PDIA2

Summary

PDIA2 (protein disulfide isomerase family A member 2, HGNC:14180) is a protein-coding gene on chromosome 16p13.3, encoding Protein disulfide-isomerase A2 (Q13087). Acts as an intracellular estrogen-binding protein.

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, two catalytically active thioredoxin (TRX) domains, two TRX-like domains and a C-terminal ER-retention sequence. The protein plays a role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds through its thiol isomerase, oxidase, and reductase activity. The encoded protein also possesses estradiol-binding activity and can modulate intracellular estradiol levels.

Source: NCBI Gene 64714 — RefSeq curated summary.

At a glance

• Gene–disease (curated): aortic valve disorder (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 197 total
• Druggable target: yes
• MANE Select transcript: NM_006849

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14180
Approved symbol	PDIA2
Name	protein disulfide isomerase family A member 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	PDA2, PDI, PDIR
Ensembl gene	ENSG00000185615
Ensembl biotype	protein_coding
OMIM	608012
Entrez	64714

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000219406, ENST00000404312, ENST00000435833, ENST00000456379, ENST00000462950, ENST00000467212, ENST00000482665, ENST00000851624, ENST00000964532, ENST00000964533, ENST00000964534, ENST00000964535

RefSeq mRNA: 1 — MANE Select: NM_006849 NM_006849

CCDS: CCDS42089

Canonical transcript exons

ENST00000219406 — 11 exons

Exon	Start	End
ENSE00000663700	284387	284593
ENSE00000842163	283164	283368
ENSE00003473804	285506	285703
ENSE00003515152	285312	285437
ENSE00003528209	284878	285015
ENSE00003592861	285084	285200
ENSE00003621192	286554	286735
ENSE00003629102	284659	284792
ENSE00003645129	286353	286473
ENSE00003672486	286835	286945
ENSE00003900487	287069	287215

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 99.64.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.3988 / max 1554.8764, expressed in 113 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151892	1.3900	111
151893	0.0089	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.44	gold quality
cerebellar hemisphere	UBERON:0002245	99.34	gold quality
cerebellar cortex	UBERON:0002129	99.25	gold quality
cerebellum	UBERON:0002037	97.84	gold quality
right frontal lobe	UBERON:0002810	96.94	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.70	gold quality
anterior cingulate cortex	UBERON:0009835	94.21	gold quality
cingulate cortex	UBERON:0003027	94.15	gold quality
spinal cord	UBERON:0002240	93.03	gold quality
paraflocculus	UBERON:0005351	92.75	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.66	gold quality
pancreas	UBERON:0001264	92.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.17	gold quality
body of stomach	UBERON:0001161	91.33	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.43	gold quality
amygdala	UBERON:0001876	90.32	gold quality
cerebellar vermis	UBERON:0004720	89.41	gold quality
nucleus accumbens	UBERON:0001882	88.79	gold quality
hypothalamus	UBERON:0001898	88.64	gold quality
stomach	UBERON:0000945	88.15	gold quality
middle frontal gyrus	UBERON:0002702	86.71	gold quality
caudate nucleus	UBERON:0001873	86.56	gold quality
fundus of stomach	UBERON:0001160	86.24	gold quality
central nervous system	UBERON:0001017	85.80	gold quality
cardia of stomach	UBERON:0001162	85.60	gold quality
brain	UBERON:0000955	85.57	gold quality
Ammon’s horn	UBERON:0001954	85.53	gold quality
substantia nigra	UBERON:0002038	85.18	gold quality
putamen	UBERON:0001874	85.12	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	26.68
E-MTAB-5061	yes	19.48
E-ENAD-27	yes	6.62
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

Literature-anchored findings (GeneRIF, showing 40)

• Evidence that protein disulfide isomerase (PDI) is involved in DNA-nuclear matrix anchoring. (PMID:11968009)
• role of association with ubiquilin in the endoplasmic reticulum in stress-induced apoptotic cell death (PMID:12095988)
• dissociation of PDI from substrates observed in the presence of glutathione disulfide can be explained by competition for the peptide-binding site on PDI (PMID:12485997)
• PDI has a role in conferring resistance to apoptosis under hypoxia and a potential role in the oxygen-sensing apparatus (PMID:12766950)
• study of the principal substrate binding site of PDI (PMID:14684740)
• Protein disulphide-isomerase is responsible for the reductive separation of ricin into its A and B chains in the mammalian endoplasmic reticulum. (PMID:15225124)
• Low resolution structure of the entire PDI molecule in solution has been determined for the first time by the small angle X-ray scattering technique (PMID:16407203)
• Ero1alpha and Ero1beta are retained in the endoplasmic reticulum by interactions with PDI and ERp44 (PMID:16677073)
• PDI stabilizes a peptide-receptive site by regulating oxidation state of the disulfide bond in MHC peptide-binding groove, an essential function for selecting optimal peptides; link between thiol-based redox regulation & antigen processing established (PMID:17055437)
• These data indicate that cytosolic PDI is a substrate of caspase-3 and -7, and that it has an anti-apoptotic action. (PMID:17978580)
• Study shows that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. (PMID:18508857)
• Platelet microparticle-associated PDI promotes platelet aggregation and inactivates insulin. (PMID:18691554)
• The x region of PDI can adopt alternative conformations during the functional cycle of PDI action and that these are linked to the ability of PDI to interact with folding substrates. (PMID:18801374)
• a role for both GRP78 and PDI in insulin biosynthesis, although an excess of PDI disrupts normal proinsulin processing. (PMID:19103594)
• structures and functions of human PDIp are redox-regulated through formation of an inter-subunit disulfide bond between two cysteine-4 residues (PMID:19150607)
• the solution structure of the second and third domains of human protein disulfide isomerase (b and b’, respectively) by triple-resonance NMR spectroscopy and molecular modeling (PMID:19187238)
• PDIp can also serve as an effective modulator of the cellular levels and biological actions of endogenous estrogens in the pancreas where estrogen receptors alpha and beta and PDIp are co-present. (PMID:19429457)
• The b’ domain of PDI contributes to binding unfolded proteins; its structure is stabilized by the b domain. (PMID:19636846)
• the majority of PDI in platelets is intracellular where it is exclusively located in the dense tubular system (PMID:19805615)
• The absence of PDIp expression in pancreatic adenocarcinoma may serve as an additional biomarker for pancreatic cancer. (PMID:19821078)
• The b domain of human PDI tends to form homodimers - both in isolation and in other contexts. This tendency is moderated by the adjacent x region, which can bind to a surface patch on the b domain. (PMID:19844948)
• A haplotype within the AXIN1-PDIA2 locus (p-value of 2.926x10(-06)) and a haplotype within the Endoglin gene (p-value of 5.881x10(-04)) were found to be strongly associated with bicuspid aortic valve (PMID:20098615)
• an appropriate Ero1alpha-PDI ratio is critical for regulating the binding-release cycle of CTA1 by PDI during retro-translocation, and PDI’s redox state has a role in targeting it to the retro-translocon (PMID:20130085)
• PDI has a role in regulating tissue factor that involves FVIIa activity [review] (PMID:20163832)
• Among target genes of XBP-1, expression of protein disulfide isomerase (PDI), but not glucose- regulated protein 78 (GRP78), was increased in AD (PMID:20368688)
• Selective expression of pancreas-specific protein disulfide-isomerase confers strong protection against heat shock and oxidative-stress-induced cell death. (PMID:20423326)
• new mechanism for PDI contribution to coagulation on endothelial cells, namely, the regulation of PS exposure, where PDI acts as a negative regulator of coagulation (PMID:20448108)
• Plasticity of human protein disulfide isomerase: evidence for mobility around the X-linker region and its functional significance. (PMID:20516074)
• These results suggest that PDI could be a therapeutic target to prevent ER stress in neuronal cells in Alzheimer disease. (PMID:20550946)
• Ero1alpha is expressed on blood platelets in association with protein-disulfide isomerase and contributes to redox-controlled remodeling of alphaIIbbeta3. (PMID:20562109)
• PDI is a major target of post-streptococcal autoimmunity. (PMID:20886095)
• The hydrogen bond, formed between the 3-hydroxyl group of Estradiol (E(2)) (donor) and pancreas-specific protein disulfide isomerase’s His278 (acceptor), is indispensable for its binding. (PMID:21080683)
• PDI knockdown-induced cell death is cell-line-dependent and involves apoptosis in MCF-7 cells. (PMID:21297336)
• Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in acute myeloid leukemia. (PMID:21471526)
• Data show that diabetic patients had a greater number of transferase-mediated dUTP nick-end labeling-positive cells than nondiabetic patients despite a greater myocardial protein disulfide isomerase (PDI)expression suggesting altered PDI function. (PMID:21637911)
• the intramolecular electron transfer from the a domain to the a’ domain within PDI during its oxidation by ERO1alpha. (PMID:21757736)
• tein disulfide isomerase redox-dependent association with p47(phox): evidence for an organizer role in leukocyte NADPH oxidase activation. (PMID:21791598)
• surface-associated PDI is an important regulator of coagulation factor ligation to thrombin-stimulated platelets and of subsequent feedback activation of platelet thrombin generation (PMID:21929690)
• mechanistic insights into the redox-regulated chaperone activity of human PDI. (PMID:22090031)
• PDI exhibits unfoldase activity for proinsulin, increasing retention of proinsulin within the ER of pancreatic beta-cells (PMID:22105075)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdia2	ENSDARG00000018263
danio_rerio	pdia8	ENSDARG00000033599
danio_rerio	zgc:136472	ENSDARG00000058445
mus_musculus	Pdia2	ENSMUSG00000024184
rattus_norvegicus	Pdia2	ENSRNOG00000063310
drosophila_melanogaster	ERp60	FBGN0033663
drosophila_melanogaster	CG5554	FBGN0034914
drosophila_melanogaster	Tmx3	FBGN0036579
drosophila_melanogaster	Pdi	FBGN0286818
caenorhabditis_elegans		WBGENE00001073
caenorhabditis_elegans		WBGENE00003962
caenorhabditis_elegans		WBGENE00003963
caenorhabditis_elegans	pdi-3	WBGENE00003964
caenorhabditis_elegans	M04D5.1	WBGENE00014807
caenorhabditis_elegans	ZK973.11	WBGENE00022836

Paralogs (13): ERP44 (ENSG00000023318), PDIA5 (ENSG00000065485), TMX4 (ENSG00000125827), ERP27 (ENSG00000139055), TMX1 (ENSG00000139921), PDIA6 (ENSG00000143870), TXNDC11 (ENSG00000153066), PDIA4 (ENSG00000155660), TMX3 (ENSG00000166479), PDIA3 (ENSG00000167004), PDILT (ENSG00000169340), P4HB (ENSG00000185624), TXNDC5 (ENSG00000239264)

Protein

Protein identifiers

Protein disulfide-isomerase A2 — Q13087 (reviewed: Q13087)

Alternative names: Pancreas-specific protein disulfide isomerase

All UniProt accessions (3): Q13087, H0Y4J5, Q4TT65

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an intracellular estrogen-binding protein. May be involved in modulating cellular levels and biological functions of estrogens in the pancreas. May act as a chaperone that inhibits aggregation of misfolded proteins.

Subunit / interactions. Monomer; predominantly as monomer under reducing conditions. Homodimer; disulfide-linked. Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Highly expressed in pancreas (at protein level).

Post-translational modifications. The disulfide-linked homodimer exhibits an enhanced chaperone activity. Glycosylated.

Similarity. Belongs to the protein disulfide isomerase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13087-1	1	yes
Q13087-2	2

RefSeq proteins (1): NP_006840* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005792	Prot_disulphide_isomerase	Family
IPR013766	Thioredoxin_domain	Domain
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00085, PF13848

Enzyme classification (BRENDA):

• EC 5.3.4.1 — protein disulfide-isomerase (BRENDA: 81 organisms, 481 substrates, 347 inhibitors, 35 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
CYSTEINE	1–3	3
MYCOTHIOL-COUPLED HYDROXYETHYL DISULFIDE	0.46–33.69	3
RIBONUCLEASE	0.002–0.01	3
RNASE A	0.007–0.05	3
2-MERCAPTOETHANOL	0.2–0.8	2
DITHIOTHREITOL	0.003–0.0054	2
GSH	5–17	2
RNASE	0.028–0.063	2
SCRAMBLED RIBONUCLEASE	0.0011–0.0033	2
DENATURED-REDUCED LYSOZYME	0.0253	1
INSULIN	2.026	1
INSULIN-(SS)	0.005	1
SCRAMBLED REOXIDIZED LYSOZYME	0.0116	1
SCRAMBLED RNASE	0.02	1
SRNASE	—	0

UniProt features (37 total): sequence variant 7, site 6, active site 4, glycosylation site 3, disulfide bond 3, mutagenesis site 3, domain 2, sequence conflict 2, compositionally biased region 2, signal peptide 1, chain 1, splice variant 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13087-F1	86.97	0.73

Functional residue map

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

Catalytic / active sites (10): 418 (nucleophile); 421 (nucleophile); 72 (contributes to redox potential value); 73 (contributes to redox potential value); 138 (lowers pka of c-terminal cys of first active site); 419 (contributes to redox potential value); 420 (contributes to redox potential value); 482 (lowers pka of c-terminal cys of second active site); 71 (nucleophile); 74 (nucleophile)

Disulfide bonds (3): 18, 71–74, 418–421

Glycosylation sites (3): 127, 284, 516

Mutagenesis-validated functional residues (3):

Position	Phenotype
18	impairs interchain disulfide bridge formation.
284	increases formation of a highly stable disulfide-bonded pdia2 dimer.
364	no effect on interchain disulfide bridge formation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells

MSigDB gene sets: 0 (showing top):

GO Biological Process (5): protein folding (GO:0006457), protein retention in ER lumen (GO:0006621), protein folding in endoplasmic reticulum (GO:0034975), response to endoplasmic reticulum stress (GO:0034976), platelet aggregation (GO:0070527)

GO Molecular Function (7): protein disulfide isomerase activity (GO:0003756), steroid binding (GO:0005496), protein-disulfide reductase activity (GO:0015035), disulfide oxidoreductase activity (GO:0015036), protein binding (GO:0005515), lipid binding (GO:0008289), isomerase activity (GO:0016853)

GO Cellular Component (2): endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Cell Lineages of the Exocrine Pancreas	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity, acting on a protein	2
binding	2
cellular process	1
protein maturation	1
maintenance of protein localization in endoplasmic reticulum	1
protein folding	1
cellular response to stress	1
platelet activation	1
homotypic cell-cell adhesion	1
intramolecular oxidoreductase activity, transposing S-S bonds	1
lipid binding	1
disulfide oxidoreductase activity	1
oxidoreductase activity, acting on a sulfur group of donors	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDIA2	TXN	P10599	806
PDIA2	HSP90B1	P14625	748
PDIA2	ERO1B	Q86YB8	708
PDIA2	DNAJB11	Q9UBS4	695
PDIA2	PDIA4	P13667	632
PDIA2	TMX2	Q9Y320	512
PDIA2	TXNDC12	O95881	511
PDIA2	HSPA5	P11021	509
PDIA2	ERP29	P30040	507
PDIA2	TMX4	Q9H1E5	500
PDIA2	CNDP2	Q96KP4	471
PDIA2	INS	P01308	466
PDIA2	HYOU1	Q9Y4L1	458
PDIA2	AGR3	Q8TD06	448
PDIA2	UGT1A10	Q9HAW8	439

IntAct

19 interactions, top by confidence:

A	B	Type	Score
PDIA2	KRTAP6-1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-1	PDIA2	psi-mi:“MI:0915”(physical association)	0.560
PDIA2	ABL1	psi-mi:“MI:0915”(physical association)	0.400
CRK	PDIA2	psi-mi:“MI:0915”(physical association)	0.400
SRC	PDIA2	psi-mi:“MI:0915”(physical association)	0.400
FYN	PDIA2	psi-mi:“MI:0915”(physical association)	0.400
GRB2	PDIA2	psi-mi:“MI:0915”(physical association)	0.400
PDIA2	NCK1	psi-mi:“MI:0915”(physical association)	0.400
PIK3R1	PDIA2	psi-mi:“MI:0915”(physical association)	0.400
PDIA2	PLCG1	psi-mi:“MI:0915”(physical association)	0.400
PDIA2	P4HB	psi-mi:“MI:0403”(colocalization)	0.270
CALR	PDIA2	psi-mi:“MI:0403”(colocalization)	0.270
KRTAP6-1	PDIA2	psi-mi:“MI:0915”(physical association)	0.000
KRTAP12-1	PDIA2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): PDIA2 (Reconstituted Complex), ERO1L (Affinity Capture-Western), MTTP (Affinity Capture-Western), PDIA2 (Reconstituted Complex), PDIA2 (Affinity Capture-Western), PDIA2 (Affinity Capture-Western), P4HA3 (Affinity Capture-Western), MAPT (Reconstituted Complex), ACTB (Affinity Capture-Western), PDIA2 (Affinity Capture-Western), ACTB (Co-localization), PDIA2 (FRET), ACTB (Reconstituted Complex), PDIA2 (Two-hybrid), KRTAP12-1 (Two-hybrid)

ESM2 similar proteins: A5PK19, A6QLU8, D3Z6P0, D3ZAA9, P00435, P04041, P09102, P11352, P11909, P21195, P22352, P23764, P37141, P38660, P46412, P47823, P97346, Q08602, Q13087, Q13144, Q14168, Q148E0, Q15084, Q4AEH3, Q4AEH4, Q4AEH5, Q503L9, Q58E26, Q5CZL1, Q5R6T1, Q5RCH2, Q5RFG3, Q5RGJ5, Q5VZ03, Q63081, Q64350, Q6DKJ4, Q6GM16, Q6IQS6, Q8CHW4

Diamond homologs: A0A8M1N5Y4, A3KPF5, D4B2L8, O13704, O13811, O22022, O22263, O48773, O83889, P05307, P07591, P07887, P08003, P09103, P0A4L1, P0A4L2, P0AGG4, P0AGG5, P0AGG6, P0AGG7, P11598, P12243, P12865, P13667, P17967, P21195, P23400, P27773, P30101, P33791, P34329, P37395, P38657, P38658, P38659, P38660, P38661, P46843, P50254, P50338

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 12 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Downstream signal transduction	6	190.3×	6e-11
FCGR3A-mediated phagocytosis	6	93.6×	3e-09
VEGFA-VEGFR2 Pathway	5	58.0×	9e-07

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	5	156.3×	3e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	163
Likely benign	19
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1619 predictions. Top by Δscore:

Variant	Effect	Δscore
16:283364:ATTCT:A	donor_gain	1.0000
16:283365:TTCT:T	donor_gain	1.0000
16:283365:TTCTG:T	donor_loss	1.0000
16:283366:TCT:T	donor_gain	1.0000
16:283366:TCTG:T	donor_loss	1.0000
16:283367:CT:C	donor_gain	1.0000
16:283367:CTG:C	donor_loss	1.0000
16:283368:TG:T	donor_loss	1.0000
16:283369:G:GG	donor_gain	1.0000
16:283369:GTGA:G	donor_loss	1.0000
16:285082:A:AG	acceptor_gain	1.0000
16:285083:G:GG	acceptor_gain	1.0000
16:285196:GCCAG:G	donor_gain	1.0000
16:285310:A:AG	acceptor_gain	1.0000
16:285311:G:GA	acceptor_gain	1.0000
16:285311:GAC:G	acceptor_gain	1.0000
16:285389:G:GT	donor_gain	1.0000
16:285411:G:GT	donor_gain	1.0000
16:285411:G:T	donor_gain	1.0000
16:285500:CCACA:C	acceptor_loss	1.0000
16:285501:CACAG:C	acceptor_loss	1.0000
16:285502:ACAGG:A	acceptor_loss	1.0000
16:285503:CAGG:C	acceptor_loss	1.0000
16:285504:A:AT	acceptor_loss	1.0000
16:285619:G:GT	donor_gain	1.0000
16:285619:GAA:G	donor_gain	1.0000
16:285622:G:GG	donor_gain	1.0000
16:285728:G:GT	donor_gain	1.0000
16:285729:A:T	donor_gain	1.0000
16:286469:GTTCT:G	donor_gain	1.0000

AlphaMissense

3409 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:286644:C:A	A444D	0.987
16:286465:T:A	V411D	0.986
16:286595:T:A	W428R	0.981
16:286595:T:C	W428R	0.981
16:286694:T:C	F461L	0.980
16:286696:C:A	F461L	0.980
16:286696:C:G	F461L	0.980
16:286880:T:C	F490L	0.980
16:286882:C:A	F490L	0.980
16:286882:C:G	F490L	0.980
16:283365:T:C	F66L	0.974
16:283367:C:A	F66L	0.974
16:283367:C:G	F66L	0.974
16:286881:T:C	F490S	0.972
16:286411:T:A	L393H	0.971
16:285189:T:C	F262L	0.970
16:285191:C:A	F262L	0.970
16:285191:C:G	F262L	0.970
16:286576:C:G	C421W	0.970
16:286597:G:C	W428C	0.970
16:286597:G:T	W428C	0.970
16:286666:C:A	N451K	0.969
16:286666:C:G	N451K	0.969
16:286575:G:A	C421Y	0.968
16:286462:T:C	F410S	0.967
16:286641:T:A	I443N	0.967
16:286565:T:C	C418R	0.966
16:285360:T:C	F282L	0.963
16:285362:T:A	F282L	0.963
16:285362:T:G	F282L	0.963

dbSNP variants (sampled 300 via entrez): RS1000753876 (16:286714 C>T), RS1001017192 (16:282190 G>A), RS1001040478 (16:283963 C>A), RS1001384375 (16:284228 G>A), RS1001436720 (16:284110 T>C,G), RS1001771949 (16:286730 CGGAAGGTAT>C), RS1002391994 (16:283647 C>T), RS1002735731 (16:287524 A>G), RS1002788657 (16:286675 T>C), RS1003087839 (16:284416 C>A,T), RS1004847941 (16:282059 G>A), RS1005671937 (16:281531 C>A,T), RS1005731081 (16:287697 C>T), RS1006683948 (16:287107 A>G), RS1006944293 (16:284223 C>T)

Disease associations

OMIM: gene MIM:608012 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
aortic valve disorder	Limited	Autosomal dominant

Mondo (1): aortic valve disorder (MONDO:0003803)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005951_12	Body mass index	5.000000e-11
GCST90002390_636	Mean corpuscular hemoglobin	2.000000e-53
GCST90002391_166	Mean corpuscular hemoglobin concentration	3.000000e-23
GCST90002392_482	Mean corpuscular volume	4.000000e-44
GCST90002397_226	Mean spheric corpuscular volume	9.000000e-12
GCST90002403_661	Red blood cell count	5.000000e-20

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739853 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1048786	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1048786	PDIA2	3	0.00	1	methylphenidate

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
OTX015	decreases expression	1
sodium arsenite	decreases expression	1
lactacystin	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	decreases expression	1
Ascorbic Acid	decreases expression	1
Cadmium	decreases expression	1
Chlorpromazine	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	decreases expression	1
Malathion	decreases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4729812	ADMET	Inhibition of PDIA2 (unknown origin) at 40 uM using bovine insulin as substrate preincubated for 1 hr followed by substrate addition	Characterization of Aminobenzylphenols as Protein Disulfide Isomerase Inhibitors in Glioblastoma Cell Lines. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TC73	HAP1 PDIA2 (-) 1	Cancer cell line	Male
CVCL_XR48	HAP1 PDIA2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01536717	PHASE4	SUSPENDED	Comparison of the Local Anaesthetics Articaine and Bupivacaine in Treatment of Acute Sternum Pain After Heart Surgery
NCT01559298	PHASE4	COMPLETED	Aspirin Versus Aspirin + ClopidogRel Following Transcatheter Aortic Valve Implantation: the ARTE Trial
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02247128	PHASE4	COMPLETED	Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation
NCT02640794	PHASE4	COMPLETED	Aspirin Versus Aspirin+Clopidogrel as Antithrombotic Treatment Following TAVI
NCT03121053	PHASE4	UNKNOWN	Preventing contrAst Induced Nephropathy After TranscathEter Aortic Valve Replacement
NCT03807921	PHASE4	COMPLETED	Anticoagulation for Aortic Bioprosthesis (ANTIPRO)
NCT04437303	PHASE4	COMPLETED	Periprocedural Continuation Versus Interruption of Oral Anticoagulant Drugs During Transcatheter Aortic Valve Implantation (POPular PAUSE TAVI)
NCT05076604	PHASE4	COMPLETED	Effects of Microplegia on Transfusion Rates After Cardiac Surgery
NCT06235424	PHASE4	UNKNOWN	Del Nido Versus HTK Cardioplegia in Adult Aortic Valve Replacement
NCT02098772	PHASE3	COMPLETED	Phase III Study Comparing Two Methods of Cardioplegia in Aortic Valve Surgery Custodiol-N Versus Custodiol
NCT04142658	PHASE3	TERMINATED	PROACT Xa - A Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely on Apixaban
NCT05162742	PHASE3	ACTIVE_NOT_RECRUITING	Colchicine and Inflammation in Aortic Stenosis
NCT05687448	PHASE3	NOT_YET_RECRUITING	DIrect Oral Anticoagulation and Bioprothesis Aortic Valve
NCT02128841	PHASE2	TERMINATED	Comparison of Antithrombotic Treatments After Aortic Valve Replacement. Rivaroxaban: A New Antithrombotic Treatment for Patients With Mechanical Prosthetic Aortic Heart Valve.
NCT03163329	PHASE2	UNKNOWN	The Safety and Effectiveness of Transcatheter Aortic Valve Raplacemet in Intermediate Risk Patients With Bicuspid Aortic Stenosis
NCT03305536	PHASE2	UNKNOWN	Decalcification of the Aortic Valve by Vitamin K2 (Menaquinone-7)
NCT07027670	PHASE2	COMPLETED	Treatment With 5-AminoLEvuliNic Acid Before Cardiac Surgery
NCT00257777	Not specified	COMPLETED	Intermittent Cold Blood vs Crystalloid Cardioplegia in Aortic Valve Surgery
NCT00465218	Not specified	COMPLETED	Transcranial Doppler (TCD) Assessment During Early Anti-thrombotic Therapy After Bioprosthetic Aortic Valve Replacement
NCT00486928	Not specified	COMPLETED	Twenty-five-year Experience With the Medtronic-Hall Valve Prosthesis
NCT00590889	Not specified	TERMINATED	Artificial Valve Endocarditis Reduction Trial
NCT00619151	Not specified	TERMINATED	CarboMedics Top Hat vs St. Jude Medical Regent Valve Comparing Sizing and Hemodynamics
NCT00665301	Not specified	COMPLETED	Cardiac Output Pulmonary Arterial Catheter Compared to FloWave™ 1000
NCT00677638	Not specified	UNKNOWN	Transapical Implantation of Ventor Embracer™ Valve in Patients With Severe Aortic Valve Disease
NCT00705913	Not specified	TERMINATED	Randomized Sizing and Hemodynamic Study Mitroflow vs. Magna
NCT00708409	Not specified	UNKNOWN	Long-Term Follow-up After the Autograft Aortic Valve Procedure (Ross Operation)
NCT00883285	Not specified	COMPLETED	Incidence and Severity of Silent and Apparent Cerebral Embolism After Conventional and Minimal-invasive Transfemoral Aortic Valve Replacement
NCT00934596	Not specified	COMPLETED	CO2 Versus Lund De-airing Technique in Heart Surgery
NCT01171625	Not specified	COMPLETED	Carpentier-Edwards PERIMOUNT Magna Ease Pericardial Bioprosthesis, Model 3300TFX
NCT01194362	Not specified	COMPLETED	A Study to Identify Differences in Gene Expression in Patients With Bicuspid and Tricuspid Valve Disease
NCT01256710	Not specified	TERMINATED	Trifecta™ Durability Study
NCT01281397	Not specified	TERMINATED	Bleeding Prediction in Patients Following Cardiac Surgery Using Whole Blood Aggregometry and Thromboelastometry
NCT01293188	Not specified	COMPLETED	Observatory of Anticoagulation After Bioprosthetic Aortic Valve Replacement
NCT01353287	Not specified	COMPLETED	Transcatheter Aortic Valve Intervention-Live Transmission
NCT01383720	Not specified	COMPLETED	REpositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus™ Valve SystEm
NCT01631188	Not specified	TERMINATED	Use of Transvenous Pacing Wire During Minimally Invasive Port Access Aortic Valve Surgery
NCT01651052	Not specified	COMPLETED	Clinical Trial of the Edwards Aortic Bioprosthesis, Model 11000
NCT01808274	Not specified	COMPLETED	Safety and Performance Study of the Edwards CENTERA Self-Expanding Transcatheter Heart Valve
NCT01808287	Not specified	COMPLETED	Safety and Performance Study of the Edwards SAPIEN 3 Transcatheter Heart Valve/ The SAPIEN 3 Study