PCSK5
protein-codingproprotein convertase subtilisin/kexin type 5, the group of Proprotein convertase subtilisin/kexin family
Gene summary
This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER. It then sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. This encoded protein is widely expressed and one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It mediates posttranslational endoproteolytic processing for several integrin alpha subunits and is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160. Alternative splicing results in multiple transcript variants, some of which encode distinct isoforms, including a protease packaged into dense core granules (PC5A) and a type 1 membrane bound protease (PC5B). [provided by RefSeq, May 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~472.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100614
Submitter: ClinGen
*PCSK5* was first reported in relation to autosomal dominant syndromic congenital heart disease in 2008 (Szumska et al., PMID: 18519639). Structural congenital heart defects (CHD) has been observed with other syndromic features such as VACTERL (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, renal anomalies, and limb abnormalities), Caudal regression syndrome, Currarino syndrome, heterotaxy, and cleft lip/palate in patients carrying *PCSK5* variants. At least ten unique variants (8 missense, 1 in-frame indel, 1 nonsense) have been reported in eleven individuals with syndromic CHD (PMID: 18519639, 24416387, 26055999, 30896870, 33131162). Of these, only the proband with the in-frame indel variant was scorable; the remaining variants had high minor allele frequencies in gnomAD v4.1.0. However, the proband was not scored either due to uncertainties of the pathogenicity of *PCSK5* variants in syndromic CHD. This gene-disease relationship is supported by evidence of biochemical function, functional alteration, and an ENU-induced recessive mouse model replicating many of the VACTERL phenotypes (PMIDs: 21480163, 28446132,18519639). In summary, the evidence supporting the relationship between *PCSK5* and autosomal dominant syndromic CHD has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *PCSK5* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date April 1st, 2025 (SOP Version 11).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PCSK5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001372043.1. 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 | 10 | 9 | 22 | ||
| missense | 104 | 11 | 6 | 121 | ||
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 115 | 21 | 15 | 151 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001358972.1 | 38 | MANE Select | |
| Ensembl | ENSP00000500971.1 | 38 | MANE Select | |
| RefSeq | NP_001177411.1 | 37 | Standard | |
| RefSeq | NP_006191.2 | 21 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pcsk5a | Danio rerio | Structure: lateral line Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Transport of small molecules
- NGF processing
- Expression and Processing of Neurotrophins
- Signaling by NTRKs
Biological Process
- kidney development
- renin secretion into blood stream
- cardiac septum development
- signal peptide processing
- cell-cell signaling
Molecular Function
- endopeptidase activity
- serine-type endopeptidase activity
- protein binding
- peptidase activity
- peptide binding
Cellular Component
- extracellular region
- extracellular space
- Golgi apparatus
- Golgi lumen
- trans-Golgi network
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000545128
- Coding exons
- 37
- Length
- 471696
- Individuals with no LoFs
- 125613
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 135
- Defined
- 125748
- p
- 0.000537
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.57 | 840 | 1.08e+3 | 0.780 | 0.0000610 | 12320 |
| Missense (PolyPhen) | 206 | 423.92 | 0.48594 | 4761 | ||
| Synonymous | 0.623 | 398 | 414 | 0.961 | 0.0000264 | 3274 |
| Loss of Function | 5.79 | 39 | 102 | 0.382 | 0.00000514 | 1249 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00056 | 0.00049 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.0013 | 0.0013 | notable |
| East Asian | 0.0018 | 0.0017 | notable |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00059 | 0.00055 | rare |
| South Asian | 0.00023 | 0.00020 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive and regulated secretory pathways. Plays an essential role in pregnancy establishment by proteolytic activation of a number of important factors such as BMP2, CALD1 and alpha-integrins. {ECO:0000269|PubMed:19764806, ECO:0000269|PubMed:20555025, ECO:0000269|PubMed:22740495}.;
Recessive Scores
- pRec
- 0.242
Intolerance Scores
- LoFtool
- 0.825
- RVIS EVS
- 2.84
- RVIS percentile EVS
- 99.1
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.774
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |