PNP
protein-codingpurine nucleoside phosphorylase
Gene summary
This gene encodes an enzyme which reversibly catalyzes the phosphorolysis of purine nucleosides. The enzyme is trimeric, containing three identical subunits. Mutations which result in nucleoside phosphorylase deficiency result in defective T-cell (cell-mediated) immunity but can also affect B-cell immunity and antibody responses. Neurologic disorders may also be apparent in patients with immune defects. A known polymorphism at aa position 51 that does not affect enzyme activity has been described. A pseudogene has been identified on chromosome 2. [provided by RefSeq, Jul 2008]
- NP
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013171
Submitter: ClinGen
PNP was first reported in relation to autosomal recessive purine nucleoside phosphorylase deficiency in 1987 (Williams et al., PMID: 3029074). Purine nucleoside phosphorylase (PNP) deficiency is a defect in purine metabolism that causes severe combined immunodeficiency with typically profound T-cell deficiency and variable B-cell dysfunction. In addition to early-onset susceptibility to infection, those with PNP deficiency often also have neurological dysfunction which may include intellectual disability, increased or decreased muscle tone, spasticity, and/or ataxia. Some also have autoimmune dysfunction such as autoimmune hemolytic anemia. Hypouricemia is a biochemical sign of PNP deficiency. Heterozygotes are not known to be affected, though they may have decreased PNP enzyme activity. Seven variants including missense, nonsense, frameshift, and splice site that have been reported in seven probands in seven publications are included in this curation (PMIDs: 3029074, 9737781, 22669887, 22578971, 34060650, 37328647, 38954121). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by functional assays and animal models (PMIDs: 1931007, 35641516, 9122228, 10859343). Deficiency of purine nucleoside phosphorylase causes an accumulation of the enzyme’s substrates including deoxyguanosine, which has known cell toxicity. Increased levels of apoptosis were observed in induced pluripotent stem cell‑derived neurons of PNP deficient patients. Multiple mouse models including three missense strains and one knockout mouse recapitulate the human phenotype of T cell deficiency. In summary, there is definitive evidence supporting the relationship between PNP and autosomal recessive purine nucleoside phosphorylase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date June 19, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0013171
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013171
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013171
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Biochemical; Neurologic; Oncologic
Intervention: Allergy/Immunology/Infectious ; Oncologic
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Surveillance for malignancy (eg, lymphoma has been described) can be beneficial; BMT/HSCT has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PNP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000270.4. 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 | 2 | 51 | 53 | |||
| missense | 2 | 10 | 101 | 5 | 118 | |
| nonsense | 8 | 4 | 12 | |||
| start loss | 0 | |||||
| frameshift | 9 | 2 | 11 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 1 | 5 | ||
| Total | 20 | 19 | 104 | 56 | 0 | 199 |
Highest pathogenic variant AF is 0.00016665758
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000261.2 | 6 | MANE Select | |
| Ensembl | ENSP00000354532.6 | 6 | MANE Select | |
| Ensembl | ENSP00000450663.1 | 3 | Standard | |
| Ensembl | ENSP00000452421.2 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pyrimidine metabolism - Homo sapiens (human)
- Nicotinate and nicotinamide metabolism - Homo sapiens (human)
- Purine metabolism - Homo sapiens (human)
- Purine Nucleoside Phosphorylase Deficiency
- Mercaptopurine Action Pathway
Biological Process
- nucleobase-containing compound metabolic process
- inosine catabolic process
- purine nucleotide catabolic process
- nicotinamide riboside catabolic process
- immune response
Molecular Function
- nucleoside binding
- purine nucleobase binding
- purine-nucleoside phosphorylase activity
- drug binding
- phosphate ion binding
Cellular Component
- extracellular region
- nucleus
- cytoplasm
- cytosol
- cytoskeleton
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361505
- Coding exons
- 6
- Length
- 8141
- Individuals with no LoFs
- 125719
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 125748
- p
- 0.000115
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.439 | 146 | 162 | 0.903 | 0.00000861 | 1898 |
| Missense (PolyPhen) | 51 | 60.787 | 0.83899 | 763 | ||
| Synonymous | -0.0240 | 57 | 56.8 | 1.00 | 0.00000286 | 571 |
| Loss of Function | 1.14 | 10 | 14.7 | 0.679 | 9.54e-7 | 135 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta- (deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. {ECO:0000269|PubMed:2104852}.;
Recessive Scores
- pRec
- 0.352
Intolerance Scores
- LoFtool
- 0.289
- RVIS EVS
- 0.59
- RVIS percentile EVS
- 82.51
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.965
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |