PDIA6

Summary

PDIA6 (protein disulfide isomerase family A member 6, HGNC:30168) is a protein-coding gene on chromosome 2p25.1, encoding Protein disulfide-isomerase A6 (Q15084). May function as a chaperone that inhibits aggregation of misfolded proteins.

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, a TRX-like domain, and a C-terminal ER-retention sequence. This protein inhibits the aggregation of misfolded proteins and exhibits both isomerase and chaperone activity. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 10130 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple congenital anomalies/dysmorphic syndrome (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 75 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005742

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30168
Approved symbol	PDIA6
Name	protein disulfide isomerase family A member 6
Location	2p25.1
Locus type	gene with protein product
Status	Approved
Aliases	P5, ERp5
Ensembl gene	ENSG00000143870
Ensembl biotype	protein_coding
OMIM	611099
Entrez	10130

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 18 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000272227, ENST00000381611, ENST00000404371, ENST00000404824, ENST00000458536, ENST00000489662, ENST00000540494, ENST00000617249, ENST00000852337, ENST00000852338, ENST00000852339, ENST00000852340, ENST00000852341, ENST00000921616, ENST00000921617, ENST00000921618, ENST00000921619, ENST00000960556, ENST00000960557

RefSeq mRNA: 5 — MANE Select: NM_005742 NM_001282704, NM_001282705, NM_001282706, NM_001282707, NM_005742

CCDS: CCDS1675, CCDS62852, CCDS62853, CCDS62854, CCDS62855

Canonical transcript exons

ENST00000272227 — 13 exons

Exon	Start	End
ENSE00000962412	10797081	10797207
ENSE00000962413	10793096	10793202
ENSE00000962414	10791795	10791925
ENSE00000962415	10790719	10790833
ENSE00000962416	10789749	10789889
ENSE00000962418	10788897	10788981
ENSE00000962419	10788697	10788769
ENSE00000962420	10787281	10787439
ENSE00000962421	10784934	10785030
ENSE00001401250	10812678	10812785
ENSE00001893291	10783391	10784326
ENSE00003543476	10802499	10802640
ENSE00003685509	10797700	10797757

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 114.3858 / max 797.5544, expressed in 1826 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26885	92.4472	1823
26886	20.8599	1809
26883	0.8593	525
26888	0.1127	41
26887	0.0612	21
26889	0.0396	21
26890	0.0057	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.62	gold quality
adrenal tissue	UBERON:0018303	99.20	gold quality
islet of Langerhans	UBERON:0000006	99.19	gold quality
caput epididymis	UBERON:0004358	99.06	gold quality
stromal cell of endometrium	CL:0002255	99.01	gold quality
endometrium	UBERON:0001295	98.98	gold quality
body of pancreas	UBERON:0001150	98.96	gold quality
esophagus squamous epithelium	UBERON:0006920	98.83	gold quality
pancreas	UBERON:0001264	98.82	gold quality
smooth muscle tissue	UBERON:0001135	98.73	gold quality
germinal epithelium of ovary	UBERON:0001304	98.72	gold quality
rectum	UBERON:0001052	98.70	gold quality
tibia	UBERON:0000979	98.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.68	gold quality
cauda epididymis	UBERON:0004360	98.67	gold quality
parotid gland	UBERON:0001831	98.61	gold quality
pancreatic ductal cell	CL:0002079	98.58	gold quality
epithelial cell of pancreas	CL:0000083	98.54	gold quality
right lobe of thyroid gland	UBERON:0001119	98.53	gold quality
epithelium of nasopharynx	UBERON:0001951	98.52	gold quality
colonic mucosa	UBERON:0000317	98.44	gold quality
ventricular zone	UBERON:0003053	98.43	gold quality
vermiform appendix	UBERON:0001154	98.38	gold quality
left lobe of thyroid gland	UBERON:0001120	98.37	gold quality
thyroid gland	UBERON:0002046	98.35	gold quality
renal glomerulus	UBERON:0000074	98.23	gold quality
placenta	UBERON:0001987	98.23	gold quality
pylorus	UBERON:0001166	98.22	gold quality
epithelium of esophagus	UBERON:0001976	98.19	gold quality
mucosa of transverse colon	UBERON:0004991	98.19	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	113.51
E-MTAB-9467	yes	61.20
E-HCAD-4	yes	55.09
E-HCAD-1	yes	49.38
E-CURD-122	yes	45.38
E-CURD-46	yes	39.40
E-MTAB-8410	yes	33.12
E-HCAD-9	yes	20.01
E-MTAB-9067	yes	17.42
E-GEOD-93593	yes	16.44
E-MTAB-10042	yes	13.54
E-MTAB-10553	yes	9.68
E-CURD-112	yes	7.97
E-MTAB-9388	no	2842.07
E-MTAB-6379	no	2128.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, YY1

miRNA regulators (miRDB)

80 targeting PDIA6, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4698	99.84	71.41	4303
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-4307	99.82	70.45	3374
HSA-MIR-4420	99.82	70.08	1624

Literature-anchored findings (GeneRIF, showing 29)

• observed to have peptide-binding ability, and chaperone activity was confirmed with rhodanese and citrate synthase as substrates, but not with D-glyceraldehyde-3-phosphate dehydrogenase, showing substrate specificity with respect to chaperone activity (PMID:12204115)
• ERP5 regulates the binding of fibrinogen, cell-surface exposure of P-selectin, and coassociation of beta 3 integrin in stimulated platelets. (PMID:15466936)
• Pharmacological inhibition of thioreductase activity and ERp5 gene silencing revealed that cell-surface ERp5 function is required for MICA shedding (PMID:17495932)
• P5 forms a non-covalent complex with immunoglobulin heavy chain binding protein (BiP) and shows specificity towards BiP client proteins. (PMID:19887585)
• Data show that the lymph node (LN) stroma displayed in situ high levels of transcription and expression of the disulfide-isomerase ERp5 and of the disintegrin-metalloproteinase ADAM10, able to shed the ligands for NKG2D (NKG2D-L) from the cell membrane. (PMID:22167753)
• levels of expression of ERp5 and GRP78 correlated with the level of expression of membrane-bound MICA in chronic lymphocytic leukemia patients. (PMID:22215138)
• CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6. (PMID:24464223)
• Txnip is located in the endoplasmic reticulum and interacts with endogenous PDIA6. Txnip increases PDI activity. (PMID:24843047)
• PDIA3 and PDIA6 gene expression is a neoplasm aggressiveness marker in primary ductal breast cancer. (PMID:26125904)
• Restoration of miR-127-3p and miR-376a-3p counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells by targeting COA1, GLE1 and PDIA6. (PMID:26655997)
• ACE and PDIA6 were identified as potential HSPA2-interacting proteins; this assemblage resides in membrane raft microdomains located in the peri-acrosomal region of the sperm head. (PMID:26676989)
• The results of this study suggest that PDIA6 is an important component of EGFR-mediated migration and invasion of U87MG cells. (PMID:27540907)
• Downregulation of PDIA6 inhibited BC cell proliferation and invasion in vitro as well as tumor growth and metastasis in vivo. In addition, PDIA6 downregulation suppressed the Wnt/beta-catenin signaling pathway. (PMID:27760590)
• Results indicate that re-expression of miR-127-3p and miR-376a-3p induces a strong tumor suppressor effect in GCTSC, which is partially mediated via COA1 and PDIA6. (PMID:28866093)
• the chaperone 78-kDa glucose-regulated protein (GRP78) protects the MPD against PDI-dependent disulfide-bond isomerization by binding to this domain and, thereby, preventing ADAM17 inhibition. (PMID:28949004)
• ERp5 triggers fibrinogen dissociation from aIIbb3 integrin. (PMID:29932420)
• Study reported for the first time that one of the proteins that binds to P5 in U251 glioblastoma cells is vimentin, and the present findings indicated that P5 may be an attractive target for novel molecular targeted therapy of glioblastoma. (PMID:30431130)
• PDIA6 is overexpressed in NSCLC and inhibits cisplatin-induced NSCLC cell apoptosis and autophagy via the MAP4K1/JNK/c-Jun signaling pathway, suggesting that PDIA6 may serve as a biomarker and therapeutic target for NSCLC patients. (PMID:30922965)
• The cell surface trafficking of PDIA1, PDIA3, and PDIA6 is dependent on KDELR1, which travels in a dynamic manner to the cell surface. This transport is assumed to result in PDI cell surface association, which differs from PDI inducible secretion into the extracellular space. (PMID:30958660)
• One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the genome-wide association study (GWAS). (PMID:31230729)
• Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes. (PMID:33495992)
• PDIA6 contributes to aerobic glycolysis and cancer progression in oral squamous cell carcinoma. (PMID:33761940)
• PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of beta-catenin and PD-L1. (PMID:34325342)
• Protein disulfide isomerase family 6 promotes the imatinib-resistance of renal cell carcinoma by regulation of Wnt3a-Frizzled1 axis. (PMID:34781823)
• Melanoma RBPome identification reveals PDIA6 as an unconventional RNA-binding protein involved in metastasis. (PMID:35848924)
• Downregulated miR-181a alleviates H2O2-induced oxidative stress and cellular senescence by targeting PDIA6 in human foreskin fibroblasts. (PMID:36244946)
• PDIA6, which is regulated by TRPM2-AS/miR-424-5p axis, promotes endometrial cancer progression via TGF-beta pathway. (PMID:38097564)
• The SOX2/PDIA6 axis mediates aerobic glycolysis to promote stemness in non-small cell lung cancer cells. (PMID:38441855)
• Increased ER stress by depletion of PDIA6 impairs primary ciliogenesis and enhances sensitivity to ferroptosis in kidney cells. (PMID:39044457)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdia6	ENSDARG00000009001
mus_musculus	Pdia6	ENSMUSG00000020571
rattus_norvegicus	Pdia6	ENSRNOG00000050197
drosophila_melanogaster	CaBP1	FBGN0025678
caenorhabditis_elegans		WBGENE00015168

Paralogs (13): ERP44 (ENSG00000023318), PDIA5 (ENSG00000065485), TMX4 (ENSG00000125827), ERP27 (ENSG00000139055), TMX1 (ENSG00000139921), TXNDC11 (ENSG00000153066), PDIA4 (ENSG00000155660), TMX3 (ENSG00000166479), PDIA3 (ENSG00000167004), PDILT (ENSG00000169340), PDIA2 (ENSG00000185615), P4HB (ENSG00000185624), TXNDC5 (ENSG00000239264)

Protein

Protein identifiers

Protein disulfide-isomerase A6 — Q15084 (reviewed: Q15084)

Alternative names: Endoplasmic reticulum protein 5, Protein disulfide isomerase P5, Thioredoxin domain-containing protein 7

All UniProt accessions (3): Q15084, A0A384NPU5, C9JNG5

UniProt curated annotations — full annotation on UniProt →

Function. May function as a chaperone that inhibits aggregation of misfolded proteins. Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling. May also regulate the UPR via the EIF2AK3 UPR sensor. Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin.

Subunit / interactions. 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. Interacts with MICA on the surface of tumor cells, leading to MICA disulfide bond reduction which is required for its release from tumor cells. Interacts with ITGB3 following platelet stimulation. Interacts with ERN1; the interaction is direct. Interacts with EIF2AK3.

Subcellular location. Endoplasmic reticulum lumen. Cell membrane. Melanosome.

Tissue specificity. Expressed in platelets (at protein level).

Similarity. Belongs to the protein disulfide isomerase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q15084-1	1	yes
Q15084-2	2
Q15084-3	3
Q15084-4	4
Q15084-5	5

RefSeq proteins (5): NP_001269633, NP_001269634, NP_001269635, NP_001269636, NP_005733* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005788	PDI_thioredoxin-like_dom	Domain
IPR013766	Thioredoxin_domain	Domain
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR057305	Thioredox_PDIA6_C	Domain

Pfam: PF00085, PF24541

UniProt features (73 total): helix 15, strand 14, turn 8, site 6, mutagenesis site 6, active site 4, modified residue 4, splice variant 4, domain 2, disulfide bond 2, sequence conflict 2, signal peptide 1, chain 1, sequence variant 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4EF0	X-RAY DIFFRACTION	1.5
8CPQ	X-RAY DIFFRACTION	1.8
4GWR	X-RAY DIFFRACTION	1.81
3VWW	X-RAY DIFFRACTION	1.93
3W8J	X-RAY DIFFRACTION	2.1
1X5D	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15084-F1	87.20	0.66

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): 193 (nucleophile); 56 (contributes to redox potential value); 57 (contributes to redox potential value); 118 (lowers pka of c-terminal cys of first active site); 191 (contributes to redox potential value); 192 (contributes to redox potential value); 256 (lowers pka of c-terminal cys of second active site); 55 (nucleophile); 58 (nucleophile); 190 (nucleophile)

Post-translational modifications (4): 129, 156, 158, 428

Disulfide bonds (2): 55–58, 190–193

Mutagenesis-validated functional residues (6):

Position	Phenotype
55	50% decrease in enzyme activity; when associated with s-58. abolishes enzyme activity; when associated with s-58; s-190
58	accelerates dephosphorylation of ern1; when associated with a-193.
58	50% decrease in enzyme activity; when associated with s-55. 90% decrease in enzyme activity; when associated with s-193.
190	25% decrease in enzyme activity; when associated with s-193. abolishes enzyme activity; when associated with s-55; s-58
193	accelerates dephosphorylation of ern1; when associated with a-58.
193	90% decrease in enzyme activity; when associated with s-58. 25% decrease in enzyme activity; when associated with s-190.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation

MSigDB gene sets: 257 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, MORF_DNMT1, chr2p25, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, MORF_HDAC1, MORF_UBE2N, GOBP_PROTEIN_MATURATION, MORF_BUB3, DAZARD_RESPONSE_TO_UV_SCC_UP, LASTOWSKA_COAMPLIFIED_WITH_MYCN, GOBP_PROTEIN_FOLDING, GARY_CD5_TARGETS_DN

GO Biological Process (2): protein folding (GO:0006457), response to endoplasmic reticulum stress (GO:0034976)

GO Molecular Function (4): protein disulfide isomerase activity (GO:0003756), protein-disulfide reductase activity (GO:0015035), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (13): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), plasma membrane (GO:0005886), cilium (GO:0005929), centriolar satellite (GO:0034451), endoplasmic reticulum chaperone complex (GO:0034663), ciliary basal body (GO:0036064), melanosome (GO:0042470), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
IRE1alpha activates chaperones	1
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity, acting on a protein	2
cytoplasm	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cellular process	1
protein maturation	1
cellular response to stress	1
intramolecular oxidoreductase activity, transposing S-S bonds	1
disulfide oxidoreductase activity	1
binding	1
catalytic activity	1
endomembrane system	1
endoplasmic reticulum	1
intracellular organelle lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
centrosome	1
endoplasmic reticulum protein-containing complex	1
microtubule organizing center	1
cilium	1
pigment granule	1
extracellular vesicle	1

Protein interactions and networks

STRING

2798 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDIA6	HSPA5	P11021	836
PDIA6	MICB	P79525	819
PDIA6	HSP90B1	P14625	810
PDIA6	CS	O75390	788
PDIA6	HYOU1	Q9Y4L1	755
PDIA6	EIF2AK3	Q9NZJ5	751
PDIA6	TXN	P10599	744
PDIA6	DNAJB11	Q9UBS4	737
PDIA6	RRM2	P31350	717
PDIA6	CALR	P27797	712
PDIA6	ERN1	O75460	707
PDIA6	PDIA3	P30101	692
PDIA6	PPIB	P23284	685
PDIA6	KLRK1	P26718	667
PDIA6	DNAJC3	Q13217	617

IntAct

226 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
PDIA6	HSPA5	psi-mi:“MI:0915”(physical association)	0.560
SGTB	PDIA6	psi-mi:“MI:0915”(physical association)	0.560
GET3	PDIA6	psi-mi:“MI:0915”(physical association)	0.560
PDIA6	SGTB	psi-mi:“MI:0915”(physical association)	0.560
APP	PDIA6	psi-mi:“MI:0915”(physical association)	0.560
PDIA6	TXNRD1	psi-mi:“MI:0914”(association)	0.560
TXNRD1	PDIA6	psi-mi:“MI:0915”(physical association)	0.560
MTNR1A	PGRMC1	psi-mi:“MI:0914”(association)	0.530
MTNR1B	IRS4	psi-mi:“MI:0914”(association)	0.530

