P4HB

Chr 17AD

prolyl 4-hydroxylase subunit beta

Also known as: CLCRP1, DSI, ERBA2L, GIT, P4Hbeta, PDI, PDIA1, PHDB

NCBI Gene: 5034ENSG00000185624UniProt: P07237

This gene encodes the beta subunit of prolyl 4-hydroxylase, a highly abundant multifunctional enzyme that belongs to the protein disulfide isomerase family. When present as a tetramer consisting of two alpha and two beta subunits, this enzyme is involved in hydroxylation of prolyl residues in preprocollagen. This enzyme is also a disulfide isomerase containing two thioredoxin domains that catalyze the formation, breakage and rearrangement of disulfide bonds. Other known functions include its ability to act as a chaperone that inhibits aggregation of misfolded proteins in a concentration-dependent manner, its ability to bind thyroid hormone, its role in both the influx and efflux of S-nitrosothiol-bound nitric oxide, and its function as a subunit of the microsomal triglyceride transfer protein complex. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cole-Carpenter syndrome 1MIM #112240
AD
0
Active trials
438
ClinVar variants
24
Pathogenic / LP
1.3
Missense Z
0.22
LOEUF· LoF intolerant
14
Pubs (2 yr)
Clinical Summary— P4HB
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 184 VUS of 438 total submissions
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GeneReview available — P4HB
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.22LOEUF
pLI 0.997
Z-score 4.06
OE 0.05 (0.02–0.22)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
1.31Z-score
OE missense 0.78 (0.70–0.87)
224 obs / 286.2 exp
Tolerant

Mild missense constraint

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.0.05 (0.02–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.70–0.87)
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.1.12
0≤1.21.6
LoF obs/exp: 1 / 21.2Missense obs/exp: 224 / 286.2Syn Z: -1.03

ClinVar Variant Classifications

438 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic5
VUS184
Likely Benign164
Benign57
Conflicting9
19
Pathogenic
5
Likely Pathogenic
184
VUS
164
Likely Benign
57
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
18
0
19
Likely Pathogenic
1
1
3
0
5
VUS
3
161
19
1
184
Likely Benign
0
9
66
89
164
Benign
0
8
39
10
57
Conflicting
—9
Total4180145100438

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

View in ClinVar →

Protein Context — Lollipop Plot

P4HB · protein map & ClinVar variants

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

Gene2Phenotype Curations

P4HB-related Cole-Carpenter syndrome

strong
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cole-Carpenter syndrome 1

MIM #112240

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive analysis of bulk and single-cell transcriptomic data reveals a novel signature associated with endoplasmic reticulum stress, lipid metabolism, and liver metastasis in pancreatic cancer.
Liu X et al.·J Transl Med
2024
A meta-analysis and bioinformatics analysis of P4HB expression levels in the prognosis of cancer patients.
Wang F et al.·Pathol Res Pract
2023Review
DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum.
Bardai G et al.·Osteoporos Int
2016
Targeting the ER stress sensor IRE1 protects the liver from fibrosis through the downregulation of the proteostasis factor P4HB/PDIA1.
Hazari Y et al.·Hepatology
2026
USP5-induced deubiquitination of P4HB alleviates ER stress-mediated apoptosis in intestinal ischemia/reperfusion.
Ning S et al.·Cell Mol Life Sci
2025
The P4HB/LGALS3BP/NF-kB axis promotes the progression of MIA to IAC in lung adenocarcinoma.
Mu G et al.·Sci Rep
2025
Protein Markers in Osteoporosis.
Porcelli T et al.·Protein Pept Lett
2020Review
Novel control for erectile dysfunction research.
Deng J et al.·J Sex Med
2025
Clinical outcomes of oncologic hernia repair using Poly-4-Hydroxybutyrate (P4HB) mesh.
Levy J et al.·Hernia
2025
Onlay Poly-4-Hydroxybutyrate (P4HB) Mesh for Complex Hernia: Early Clinical and Patient Reported Outcomes.
Christopher AN et al.·J Surg Res
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Long-term Outcomes of Poly-4-Hydroxybutyrate (P4HB) in Aesthetic Breast Surgery: An International Experience.
Tomur S et al.·Aesthet Surg J
2026
Short- and long-term complications after slowly resorbable biosynthetic P4HB mesh (Phasix) implantation in European centres: a protocol paper for a multiregistry study.
van den Berg R et al.·BMJ Open
2025Open Access
miR-188-5p accelerates intervertebral disc degeneration by mediating P4HB to regulate ferroptosis in nucleus pulposus cells.
Yan J et al.·Eur J Med Res
2025Open Access
Bio-resorbable poly-4-hydroxybutyrate (P4HB) mesh for abdominal wall reconstruction is effective in high-risk patients and contaminated abdomen.
Srivastava AK et al.·Hernia
2025Cohort
The Use of Poly-4-Hydroxybutyrate (P4HB) Scaffold in Cosmetic Breast Surgery: A Systematic Review and Meta-Analysis.
Milani-Reis A et al.·Aesthetic Plast Surg
2025Review
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Successful conservative treatment of a poly-4-hydroxybutyrate mesh infection: A case report
Lambrecht M et al.·Ann Med Surg (Lond)
2021Case report
Evaluation of Electrospun Poly-4-Hydroxybutyrate as Biofunctional and Degradable Scaffold for Pelvic Organ Prolapse in a Vaginal Sheep Model
van Rest KLC et al.·Macromol Biosci
2025Functional
Absorbable Electrospun Poly-4-hydroxybutyrate Scaffolds as a Potential Solution for Pelvic Organ Prolapse Surgery
Verhorstert K et al.·ACS Appl Bio Mater
2022
Artificial Intelligence, Genuine Outcome: Analysis of 72 Consecutive Cases of Subfascial Augmentation Mastopexy With Smooth Round Implants Supported by P4HB Scaffold
Bistoni G et al.·Aesthet Surg J
2024Cohort
Fully resorbable poly-4-hydroxybutyrate (P4HB) mesh for soft tissue repair and reconstruction: A scoping review
Deeken CR et al.·Front Surg
2023Review
The impact of bacterial contamination on the host response towards fully absorbable poly-4-hydroxybutyrate and nonabsorbable polypropylene pelvic floor implants
Verhorstert KWJ et al.·Mater Today Bio
2022
A prospective, multicenter trial of a long-term bioabsorbable mesh with Sepra technology in cohort of challenging laparoscopic ventral or incisional hernia repairs (ATLAS trial)
Hope WW et al.·Ann Med Surg (Lond)
2021Cohort
P4HB regulates tumor-associated macrophage polarization and chemotaxis by enhancing IL-6 cytokine secretion in glioblastoma
Wang M et al.·Ann Med Surg (Lond)
2025
Evaluation of the short-term host response and biomechanics of an absorbable poly-4-hydroxybutyrate scaffold in a sheep model following vaginal implantation Evaluation of the short term host response and biomechanics of an absorbable poly-4-hydroxybutyrate scaffold in a sheep model following vaginal implantation
Diedrich CM et al.·BJOG
2022Functional
Expression, localization, and function of P4HB in the spermatogenesis of Chinese mitten crab (Eriocheir sinensis)
Tang Y et al.·PeerJ
2023
Top 10 full-text resultsSearch PubTator3 ↗

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

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients