DFM7, E9Q9F6, F6UF99, O18638, O42204, O43736, O89051, P0DP43, P10379, P58239, P91682, Q06AV4, Q06BR2, Q10651, Q14D04, Q29TV8, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5PQS3, Q5R876, Q5SC59, Q5SC60, Q5SY80, Q5XIE8, Q60HC1, Q61500, Q6GPK2, Q86XM0, Q86XP6, Q8HYA9, Q8IZ07, Q90372

Diamond homologs: O13505, O77392, O77460, P00817, P13998, P19117, P28239, P37980, P83777, P87118, Q15181, Q18680, Q4R543, Q54PV8, Q5B912, Q5R8T6, Q6BWA5, Q6C1T4, Q6FRB7, Q6MVH7, Q757J8, Q8SR69, Q91VM9, Q93Y52, Q9C0T9, Q9D819, Q9H2U2, Q9LXC9, P75250, P77992, P80562, Q8DHR2, Q8EVW9, Q8TVE2, Q93V56, Q9KCG7, Q821T4, Q9LFF9, A2X8Q3, O23979

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrion organization	5	18.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	9
Uncertain significance	144
Likely benign	171
Benign	56

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
2314983	NM_176869.3(PPA2):c.540T>A (p.Cys180Ter)	Pathogenic
3343864	NM_176869.3(PPA2):c.524C>G (p.Ser175Ter)	Pathogenic
372221	NM_176869.3(PPA2):c.881A>C (p.Gln294Pro)	Pathogenic
372223	NM_176869.3(PPA2):c.280A>G (p.Met94Val)	Pathogenic
372224	NM_176869.3(PPA2):c.318G>T (p.Met106Ile)	Pathogenic
1048578	NM_176869.3(PPA2):c.606G>C (p.Trp202Cys)	Likely pathogenic
2288832	NM_176869.3(PPA2):c.528+1G>A	Likely pathogenic
3622310	NM_176869.3(PPA2):c.604T>C (p.Trp202Arg)	Likely pathogenic
3706357	NM_176869.3(PPA2):c.556G>A (p.Val186Met)	Likely pathogenic
372220	NM_176869.3(PPA2):c.182C>T (p.Ser61Phe)	Likely pathogenic
372227	NM_176869.3(PPA2):c.500C>T (p.Pro167Leu)	Likely pathogenic
3894998	NM_176869.3(PPA2):c.611T>A (p.Leu204Ter)	Likely pathogenic
4537396	NM_176869.3(PPA2):c.295C>A (p.Pro99Thr)	Likely pathogenic
873541	NM_176869.3(PPA2):c.442A>T (p.Thr148Ser)	Likely pathogenic

SpliceAI

2449 predictions. Top by Δscore:

Variant	Effect	Δscore
4:105370871:TACC:T	acceptor_loss	1.0000
4:105370874:CTG:C	acceptor_loss	1.0000
4:105370875:T:A	acceptor_loss	1.0000
4:105370880:A:C	acceptor_gain	1.0000
4:105386632:TTGTG:T	acceptor_gain	1.0000
4:105386633:TGTG:T	acceptor_gain	1.0000
4:105386635:TG:T	acceptor_gain	1.0000
4:105386637:C:CC	acceptor_gain	1.0000
4:105396342:C:CT	acceptor_gain	1.0000
4:105399030:T:C	donor_gain	1.0000
4:105399032:TTCAC:T	donor_loss	1.0000
4:105399033:TCA:T	donor_loss	1.0000
4:105399034:CACCT:C	donor_loss	1.0000
4:105399036:CCTTG:C	donor_loss	1.0000
4:105399160:AATAT:A	acceptor_gain	1.0000
4:105399161:ATAT:A	acceptor_gain	1.0000
4:105399162:TAT:T	acceptor_gain	1.0000
4:105399162:TATC:T	acceptor_loss	1.0000
4:105399163:AT:A	acceptor_gain	1.0000
4:105399163:ATCTG:A	acceptor_loss	1.0000
4:105399164:TCTGT:T	acceptor_loss	1.0000
4:105399165:C:A	acceptor_loss	1.0000
4:105399165:C:CC	acceptor_gain	1.0000
4:105399166:T:A	acceptor_loss	1.0000
4:105399167:G:C	acceptor_gain	1.0000
4:105424319:GAAT:G	acceptor_gain	1.0000
4:105446503:C:CC	acceptor_gain	1.0000
4:105446513:C:CT	acceptor_gain	1.0000
4:105456544:ATGAC:A	donor_gain	1.0000
4:105460386:C:CT	donor_gain	1.0000

AlphaMissense

2217 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:105446401:A:C	N141K	0.983
4:105446401:A:T	N141K	0.983
4:105399152:A:T	V223D	0.973
4:105446406:A:G	W140R	0.972
4:105446406:A:T	W140R	0.972
4:105424247:A:G	W202R	0.968
4:105424247:A:T	W202R	0.968
4:105446425:G:C	F133L	0.968
4:105446425:G:T	F133L	0.968
4:105446427:A:G	F133L	0.968
4:105399111:A:G	W237R	0.966
4:105399111:A:T	W237R	0.966
4:105386612:G:C	S298R	0.959
4:105386612:G:T	S298R	0.959
4:105386614:T:G	S298R	0.959
4:105449370:A:G	W101R	0.958
4:105449370:A:T	W101R	0.958
4:105424234:G:T	A206D	0.957
4:105424282:C:T	G190E	0.953
4:105473898:G:C	F51L	0.953
4:105473898:G:T	F51L	0.953
4:105473900:A:G	F51L	0.953
4:105424283:C:G	G190R	0.950
4:105424283:C:T	G190R	0.950
4:105437960:A:T	I173K	0.950
4:105446479:A:C	N115K	0.949
4:105446479:A:T	N115K	0.949
4:105424282:C:A	G190V	0.948
4:105438033:A:G	W149R	0.947
4:105438033:A:T	W149R	0.947

dbSNP variants (sampled 300 via entrez): RS1000028923 (4:105409925 C>T), RS1000040393 (4:105410156 A>G), RS1000077094 (4:105369062 A>G), RS1000087287 (4:105458890 T>C,G), RS1000146911 (4:105431042 C>T), RS1000152489 (4:105372795 A>C,G), RS1000219746 (4:105422469 A>G), RS1000222181 (4:105455769 T>C), RS1000235646 (4:105437635 G>A,C), RS1000291801 (4:105422103 T>C), RS1000323495 (4:105403598 A>G), RS1000355770 (4:105464604 G>C), RS1000374686 (4:105401416 ATT>A,ATTT), RS1000407690 (4:105401858 T>G), RS1000443624 (4:105471276 G>A)

Disease associations

OMIM: gene MIM:609988 | disease phenotypes: MIM:617222, MIM:617223

GenCC curated gene-disease

Disease	Classification	Inheritance
sudden cardiac failure, infantile	Definitive	Autosomal recessive
sudden cardiac failure, alcohol-induced	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
dilated cardiomyopathy	Strong	AR

Mondo (3): sudden cardiac failure, infantile (MONDO:0014973), sudden cardiac failure, alcohol-induced (MONDO:0014974), cardiac rhythm disease (MONDO:0007263)

Orphanet (0):

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001662	Bradycardia
HP:0001685	Myocardial fibrosis
HP:0001942	Metabolic acidosis
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0011463	Childhood onset
HP:0012819	Myocarditis
HP:0100749	Chest pain

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001547_6	Immune response to anthrax vaccine	9.000000e-06
GCST001773_4	Response to antipsychotic treatment	4.000000e-07
GCST005316_612	Intelligence (MTAG)	3.000000e-16
GCST005316_613	Intelligence (MTAG)	8.000000e-10
GCST006269_1078	General cognitive ability	3.000000e-11
GCST006269_766	General cognitive ability	6.000000e-09
GCST006922_11	Regular attendance at a religious group	5.000000e-09
GCST007044_12	Extremely high intelligence	3.000000e-08
GCST007323_73	Risk-taking tendency (4-domain principal component model)	5.000000e-11
GCST007326_91	Number of sexual partners	7.000000e-13
GCST009524_117	Household income (MTAG)	2.000000e-08
GCST009524_7	Household income (MTAG)	2.000000e-10
GCST012227_1293	Hip circumference adjusted for BMI	7.000000e-10
GCST90002396_231	Mean reticulocyte volume	8.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004337	intelligence
EFO:0009592	social interaction measurement
EFO:0008579	risk-taking behaviour
EFO:0009695	household income
EFO:0008039	BMI-adjusted hip circumference
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2636697	Efficacy	3	risperidone	Schizophrenia
rs2636719	Efficacy	3	risperidone	Schizophrenia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2636697	PPA2	3	0.00	1	risperidone
rs2636719	PPA2	3	0.00	1	risperidone

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases expression, decreases methylation	4
Acetaminophen	affects cotreatment, increases expression, decreases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	increases expression	1
Cisplatin	decreases expression	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9P0	Ubigene HEK293 PPA2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00000540	PHASE3	COMPLETED	Coronary Artery Bypass Graft (CABG) Patch Trial
NCT00000556	PHASE3	COMPLETED	Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
NCT00000561	PHASE3	COMPLETED	Mode Selection Trial in Sinus Node Dysfunction (MOST)
NCT00000609	PHASE3	COMPLETED	Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)
NCT00004559	PHASE3	COMPLETED	Fatty Acid Antiarrhythmia Trial (FAAT)
NCT00004560	PHASE3	COMPLETED	Public Access Defibrillation (PAD) Community Trial
NCT00035490	PHASE3	COMPLETED	Efficacy and Safety Evaluation of Azimilide Dihydrochloride in Patients With Implantable Cardioverter Defibrillators