PDIA4

Chr 7

protein disulfide isomerase family A member 4

Also known as: ERP70, ERP72, ERp-72

NCBI Gene: 9601ENSG00000155660UniProt: 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. [provided by RefSeq, Dec 2016]

152
ClinVar variants
61
Pathogenic / LP
0.08
pLI score
0
Active trials
Clinical Summary— PDIA4
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 84 VUS of 152 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.51LOEUF
pLI 0.078
Z-score 3.43
OE 0.27 (0.15–0.51)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.13Z-score
OE missense 1.02 (0.94–1.11)
367 obs / 360.3 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.27 (0.15–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.02 (0.94–1.11)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08
0≤1.21.6
LoF obs/exp: 7 / 25.8Missense obs/exp: 367 / 360.3Syn Z: -0.74

ClinVar Variant Classifications

152 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58
Likely Pathogenic3
VUS84
Likely Benign6
Benign1
58
Pathogenic
3
Likely Pathogenic
84
VUS
6
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
58
0
58
Likely Pathogenic
0
0
3
0
3
VUS
0
81
3
0
84
Likely Benign
0
6
0
0
6
Benign
0
1
0
0
1
Total088640152

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PDIA4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Construction and validation of a cuproptosis-related prognostic model for glioblastoma.
Zhang B et al.·Front Immunol
2023Functional
PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma.
Kang L et al.·Cell Death Dis
2023
Protein disulfide-isomerase A4 confers glioblastoma angiogenesis promotion capacity and resistance to anti-angiogenic therapy.
Tu Z et al.·J Exp Clin Cancer Res
2023
Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.
Küçükali F et al.·Brain
2025
Circulating proteins and metabolites panel for noninvasive preoperative diagnosis of epithelial ovarian cancer.
Jia Y et al.·BMC Med
2025
Targeting ferroptosis: novel therapeutic approaches and intervention strategies for kidney diseases.
Luo Y et al.·Front Immunol
2025Review
Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia.
Chen Q et al.·J Transl Med
2023
Protein Disulfide Isomerase 4 Drives Docetaxel Resistance in Prostate Cancer.
Qian S et al.·Chemotherapy
2020
Unraveling shared diagnostic genes and cellular microenvironmental changes in endometriosis and recurrent implantation failure through multi-omics analysis.
Qin D et al.·Sci Rep
2025
The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma.
Tufo G et al.·Cell Death Differ
2014
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools