POLD1

Chr 19ADAR

DNA polymerase delta 1, catalytic subunit

Also known as: CDC2, CRCS10, IMD120, MDPL, POLD

NCBI Gene: 5424ENSG00000062822UniProt: P28340

This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

{Colorectal cancer, susceptibility to, 10}MIM #612591
AD
Immunodeficiency 120MIM #620836
AR
Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndromeMIM #615381
AD
UniProtColorectal cancer 10
586
ClinVar variants
2
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical Summary— POLD1
🧬
Gene-Disease Validity (ClinGen)
non-severe combined immunodeficiency due to polymerase delta deficiency · ARLimited

Limited evidence — not for standalone diagnostic reporting

3 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
2 Pathogenic / Likely Pathogenic· 360 VUS of 586 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.53LOEUF
pLI 0.000
Z-score 4.39
OE 0.36 (0.25–0.53)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
2.46Z-score
OE missense 0.75 (0.70–0.80)
561 obs / 750.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.36 (0.25–0.53)
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 (0.70–0.80)
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.1.02
0≤1.21.6
LoF obs/exp: 20 / 55.2Missense obs/exp: 561 / 750.7Syn Z: -0.33

ClinVar Variant Classifications

586 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic1
VUS360
Likely Benign195
Benign27
Conflicting2
1
Pathogenic
1
Likely Pathogenic
360
VUS
195
Likely Benign
27
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
0
0
1
Likely Pathogenic
0
1
0
0
1
VUS
63
242
51
4
360
Likely Benign
2
15
110
68
195
Benign
0
0
2
25
27
Conflicting
—2
Total6625816397586

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

View in ClinVar →

Protein Context — Lollipop Plot

POLD1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

POLD1-related subcutaneous lipodystrophy, deafness, mandibular hypoplasia and male hypogonadism

definitive
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkinEar
G2P ↗
missense variantinframe deletioninframe insertion

POLD1-related polymerase proofreading-associated polyposis

strong
ADUndeterminedUncertain
Cancer
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Colorectal cancer, susceptibility to, 10}

MIM #612591

Molecular basis of disorder known

Autosomal dominant

Immunodeficiency 120

MIM #620836

Molecular basis of disorder known

Autosomal recessive

Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome

MIM #615381

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — POLD1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
POLE/POLD1 mutation and tumor immunotherapy.
Ma X et al.·J Exp Clin Cancer Res
2022Review
Role of POLE and POLD1 in familial cancer.
Mur P et al.·Genet Med
2020
The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of colorectal cancer, 2024 update.
Wang F et al.·Cancer Commun (Lond)
2025Guideline
Genetics, genomics and clinical features of adenomatous polyposis.
Joo JE et al.·Fam Cancer
2025Review
Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?
Rebuzzi F et al.·Int J Mol Sci
2023Review
Proteogenomic Markers of Chemotherapy Resistance and Response in Triple-Negative Breast Cancer.
Anurag M et al.·Cancer Discov
2022
Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1.
Mur P et al.·Genome Med
2023
Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.
Ma X et al.·Nat Genet
2022Functional
POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies.
Nicolas E et al.·Gene
2016Review
POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes.
Magrin L et al.·Oncogene
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Genotype-Phenotype Heterogeneity Among Patients with Lipodystrophy Harboring Rare POLD1 Variants.
Hoff FW et al.·J Clin Endocrinol Metab
2026Cohort
Case Report: Expansion of the POLD1-related polymerase proofreading-associated polyposis spectrum: first report of duodenal adenocarcinomas and characterization of two likely pathogenic variants.
Folletet A et al.·Front Oncol
2025🔓 Open AccessCase report
Structural and functional impact of the POLD1 Ser605del variant in MDPL syndrome: insights from protein-protein interactions.
Murdocca M et al.·Hum Genomics
2025🔓 Open AccessFunctional
The germline POLD1 c.1420 C > A (p.Leu474Ile) variant segregates with endometrial cancer, colorectal cancer and colonic polyps demonstrating hypermutation and defective POLD1 mutational signatures.
Buchanan DD et al.·Fam Cancer
2025
POLD1 identification as a potential prognostic and immunotherapeutic biomarker for hepatocellular carcinoma.
Liu W et al.·Int J Biol Macromol
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Familial Adenomatous Polyposis (FAP)Attenuated Familial Adenomatous Polyposis (AFAP)MUTYH-Associated Polyposis (MAP)

Familial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare)

ACTIVE NOT RECRUITING
NCT07461246Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoStarted 2024-05-13
Solid TumorAdvanced Solid TumorMetastatic Cancer

KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II

RECRUITING
NCT05525858Seoul National University Bundang HospitalStarted 2022-09-28
AlectinibAtezolizumabErlotinib
BRCA1 MutationPOLD1 Gene MutationCDKN2A Mutation

An Intervention to Increase Genetic Testing in Families Who May Share a Gene Mutation Related to Cancer Risk and An Intervention to Help Patients and Their Primary Care Providers Stay Up-to-date About Uncertain Genetic Test Results

RECRUITING
NCT05420064Phase NAMemorial Sloan Kettering Cancer CenterStarted 2022-12-01
Intervention Arm At-risk Relative/ARR ContactsMyGene PortalStandard of Care
BRCA1 Gene MutationBRCA2 Gene MutationLocally Advanced Solid Neoplasm

Pembrolizumab in Treating Participants With Metastatic, Recurrent or Locally Advanced Cancer and Genomic Instability

RECRUITING
NCT03428802Phase PHASE2Rutgers, The State University of New JerseyStarted 2018-03-08
Laboratory Biomarker AnalysisPembrolizumab
Advanced Solid Tumor

A Modular Multi-Basket Trial to Improve Personalized Medicine in Cancer Patients (Basket of Baskets)

RECRUITING
NCT03767075Phase PHASE2Vall d'Hebron Institute of OncologyStarted 2018-12-10
AtezolizumabFutibatinibAmivantamab
CarcinomaNon-Small-Cell Lung CancerAdenocarcinoma

Synergistic Effect of Elemene Plus TKIs Compared With TKIs in EGFR-mutated Advanced NSCLC：Prospective Study

RECRUITING
NCT04401059Phase PHASE4Tian XieStarted 2020-11-09
Elemene plus first or third generation EGFR-TKIsFirst or third generation EGFR-TKIs
Lipodystrophy (Genetic or Acquired, Non HIV)

The LD Lync Study - Natural History Study of Lipodystrophy Syndromes

RECRUITING
NCT03087253University of MichiganStarted 2018-02-27
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer

RECRUITING
NCT02693535Phase PHASE2American Society of Clinical OncologyStarted 2016-03-14
PalbociclibSunitinibTemsirolimus
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)

RECRUITING
NCT03297606Phase PHASE2Canadian Cancer Trials GroupStarted 2018-03-23
OlaparibDasatinibNivolumab plus Ipilimumab
TumorsPOLE Exonuclease Domain MutationPOLD1 Gene Mutation

Cohort of Tumors With POLE/D1 Mutation

RECRUITING
NCT05103969Federation Francophone de Cancerologie DigestiveStarted 2021-10-05
GastricColorectal Adenocarcinoma

Chemotherapy Sequential Tislelizumab After Radical Resection in Patients With dMMR/MSI-H or POLE/POLD1 Mutations

NOT YET RECRUITING
NCT06118658Phase PHASE2China Medical University, ChinaStarted 2023-11-01
tislelizumab

External Resources

Links to major genomics databases and tools