POLA1
protein-codingDNA polymerase alpha 1, catalytic subunit, the group of DNA polymerases
Gene summary
This gene encodes the catalytic subunit of DNA polymerase, which together with a regulatory and two primase subunits, forms the DNA polymerase alpha complex. The catalytic subunit plays an essential role in the initiation of DNA replication. [provided by RefSeq, Mar 2010]
- POLA
- NSX
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~303.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010523
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0015601
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0015601
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010523
Submitter: ClinGen
POLA1 was first reported in relation to an X-linked POLA1 deficiency in 2016 (Starokadomskyy, et al., 2016, PMID:27019227). Symptoms usually appear in infancy (first few months to first few years) and most male patients present diffuse skin hyperpigmentation with distinctive reticular pattern, characteristic facial features with frontally upswept hair and flared eyebrows, recurrent lung infections, failure to thrive and hypohidrosis. Corneal inflammation and photophobia are also present in most cases. Female carriers only have restricted pigmentary changes along Blaschko's lines but no other health issues. Patients have normal numbers of T and B cells but reduced number of NK cells. All cases reported were hemizygous for the same hypomorphic mutation that created a splice donor site in intron 13 (NM_001330360.2(POLA1):c.1393-354A>G), leading to 60-65% of transcripts being aberrant and unstable. This mutation leads to the expression of POLA1 at very low levels. The curation of POLA1 relates to X-linked pigmentary reticulate disorder (XLPDR) with MONDO ID 0010523 includes both case-level and experimental evidence. The first publication described a large Canadian family with several family members presenting skin pigmentation features and several male members of the family presenting the disease symptoms (PMID: 6794369 and 2705473). At the time, no genetic mutation was known. Several other cases were reported in other populations (PMIDs: 8302737, 15804299, 23613254, 18365917, 27019227) before the mutation was found and a few more after that (PMIDs: 32989594, 35645674, 37851432) and the mutation in intron 13 of POLA1 was confirmed in all cases. A score of 3.25 points for genetic evidence has been reached. This gene-disease association is also supported by expression, functional alteration, model systems, protein interaction and rescue models (PMIDs: 27019227 and 31672938). Protein expression in dermal fibroblasts from patients is markedly reduced a as well as wild-type mRNA levels. The misspliced POLA1 mRNA is also present at low levels, suggesting it is unstable and degrades. Also, HEK293 cells transfected with a fragment of POLA1 containing exon 13–14 and flanking sequences from control or XLPDR genomic DNA lead to two transcripts and the larger transcript sequencing confirmed presence of ex13a. Patient cells and other cells containing mutant POLA1 or silenced using siPOLA1 showed a marked decrease in the expression of MCM and and GINS proteins, which are present at the replication fork and immunoprecipitation confirmed physical interaction between POLA1 and PRIM2 and MCM4. Patients with XLPDR have lower total number and proportion of NK cells and these exhibited lower cytotoxic activity than the controls and impaired mobilization of lytic granules. The NK cells of patients also had impaired maturation, exhibiting a reduced number of mature NK cells. Patient cells also showed constitutive activation of IRF- and NF-κB-dependent genes, which resulted in a strong type I interferon response in patients with XLPDR. Patients' cells had almost undetectable cytosolic DNA-RNA hybrids and that phenotype was rescued when patient cells were transfected with WT POLA1. A score of 5 points for experimental evidence has been reached, increasing the total score to 8.25 points. In summary, POLA1 is moderately associated with XLPDR. More cases and research will be needed to elevate the classification to strong. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date February 20, 2025 (SOP Version 11).
Inheritance Pattern: XL
Disease ID:MONDO:0015601
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010523
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0015601
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010523
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010523
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0015601
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010523
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dermatologic; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Allergy/Immunology/Infectious
Rationale: Males have been described with manifestations including recurrent respiratory infections and failure to thrive due to inflammatory gastroenteritis or colitis, and awareness, and awareness may allow preventative measures and early and aggressive treatments of infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POLA1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001330360.2. 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 | 32 | 189 | 16 | 237 | ||
| missense | 2 | 6 | 534 | 56 | 19 | 617 |
| nonsense | 10 | 10 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 38 | 42 | ||
| Total | 4 | 8 | 615 | 245 | 35 | 907 |
Highest pathogenic variant AF is 0.000010370011
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001317289.1 | 37 | MANE Select | |
| Ensembl | ENSP00000368358.3 | 37 | MANE Select | |
| RefSeq | NP_001365232.1 | 36 | Standard | |
| RefSeq | NP_001427735.1 | 38 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pola1 | Danio rerio | Structure: trunk Quality: necrotic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pyrimidine metabolism - Homo sapiens (human)
- DNA replication - Homo sapiens (human)
- Purine metabolism - Homo sapiens (human)
- Mitotic G1-G1-S phases
- Retinoblastoma (RB) in Cancer
Biological Process
- G1/S transition of mitotic cell cycle
- regulation of transcription involved in G1/S transition of mitotic cell cycle
- DNA synthesis involved in DNA repair
- DNA replication
- DNA replication, synthesis of RNA primer
Molecular Function
- nucleotide binding
- nucleoside binding
- DNA binding
- chromatin binding
- DNA replication origin binding
Cellular Component
- chromatin
- nucleus
- nuclear envelope
- nucleoplasm
- alpha DNA polymerase:primase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000379059
- Coding exons
- 37
- Length
- 303068
- Individuals with no LoFs
- 107638
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 107639
- p
- 0.00000465
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.99 | 384 | 511 | 0.752 | 0.0000384 | 9673 |
| Missense (PolyPhen) | 90 | 169 | 0.53255 | 3064 | ||
| Synonymous | -0.911 | 201 | 185 | 1.09 | 0.0000142 | 2645 |
| Loss of Function | 7.04 | 0 | 57.7 | 0.00 | 0.00000452 | 1044 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000047 | 0.000040 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses (PubMed:27019227). {ECO:0000269|PubMed:27019227, ECO:0000269|PubMed:9518481}.;
- Disease
- DISEASE: Pigmentary disorder, reticulate, with systemic manifestations, X-linked (PDR) [MIM:301220]: A X-linked recessive disorder characterized by recurrent infections and sterile inflammation in various organs. Diffuse skin hyperpigmentation with a distinctive reticulate pattern is universally evident by early childhood. This is later followed in many patients by hypohidrosis, corneal inflammation and scarring, enterocolitis that resembles inflammatory bowel disease, and recurrent urethral strictures. Melanin and amyloid deposition is present in the dermis. Affected males also have a characteristic facies with frontally upswept hair and flared eyebrows. Female carriers have only restricted pigmentary changes along Blaschko's lines. {ECO:0000269|PubMed:27019227}. Note=The disease is caused by mutations affecting the gene represented in this entry. XLPDR is caused by a recurrent intronic mutation that results in missplicing and reduced POLA1 expression. This leads to a decrease in cytosolic RNA:DNA hybrids and constitutive activation of type I interferon responses, but has no effect on cell replication. {ECO:0000269|PubMed:27019227}.;
Recessive Scores
- pRec
- 0.303
Intolerance Scores
- LoFtool
- 0.0993
- RVIS EVS
- -0.8
- RVIS percentile EVS
- 12.53
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.654
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |