P4HB

prolyl 4-hydroxylase subunit beta, the group of Protein disulfide isomerases

Basic information

Region (hg38): 17:81843159-81860856

Previous symbols: [ "PO4DB", "ERBA2L" ]

Links

ENSG00000185624 ∙ NCBI:5034 ∙ OMIM:176790 ∙ HGNC:8548 ∙ Uniprot:P07237 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Cole-Carpenter syndrome 1 (Strong), mode of inheritance: AD
• Cole-Carpenter syndrome 1 (Strong), mode of inheritance: AD
• Cole-Carpenter syndrome 1 (Moderate), mode of inheritance: AD
• Cole-Carpenter syndrome 1 (Moderate), mode of inheritance: AD
• Cole-Carpenter syndrome (Supportive), mode of inheritance: AD
• osteogenesis imperfecta type 1 (Supportive), mode of inheritance: AD
• Cole-Carpenter syndrome 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cole-Carpenter syndrome 1	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	3794889; 25683117

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the P4HB gene.

• Cole-Carpenter syndrome 1 (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the P4HB gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	62	8	71
missense	1	1	97	10	9	118
nonsense						0
start loss						0
frameshift		1	2			3
inframe indel			1	1		2
splice donor/acceptor (+/-2bp)			1			1
splice region			2	5	2	9
non coding				43	30	73
Total	1	2	102	116	47

Variants in P4HB

This is a list of pathogenic ClinVar variants found in the P4HB region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
17-81843795-T-G			Benign (Aug 20, 2018)
17-81844025-T-C		Inborn genetic diseases	Uncertain significance (Jan 03, 2024)
17-81844038-GATC-G			Uncertain significance (Dec 11, 2023)
17-81844042-A-G		P4HB-related disorder	Benign (May 02, 2023)
17-81844044-C-T			Uncertain significance (Sep 11, 2023)
17-81844050-C-T		Inborn genetic diseases	Uncertain significance (Aug 17, 2022)
17-81844063-C-T			Likely benign (Jun 03, 2022)
17-81844083-C-T			Uncertain significance (Aug 23, 2023)
17-81844086-C-A			Uncertain significance (May 27, 2022)
17-81844086-C-G		Cole-Carpenter syndrome 1	Uncertain significance (Apr 25, 2019)
17-81844087-G-A			Likely benign (Aug 28, 2023)
17-81844099-T-C			Likely benign (Sep 25, 2023)
17-81844101-C-T			Benign (Jan 31, 2024)
17-81844107-A-G			Benign (Jul 09, 2023)
17-81844179-G-A			Benign (Sep 18, 2018)
17-81844251-CAG-C			Benign (Aug 20, 2018)
17-81844255-G-A			Likely benign (Oct 01, 2018)
17-81844395-C-T			Likely benign (Apr 03, 2019)
17-81845068-G-C			Likely benign (Oct 01, 2018)
17-81845074-A-C			Benign (Sep 18, 2018)
17-81845130-G-A			Likely benign (Mar 31, 2023)
17-81845146-C-A			Uncertain significance (Oct 13, 2022)
17-81845147-A-G			Likely benign (Jul 26, 2018)
17-81845160-C-G		Inborn genetic diseases	Uncertain significance (Feb 27, 2024)
17-81845166-T-C			Uncertain significance (Jul 07, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
P4HB	protein_coding	protein_coding	ENST00000331483	11	17536

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.997	0.00338	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.31	224	286	0.783	0.0000179	3362
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000868	0.0000868
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Protein processing in endoplasmic reticulum - Homo sapiens (human);Interleukin-12 family signaling;Signal Transduction;Detoxification of Reactive Oxygen Species;Signaling by Interleukins;hypoxia-inducible factor in the cardivascular system;Chylomicron assembly;VLDL assembly;Plasma lipoprotein assembly;Collagen biosynthesis and modifying enzymes;Post-translational protein phosphorylation;Cytokine Signaling in Immune system;Cellular responses to stress;Post-translational protein modification;Metabolism of proteins;Collagen formation;Extracellular matrix organization;Immune System;Transport of small molecules;Hedgehog ligand biogenesis;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Cellular responses to external stimuli;Interleukin-23 signaling;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Signaling by Hedgehog;Plasma lipoprotein assembly, remodeling, and clearance;Interleukin-12 signaling (Consensus)

Recessive Scores

• pRec: 0.599

Intolerance Scores

• loftool: 0.401
• rvis_EVS: -0.84
• rvis_percentile_EVS: 11.18

Haploinsufficiency Scores

• pHI: 0.481
• hipred: Y
• hipred_score: 0.825
• ghis: 0.530

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: P4hb
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; immune system phenotype

Gene ontology

• 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;interleukin-12-mediated signaling pathway;interleukin-23-mediated signaling pathway;post-translational protein modification;cellular protein metabolic process;cell redox homeostasis;positive regulation of viral entry into host cell;oxidation-reduction process;cellular response to hypoxia;cellular response to interleukin-7;regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
• Cellular component: extracellular region;endoplasmic reticulum;endoplasmic reticulum lumen;endoplasmic reticulum-Golgi intermediate compartment;focal adhesion;external side of plasma membrane;procollagen-proline 4-dioxygenase complex;endoplasmic reticulum chaperone complex;melanosome;extracellular exosome
• Molecular function: RNA binding;protein disulfide isomerase activity;procollagen-proline 4-dioxygenase activity;integrin binding;protein binding;peptide disulfide oxidoreductase activity;enzyme binding;protein heterodimerization activity