BioGRID (432): PDIA6 (Affinity Capture-MS), PDIA6 (Affinity Capture-MS), PDIA6 (Affinity Capture-MS), PDIA6 (Affinity Capture-MS), VWA1 (Affinity Capture-MS), PLS1 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), CCDC102A (Affinity Capture-MS), TXNRD1 (Affinity Capture-MS), BTBD9 (Affinity Capture-MS), HNRNPLL (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), ZHX3 (Affinity Capture-MS), JMJD8 (Affinity Capture-MS), PDIA6 (Reconstituted Complex)

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

3 interactions.

A	Effect	B	Mechanism
PDIA6	“up-regulates activity”	Metastasis
PDIA6	“down-regulates activity”	ERN1
PDIA6	“down-regulates activity”	EIF2AK3

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 219 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
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	5	21.8×	7e-04
mRNA stabilization	6	11.4×	3e-03
autophagosome maturation	6	10.9×	3e-03
mitophagy	6	9.9×	4e-03
autophagosome assembly	8	9.3×	7e-04
mitochondrion organization	10	7.9×	3e-04
response to endoplasmic reticulum stress	8	6.9×	3e-03
positive regulation of cell migration	14	4.5×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	54
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1723893	NM_005742.4(PDIA6):c.702del (p.Arg235fs)	Likely pathogenic

SpliceAI

1829 predictions. Top by Δscore:

Variant	Effect	Δscore
2:10787276:ATTAC:A	donor_loss	1.0000
2:10787277:TTACC:T	donor_loss	1.0000
2:10787279:A:AC	donor_gain	1.0000
2:10787279:A:AT	donor_loss	1.0000
2:10787280:C:CC	donor_gain	1.0000
2:10787280:C:CG	donor_loss	1.0000
2:10787436:CCAC:C	acceptor_gain	1.0000
2:10787437:CAC:C	acceptor_gain	1.0000
2:10787437:CACC:C	acceptor_gain	1.0000
2:10787440:C:CC	acceptor_gain	1.0000
2:10787441:T:G	acceptor_loss	1.0000
2:10788891:TCTTA:T	donor_loss	1.0000
2:10788892:CTTAC:C	donor_loss	1.0000
2:10788893:TTA:T	donor_loss	1.0000
2:10788894:TA:T	donor_loss	1.0000
2:10788895:A:AC	donor_gain	1.0000
2:10788896:C:CA	donor_loss	1.0000
2:10788896:C:CC	donor_gain	1.0000
2:10788977:ATAAT:A	acceptor_gain	1.0000
2:10788978:TAAT:T	acceptor_gain	1.0000
2:10788979:AAT:A	acceptor_gain	1.0000
2:10788979:AATC:A	acceptor_loss	1.0000
2:10788980:AT:A	acceptor_gain	1.0000
2:10788981:TCTGT:T	acceptor_loss	1.0000
2:10788982:C:CC	acceptor_gain	1.0000
2:10788982:CT:C	acceptor_loss	1.0000
2:10788983:T:A	acceptor_loss	1.0000
2:10788984:G:C	acceptor_gain	1.0000
2:10788991:C:CT	acceptor_gain	1.0000
2:10788992:C:CT	acceptor_gain	1.0000

AlphaMissense

2878 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:10784952:C:A	W412C	1.000
2:10784952:C:G	W412C	1.000
2:10784954:A:G	W412R	1.000
2:10784954:A:T	W412R	1.000
2:10787284:A:G	L385P	1.000
2:10787356:G:T	A361D	1.000
2:10787368:G:T	P357H	1.000
2:10788701:A:G	W332R	1.000
2:10788701:A:T	W332R	1.000
2:10788932:C:T	C297Y	1.000
2:10788933:A:G	C297R	1.000
2:10789876:G:T	P238H	1.000
2:10789877:G:A	P238S	1.000
2:10790818:C:A	W200C	1.000
2:10790818:C:G	W200C	1.000
2:10790820:A:G	W200R	1.000
2:10790820:A:T	W200R	1.000
2:10790831:A:G	L196P	1.000
2:10791800:G:C	C193W	1.000
2:10791801:C:A	C193F	1.000
2:10791801:C:T	C193Y	1.000
2:10791802:A:G	C193R	1.000
2:10791810:C:A	C190F	1.000
2:10791810:C:T	C190Y	1.000
2:10791811:A:G	C190R	1.000
2:10791812:C:A	W189C	1.000
2:10791812:C:G	W189C	1.000
2:10791814:A:G	W189R	1.000
2:10791814:A:T	W189R	1.000
2:10791831:A:T	V183D	1.000

dbSNP variants (sampled 300 via entrez): RS1000017519 (2:10793501 G>A), RS1000055335 (2:10808054 C>A,G,T), RS1000073764 (2:10832578 C>T), RS1000083670 (2:10787920 G>A), RS1000282763 (2:10816446 A>G), RS1000301087 (2:10793214 G>A,C,T), RS1000327316 (2:10807256 T>C), RS1000348315 (2:10822401 T>A), RS1000423339 (2:10832318 G>A,T), RS1000533152 (2:10787725 G>T), RS1000554546 (2:10812924 G>A), RS1000555586 (2:10812800 C>A,G), RS1000603496 (2:10799185 T>C), RS1000662697 (2:10806579 A>G), RS1000709491 (2:10804192 G>T)

Disease associations

OMIM: gene MIM:611099 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple congenital anomalies/dysmorphic syndrome	Strong	Autosomal recessive

Mondo (1): multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006585_2708	Blood protein levels	3.000000e-06
GCST008595_21	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	2.000000e-08
GCST009267_18	Dental caries (decayed, missing and filled teeth)	4.000000e-06
GCST009268_1	Dental caries (decayed, missing and filled tooth surfaces)	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2146308 (SINGLE PROTEIN)

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 10 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.20	Kd	62.57	nM	CHEMBL5653589
7.20	ED50	62.57	nM	CHEMBL5653589
6.29	AC50	513	nM	CHEMBL1325945
5.83	AC50	1490	nM	CHEMBL1463659
5.24	IC50	5700	nM	CHEMBL4751979
5.15	IC50	7100	nM	CHEMBL6146042

PubChem BioAssay actives

2 with measured affinity, of 11 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148966: Binding affinity to human PDIA6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0626	uM
(1E)-1-nonylidene-3-(trifluoromethyl)indene-5,6-diol	1687771: Inhibition of PDIA6 (unknown origin) expressed in Escherichia coli BL21 (DE3) incubated for 1 hr and measured by insulin reduction assay	ic50	5.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	6
Tunicamycin	increases expression	5
Cyclosporine	increases expression	4
Tobacco Smoke Pollution	affects expression, increases expression, increases metabolic processing	3
Valproic Acid	increases methylation, affects expression, increases expression	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
cobaltous chloride	decreases expression	2
Benzo(a)pyrene	increases expression, affects methylation	2
Thapsigargin	increases expression	2
Nanotubes, Carbon	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
sodium bichromate	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
zearalenol	increases expression	1
aflatoxin B2	decreases methylation	1
triphenyltin	increases expression	1
cupric oxide	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
tributyltinisothiocyanate	increases expression	1
CGP 52608	affects binding, increases reaction	1
CP 31398	decreases expression	1
K 7174	decreases expression	1
fenpyroximate	increases expression	1

ChEMBL screening assays

13 unique, capped per target: 12 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2114933	Functional	PubChem BioAssay. Secondary Assay for Selectivity of PDI Inhibitors (against ERp5) Measured in Biochemical System Using Plate Reader - 2137-04_Inhibitor_Dose_DryPowder_Activity. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL3214858	Binding	PubChem BioAssay. Turbidometric Biochemical Primary HTS to identify inhibitors of ERp5 Measured in Biochemical System Using Plate Reader - 7002-01_Inhibitor_Dose_CherryPick_Activity. (Class of assay: confirmatory)	PubChem BioAssay data set

Clinical trials (associated diseases)

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