PDIA4

Summary

PDIA4 (protein disulfide isomerase family A member 4, HGNC:30167) is a protein-coding gene on chromosome 7q36.1, encoding Protein disulfide-isomerase A4 (P13667).

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, three catalytically active thioredoxin (TRX) domains, two TRX-like domains and a C-terminal ER-retention sequence. This protein, when bound to cyclophilin B, enhances the rate of immunoglobulin G intermolecular disulfide bonding and antibody assembly.

Source: NCBI Gene 9601 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 107 total
• Druggable target: yes
• MANE Select transcript: NM_004911

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30167
Approved symbol	PDIA4
Name	protein disulfide isomerase family A member 4
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	ERP70, ERP72
Ensembl gene	ENSG00000155660
Ensembl biotype	protein_coding
OMIM	620018
Entrez	9601

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 retained_intron

ENST00000286091, ENST00000413966, ENST00000466592, ENST00000652332, ENST00000892338, ENST00000892339, ENST00000892340, ENST00000892341, ENST00000892342, ENST00000892343, ENST00000892344, ENST00000922043, ENST00000922044, ENST00000922045, ENST00000922046

RefSeq mRNA: 3 — MANE Select: NM_004911 NM_001371244, NM_001371245, NM_004911

CCDS: CCDS5893, CCDS94226

Canonical transcript exons

ENST00000652332 — 10 exons

Exon	Start	End
ENSE00001022082	149005897	149006053
ENSE00001022084	149020967	149021147
ENSE00001022086	149008159	149008310
ENSE00001022087	149012155	149012360
ENSE00001022090	149018992	149019197
ENSE00001022091	149014904	149015042
ENSE00001022093	149003062	149004209
ENSE00001022094	149011846	149012004
ENSE00003614675	149005141	149005374
ENSE00003845484	149028321	149028505

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 154.6376 / max 2361.3465, expressed in 1827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86725	138.4589	1827
86726	11.8808	1742
86724	4.2979	1533

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pylorus	UBERON:0001166	98.08	gold quality
stromal cell of endometrium	CL:0002255	98.04	gold quality
pericardium	UBERON:0002407	97.92	gold quality
right lobe of liver	UBERON:0001114	97.91	gold quality
islet of Langerhans	UBERON:0000006	97.73	gold quality
right lobe of thyroid gland	UBERON:0001119	97.70	gold quality
corpus epididymis	UBERON:0004359	97.70	gold quality
body of pancreas	UBERON:0001150	97.39	gold quality
mucosa of transverse colon	UBERON:0004991	97.34	gold quality
liver	UBERON:0002107	97.32	gold quality
left lobe of thyroid gland	UBERON:0001120	97.22	gold quality
rectum	UBERON:0001052	97.19	gold quality
thyroid gland	UBERON:0002046	97.16	gold quality
pancreas	UBERON:0001264	97.01	gold quality
smooth muscle tissue	UBERON:0001135	96.88	gold quality
ileal mucosa	UBERON:0000331	96.40	gold quality
caecum	UBERON:0001153	96.30	gold quality
gall bladder	UBERON:0002110	96.14	gold quality
trachea	UBERON:0003126	96.11	gold quality
endometrium	UBERON:0001295	96.10	gold quality
ventricular zone	UBERON:0003053	96.10	gold quality
vermiform appendix	UBERON:0001154	96.04	gold quality
tendon of biceps brachii	UBERON:0008188	96.01	gold quality
lymph node	UBERON:0000029	95.94	gold quality
cardia of stomach	UBERON:0001162	95.57	gold quality
endocervix	UBERON:0000458	95.55	gold quality
adenohypophysis	UBERON:0002196	95.55	gold quality
spleen	UBERON:0002106	95.22	gold quality
prostate gland	UBERON:0002367	95.22	gold quality
right uterine tube	UBERON:0001302	95.20	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	2238.78
E-MTAB-6386	yes	1349.59
E-CURD-7	yes	731.60
E-CURD-88	yes	113.89
E-MTAB-9467	yes	66.38
E-HCAD-4	yes	56.36
E-CURD-46	yes	50.37
E-CURD-122	yes	50.23
E-HCAD-1	yes	43.86
E-MTAB-8410	yes	42.07
E-ANND-3	yes	30.25
E-MTAB-9067	yes	15.60
E-HCAD-9	yes	15.02
E-MTAB-9543	yes	13.21
E-MTAB-10553	yes	11.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting PDIA4, 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-4283	100.00	66.42	2097
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4686	98.77	66.87	964
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548
HSA-MIR-378E	98.43	65.99	551
HSA-MIR-378F	98.43	65.66	554
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-378I	98.43	66.10	548
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-506-5P	98.02	67.41	1065

Literature-anchored findings (GeneRIF, showing 21)

• Nox1 associates with ERp72, which involves its N-terminus encompassing a Ca(2+)-binding site and the first TRX-like motif. (PMID:18620548)
• novel esophageal squamous cell carcinoma marker PDIA4 was identified by mass spectrometry and immunohistochemical analysis (PMID:21743296)
• 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)
• the faster migrating Tg adduct C primarily engages the CaBP1/P5 oxidoreductase, whereas the slower migrating Tg adduct A primarily engages ERp72. (PMID:24599957)
• up-regulated by IL11 in first trimester placenta (PMID:28487027)
• PDIA4 as a negative regulator of cancer cell apoptosis. (PMID:28534513)
• Participants with metabolic syndrome (MetS) had significantly higher serum PDIA4 levels than those without MetS (P<0.001). After adjustments, the individuals with the highest PDIA4 tertile were associated with a higher risk of MetS than those with the lowest tertile (OR = 4.83, 95% CI: 2.71-8.60). (PMID:28650993)
• MicroRNA-378a-3p contributes to ovarian cancer progression through downregulating PDIA4. (PMID:33159506)
• Protein Disulfide Isomerase 4 Drives Docetaxel Resistance in Prostate Cancer. (PMID:33238278)
• Circulating protein disulfide isomerase family member 4 is associated with type 2 diabetes mellitus, insulin sensitivity, and obesity. (PMID:35460376)
• PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue. (PMID:35674710)
• High expression of PDIA4 promotes malignant cell behavior and predicts reduced survival in cervical cancer. (PMID:36082822)
• CircPDIA4 Induces Gastric Cancer Progression by Promoting ERK1/2 Activation and Enhancing Biogenesis of Oncogenic circRNAs. (PMID:36562654)
• PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle. (PMID:36619574)
• PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma. (PMID:36906674)
• Protein disulfide-isomerase A4 confers glioblastoma angiogenesis promotion capacity and resistance to anti-angiogenic therapy. (PMID:36997943)
• LncRNA FAM225B Regulates PDIA4-Mediated Ovarian Cancer Cell Invasion and Migration via Modulating Transcription Factor DDX17. (PMID:37720188)
• PDIA4 Is a Host Factor Important for Lymphocytic Choriomeningitis Virus Infection. (PMID:38140584)
• Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway. (PMID:38167446)
• Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival. (PMID:38612722)
• Potential Anti-tumor Properties of PDIA4 in Lung Adenocarcinoma. (PMID:39348977)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdia4	ENSDARG00000018491
mus_musculus	Pdia4	ENSMUSG00000025823
rattus_norvegicus	Pdia4	ENSRNOG00000006228
drosophila_melanogaster	Tmx3	FBGN0036579
caenorhabditis_elegans		WBGENE00003962
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), TMX3 (ENSG00000166479), PDIA3 (ENSG00000167004), PDILT (ENSG00000169340), PDIA2 (ENSG00000185615), P4HB (ENSG00000185624), TXNDC5 (ENSG00000239264)

Protein

Protein identifiers

Protein disulfide-isomerase A4 — P13667 (reviewed: P13667)

Alternative names: Endoplasmic reticulum resident protein 70, Endoplasmic reticulum resident protein 72

All UniProt accessions (4): P13667, A0A090N8Y2, A0A499FI48, C9JMN9

UniProt curated annotations — full annotation on UniProt →

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. Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4. (Microbial infection) Interacts with Human astrovirus-1 and Human astrovirus-8 spike protein VP25; this interaction seems to facilitate the uncoating during virus entry into the cell. Does not interact with Human astrovirus-2 spike protein VP25.

Subcellular location. Endoplasmic reticulum lumen. Melanosome.

Similarity. Belongs to the protein disulfide isomerase family.

RefSeq proteins (3): NP_001358173, NP_001358174, NP_004902* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005788	PDI_thioredoxin-like_dom	Domain
IPR005792	Prot_disulphide_isomerase	Family
IPR013766	Thioredoxin_domain	Domain
IPR017068	Protein_diS-isomerase_A4	Family
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR041866	PDIA4_PDI_b	Domain

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 (42 total): strand 13, helix 9, turn 4, disulfide bond 3, domain 3, short sequence motif 3, signal peptide 1, chain 1, modified residue 1, sequence variant 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3IDV	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13667-F1	89.21	0.82

Functional residue map

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

Post-translational modifications (1): 366

Disulfide bonds (3): 91–94, 206–209, 555–558

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 213 (showing top): MODULE_93, MODULE_52, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GOCC_CELL_SURFACE, SHAFFER_IRF4_TARGETS_IN_PLASMA_CELL_VS_MATURE_B_LYMPHOCYTE, BROWNE_HCMV_INFECTION_24HR_UP, GOBP_PROTEIN_MATURATION, UEDA_PERIFERAL_CLOCK, MODULE_239, MYCMAX_01, BLALOCK_ALZHEIMERS_DISEASE_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_SECRETION, HNF4_01

GO Biological Process (3): protein folding (GO:0006457), protein secretion (GO:0009306), response to endoplasmic reticulum stress (GO:0034976)

GO Molecular Function (5): RNA binding (GO:0003723), protein disulfide isomerase activity (GO:0003756), protein-disulfide reductase activity (GO:0015035), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), cell surface (GO:0009986), melanosome (GO:0042470)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity, acting on a protein	2
cellular process	1
protein maturation	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
cellular response to stress	1
nucleic acid binding	1
intramolecular oxidoreductase activity, transposing S-S bonds	1
disulfide oxidoreductase activity	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cellular anatomical structure	1
pigment granule	1

Protein interactions and networks

STRING

3073 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDIA4	HSP90B1	P14625	995
PDIA4	HYOU1	Q9Y4L1	988
PDIA4	PPIB	P23284	974
PDIA4	DNAJB11	Q9UBS4	960
PDIA4	HSPA5	P11021	925
PDIA4	CANX	P27824	890
PDIA4	CALR	P27797	858
PDIA4	P4HA2	O15460	779
PDIA4	UGGT1	Q9NYU2	776
PDIA4	DCK	P27707	769
PDIA4	SDF2L1	Q9HCN8	767
PDIA4	TG	P01266	690
PDIA4	DGUOK	P78532	684
PDIA4	ERP29	P30040	682
PDIA4	P4HA1	P13674	671

IntAct

242 interactions, top by confidence:

A	B	Type	Score
CFTR	PDIA4	psi-mi:“MI:0403”(colocalization)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
PDIA4	PPIB	psi-mi:“MI:0915”(physical association)	0.610
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
PDIA4	EMC7	psi-mi:“MI:0915”(physical association)	0.590
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
MATN3	PDIA4	psi-mi:“MI:0914”(association)	0.560
MATN3	PDIA4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP4-11	PDIA4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	PDIA4	psi-mi:“MI:0915”(physical association)	0.560
PDIA4	KRTAP4-11	psi-mi:“MI:0915”(physical association)	0.560
PDIA4	LCN2	psi-mi:“MI:0915”(physical association)	0.560
PDIA4	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
PDIA4	KRTAP12-1	psi-mi:“MI:0915”(physical association)	0.560
COL1A1	PDIA4	psi-mi:“MI:0914”(association)	0.560
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
COL1A1	GOLIM4	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (662): PDIA4 (Affinity Capture-MS), PDIA4 (Affinity Capture-MS), PDIA4 (Affinity Capture-Western), PDIA4 (Affinity Capture-MS), PDIA4 (Affinity Capture-MS), PDIA4 (Affinity Capture-MS), P4HB (Co-fractionation), PDIA4 (Co-fractionation), PDIA4 (Affinity Capture-MS), PDIA4 (Proximity Label-MS), PDIA4 (Proximity Label-MS), PDIA4 (Proximity Label-MS), PDIA4 (Proximity Label-MS), PDIA4 (Proximity Label-MS), PDIA4 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M1N5Y4, A3KPF5, A8WG88, O22925, O80977, P08003, P11598, P13667, P30040, P30101, P32474, P38659, P52555, P52588, P57759, P81623, P81628, P93026, P93484, Q0E0I1, Q0JD42, Q0WL80, Q17688, Q2KIL5, Q43116, Q498R3, Q56ZQ3, Q5FVM7, Q5I0H9, Q5R5L3, Q5RDG4, Q5WA72, Q66GQ3, Q67IX6, Q6GNG3, Q6NRT6, Q6P5E4, Q7JW12, Q7XRB5, Q8IXB1

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 202 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
Constitutive Signaling by Aberrant PI3K in Cancer	9	8.0×	4e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	11	7.5×	2e-04
PIP3 activates AKT signaling	12	5.6×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	9	21.9×	1e-07
positive regulation of MAP kinase activity	5	18.7×	1e-03
cell surface receptor protein tyrosine kinase signaling pathway	18	18.1×	8e-15
protein autophosphorylation	11	9.2×	8e-06
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	19	8.6×	6e-10
positive regulation of MAPK cascade	14	6.5×	8e-06
positive regulation of cell migration	16	5.7×	8e-06
axon guidance	10	5.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	81
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1887 predictions. Top by Δscore:

Variant	Effect	Δscore
7:149004205:TTTTC:T	acceptor_gain	1.0000
7:149004206:TTTC:T	acceptor_gain	1.0000
7:149004207:TTC:T	acceptor_gain	1.0000
7:149004208:TC:T	acceptor_gain	1.0000
7:149004208:TCCT:T	acceptor_loss	1.0000
7:149004209:CC:C	acceptor_gain	1.0000
7:149004210:C:CC	acceptor_gain	1.0000
7:149004214:C:CT	acceptor_gain	1.0000
7:149004214:C:T	acceptor_gain	1.0000
7:149004215:A:T	acceptor_gain	1.0000
7:149005137:TCA:T	donor_loss	1.0000
7:149005139:A:AC	donor_gain	1.0000
7:149005140:C:CC	donor_gain	1.0000
7:149005140:CCTT:C	donor_gain	1.0000
7:149005304:C:CT	acceptor_gain	1.0000
7:149005370:AGTTG:A	acceptor_gain	1.0000
7:149005371:GTTG:G	acceptor_gain	1.0000
7:149005372:TTG:T	acceptor_gain	1.0000
7:149005373:TG:T	acceptor_gain	1.0000
7:149005374:GC:G	acceptor_loss	1.0000
7:149005375:C:CC	acceptor_gain	1.0000
7:149005375:C:CG	acceptor_loss	1.0000
7:149005891:CCTCA:C	donor_loss	1.0000
7:149005892:CTCAC:C	donor_loss	1.0000
7:149005893:TCAC:T	donor_loss	1.0000
7:149005895:A:AG	donor_loss	1.0000
7:149005896:CCAG:C	donor_gain	1.0000
7:149006052:CCCTG:C	acceptor_gain	1.0000
7:149006053:CC:C	acceptor_gain	1.0000
7:149006054:CTG:C	acceptor_gain	1.0000

AlphaMissense

4290 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:149004058:G:C	C558W	0.999
7:149004059:C:A	C558F	0.999
7:149004059:C:T	C558Y	0.999
7:149004060:A:G	C558R	0.999
7:149004068:C:A	C555F	0.999
7:149004068:C:T	C555Y	0.999
7:149004069:A:G	C555R	0.999
7:149004070:C:A	W554C	0.999
7:149004070:C:G	W554C	0.999
7:149004072:A:G	W554R	0.999
7:149004072:A:T	W554R	0.999
7:149012217:G:T	P253H	0.999
7:149012348:G:C	C209W	0.999
7:149012349:C:A	C209F	0.999
7:149012349:C:T	C209Y	0.999
7:149012350:A:G	C209R	0.999
7:149012358:C:A	C206F	0.999
7:149012358:C:T	C206Y	0.999
7:149012359:A:G	C206R	0.999
7:149012360:C:A	W205C	0.999
7:149012360:C:G	W205C	0.999
7:149003932:G:C	F600L	0.998
7:149003932:G:T	F600L	0.998
7:149003934:A:G	F600L	0.998
7:149004029:A:G	L568P	0.998
7:149004067:G:C	C555W	0.998
7:149004068:C:G	C555S	0.998
7:149004069:A:T	C555S	0.998
7:149012199:C:G	R259P	0.998
7:149012218:G:A	P253S	0.998

dbSNP variants (sampled 300 via entrez): RS1000006156 (7:149003284 G>A), RS1000050881 (7:149006629 C>T), RS1000064292 (7:149006712 G>A), RS1000416255 (7:149017509 G>A), RS1000468470 (7:149017647 T>C,G), RS1000486035 (7:149006920 A>G), RS1000599983 (7:149026366 C>A,G), RS1000617041 (7:149010658 C>A), RS1000630357 (7:149022258 C>A,T), RS1000685174 (7:149012134 G>A,C), RS1000752762 (7:149016476 T>G), RS1000800270 (7:149016697 G>C), RS1000996670 (7:149027530 C>A), RS1001173933 (7:149025069 T>A,C,G), RS1001329054 (7:149026206 C>A,T)

Disease associations

OMIM: gene MIM:620018 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000817_13	Height	3.000000e-08
GCST90020029_906	Waist circumference adjusted for body mass index	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295717 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 7 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Kd	58.21	nM	CHEMBL5653589
7.24	ED50	58.21	nM	CHEMBL5653589
5.50	IC50	3160	nM	JUGLONE
5.40	IC50	4010	nM	CHEMBL5418475

PubChem BioAssay actives

3 with measured affinity, of 16 total; 3 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	2148964: Binding affinity to human PDIA4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0582	uM
5-hydroxynaphthalene-1,4-dione	2034961: Inhibition of human recombinant ERp72 assessed as inhibition of E-GSH formation using Di-E-GSSG as substrate measured for 60 mins in presence of DTT by fluorescence based analysis	ic50	3.1600	uM
[(2R,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(8-hydroxy-1,4-dioxonaphthalen-2-yl)oxyoxan-2-yl]methyl acetate	2034961: Inhibition of human recombinant ERp72 assessed as inhibition of E-GSH formation using Di-E-GSSG as substrate measured for 60 mins in presence of DTT by fluorescence based analysis	ic50	4.0100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	5
Cyclosporine	increases expression	5
Cadmium Chloride	decreases expression, increases methylation, increases expression	4
Cisplatin	affects cotreatment, increases expression, decreases expression	3
bisphenol F	increases expression, affects cotreatment	2
bisphenol S	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tunicamycin	increases expression	2
Valproic Acid	affects expression, increases expression	2
Thapsigargin	increases expression	2
aristolochic acid I	decreases expression	1
beauvericin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	decreases expression	1
cupric oxide	decreases expression	1
transplatin	decreases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
tanespimycin	affects cotreatment, increases expression	1
2-palmitoylglycerol	increases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118774	Binding	Binding affinity to PDIA4 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg 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_D7WQ	Ubigene A-549 PDIA4 KO	Cancer cell line	Male
CVCL_E0JV	Ubigene HeLa PDIA4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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