POLA1

Chr XXLR

DNA polymerase alpha 1, catalytic subunit

Also known as: NSX, PDR, POLA, VEODS, p180

NCBI Gene: 5422ENSG00000101868UniProt: P09884

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]

Primary Disease Associations & Inheritance

Pigmentary disorder, reticulate, with systemic manifestations, X-linkedMIM #301220
XLR
Van Esch-O'Driscoll syndromeMIM #301030
XLR
407
ClinVar variants
13
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— POLA1
🧬
Gene-Disease Validity (ClinGen)
X-linked reticulate pigmentary disorder · XLModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 229 VUS of 407 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.05LOEUF
pLI 1.000
Z-score 7.04
OE 0.00 (0.00–0.05)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.99Z-score
OE missense 0.75 (0.69–0.82)
384 obs / 510.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.05)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.69–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 0 / 57.7Missense obs/exp: 384 / 510.9Syn Z: -0.91

ClinVar Variant Classifications

407 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic1
VUS229
Likely Benign139
Benign22
Conflicting4
12
Pathogenic
1
Likely Pathogenic
229
VUS
139
Likely Benign
22
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
0
1
0
0
1
VUS
0
214
13
2
229
Likely Benign
0
8
52
79
139
Benign
0
5
8
9
22
Conflicting
—4
Total02288590407

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

POLA1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

POLA1-related pigmentary disorder, reticulate, with systemic manifestations

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗
splice acceptor variantmissense variantinframe deletion

POLA1-related Van Esch-O'Driscoll syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pigmentary disorder, reticulate, with systemic manifestations, X-linked

MIM #301220

Molecular basis of disorder known

X-linked recessive

Van Esch-O'Driscoll syndrome

MIM #301030

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.
Tummala H et al.·EMBO Mol Med
2024
Immune Dysfunction in Mendelian Disorders of POLA1 Deficiency.
Starokadomskyy P et al.·J Clin Immunol
2021Review
The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.
Giudice E et al.·Nat Commun
2024Clinical trial
A patient with POLA1 splice variant expands the yet evolving phenotype of Van Esch O'Driscoll syndrome.
Endrakanti M et al.·Eur J Med Genet
2021Case report
A Xp22.11-p21.3 microdeletion in a three-generation family supports male lethality of POLA1 nullisomy resulting in reduced fertility of female carriers.
Begemann A et al.·Eur J Med Genet
2022
Characterization of DNA Polymerase Genes in Amazonian Amerindian Populations.
Cohen-Paes A et al.·Genes (Basel)
2022
NK cell defects in X-linked pigmentary reticulate disorder.
Starokadomskyy P et al.·JCI Insight
2019
Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.
Baxter SK et al.·J Allergy Clin Immunol
2022
Whole-exome sequencing screening for candidate genes and potential pathogenic variants associated with early-onset high myopia in 47 Chinese families.
Rui X et al.·Sci Rep
2025
Prognostic roles of metabolic reprogramming-associated genes in patients with hepatocellular carcinoma.
Cui L et al.·Aging (Albany NY)
2020Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools