POLD3

Chr 11AR

DNA polymerase delta 3, accessory subunit

Also known as: IMD122, P66, P68, PPP1R128

NCBI Gene: 10714ENSG00000077514UniProt: Q15054

This gene encodes the 66-kDa 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. The encoded protein plays a role in regulating the activity of DNA polymerase delta through interactions with other subunits and the processivity cofactor proliferating cell nuclear antigen (PCNA). Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

Immunodeficiency 122MIM #620869
AR
66
ClinVar variants
8
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— POLD3
🧬
Gene-Disease Validity (ClinGen)
immunodeficiency 122 · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
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
8 Pathogenic / Likely Pathogenic· 52 VUS of 66 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.24LOEUF
pLI 0.998
Z-score 4.43
OE 0.07 (0.03–0.24)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
0.09Z-score
OE missense 0.98 (0.88–1.10)
232 obs / 235.7 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.0.07 (0.03–0.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.88–1.10)
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.0.93
0≤1.21.6
LoF obs/exp: 2 / 26.7Missense obs/exp: 232 / 235.7Syn Z: 0.48

ClinVar Variant Classifications

66 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
VUS52
Likely Benign1
Benign5
8
Pathogenic
52
VUS
1
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
8
0
8
Likely Pathogenic
0
0
0
0
0
VUS
0
49
3
0
52
Likely Benign
0
0
0
1
1
Benign
0
4
0
1
5
Total05311266

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

View in ClinVar →

Protein Context — Lollipop Plot

POLD3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Immunodeficiency 122

MIM #620869

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment.
Mehawej C et al.·Clin Immunol
2023
Interaction of CCND2, CDKN1A, and POLD3 Variants in Mexican Patients with Colorectal Cancer.
Alvizo-Rodríguez CR et al.·Turk J Gastroenterol
2022Cohort
POLD3 haploinsufficiency is linked to non-syndromic sensorineural adult-onset progressive hearing and balance impairments.
Chouery E et al.·Eur J Hum Genet
2025
POLD3 knockdown effects on low-grade glioma: insights from bioinformatics and experimental validation.
Yang Z et al.·BMC Cancer
2025
POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies.
Nicolas E et al.·Gene
2016Review
Identification of Frameshift Variants in POLH Gene Causing Xeroderma Pigmentosum in Two Consanguineous Pakistani Families.
Zamani GY et al.·Genes (Basel)
2022
Deciphering the ghost proteome in ovarian cancer cells by deep proteogenomic characterization.
Garcia-Del Rio DF et al.·Cell Death Dis
2024
A novel investigation into an E2F transcription factor-related prognostic model with seven signatures for colon cancer patients.
Shen X et al.·IET Syst Biol
2023Cohort
Microarray-based measurement of microRNA-449c-5p levels in hepatocellular carcinoma and bioinformatic analysis of potential signaling pathways.
Jiang L et al.·Pathol Res Pract
2019
Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.
Spier I et al.·Int J Cancer
2015Cohort
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
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

External Resources

Links to major genomics databases and tools