P4HB
protein-codingprolyl 4-hydroxylase subunit beta, the group of Protein disulfide isomerases
Gene summary
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]
- PO4DB
- ERBA2L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007204
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007204
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007204
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007204
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007204
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008146
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016085
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to P4HB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000918.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 97 | 5 | 105 | ||
| missense | 1 | 1 | 168 | 22 | 5 | 197 |
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | |||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 1 | 2 | 181 | 119 | 10 | 313 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000909.2 | 11 | MANE Select | |
| Ensembl | ENSP00000327801.4 | 11 | MANE Select | |
| Ensembl | ENSP00000388117.2 | 9 | Standard | |
| Ensembl | ENSP00000388117.2 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein processing in endoplasmic reticulum - Homo sapiens (human)
- Interleukin-12 family signaling
- Signal Transduction
- Detoxification of Reactive Oxygen Species
- Signaling by Interleukins
Biological Process
- protein folding
- peptidyl-proline hydroxylation to 4-hydroxy-L-proline
- chylomicron assembly
- very-low-density lipoprotein particle assembly
- response to endoplasmic reticulum stress
Molecular Function
- RNA binding
- protein disulfide isomerase activity
- procollagen-proline 4-dioxygenase activity
- integrin binding
- protein binding
Cellular Component
- extracellular region
- endoplasmic reticulum
- endoplasmic reticulum lumen
- endoplasmic reticulum-Golgi intermediate compartment
- focal adhesion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000331483
- Coding exons
- 11
- Length
- 17536
- Individuals with no LoFs
- 125741
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125748
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.31 | 224 | 286 | 0.783 | 0.0000179 | 3362 |
| Missense (PolyPhen) | 50 | 93.219 | 0.53637 | 1018 | ||
| Synonymous | -1.03 | 143 | 128 | 1.12 | 0.00000979 | 943 |
| Loss of Function | 4.06 | 1 | 21.2 | 0.0473 | 0.00000101 | 276 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations, functions as a chaperone that inhibits aggregation of misfolded proteins. At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration (PubMed:21670307). {ECO:0000269|PubMed:10636893, ECO:0000269|PubMed:12485997, ECO:0000269|PubMed:21670307}.;
- Disease
- DISEASE: Cole-Carpenter syndrome 1 (CLCRP1) [MIM:112240]: A form of Cole-Carpenter syndrome, a disorder characterized by features of osteogenesis imperfecta such as bone deformities and severe bone fragility with frequent fractures, in association with craniosynostosis, ocular proptosis, hydrocephalus, growth failure and distinctive facial features. Craniofacial findings include marked frontal bossing, midface hypoplasia, and micrognathia. Despite the craniosynostosis and hydrocephalus, intellectual development is normal. CLCRP1 inheritance is autosomal dominant. {ECO:0000269|PubMed:25683117}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.599
Intolerance Scores
- LoFtool
- 0.401
- RVIS EVS
- -0.84
- RVIS percentile EVS
- 11.18
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |