POLD2

protein-coding

DNA polymerase delta 2, accessory subunit, the group of DNA polymerases

Gene summary

This gene encodes the 50-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. The encoded protein is required for the stimulation of DNA polymerase delta activity by the processivity cofactor proliferating cell nuclear antigen (PCNA). Expression of this gene may be a marker for ovarian carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Mar 2012]

MANE transcript

NM_006230.4

Inheritance

ClinVar variants

U:189B:90

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr7:44,114,631-44,124,358

External References & Databases

Ensembl (ENSG00000106628)

Transcript & Mutation Effects

hg38 • Region Span ~9.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-severe combined immunodeficiency due to polymerase delta deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0800145

Submitter: ClinGen

POLD2 was first reported in relation to an autosomal recessive non-severe combined immunodeficiency due to polymerase delta deficiency in 2019 (Conde, et al., 2019, PMID:31449058). To date, there is only one proband with a POLD2 homozygous missense variant and the disease. The proband displayed severe intellectual disability, short stature, recurrent upper and lower respiratory infections, CD4+ T, B, and NK cell lymphopenia, and high frequency of CCR7-CD45RA+ TEMRA CD8+ T cells. Patient fibroblasts showed slower S phase progression with faster replication fork progression compared to healthy donor fibroblasts and reduced number of replication origin initiation events. Heterozygous carriers are not known to be affected. This gene-disease association is also supported by one animal model (PMID:36528861). Homozygous POLD2 knock out mice were embryonic lethal by the gastrulation stage with an apparent deficiency in cellular proliferation, as mutant cells failed to grow from the zona pellucida. The gene-disease association is also supported by biochemical function showing that POLD2 provides the scaffolding for the assembly of DNA polymerase Delta, which is a critical enzyme for both DNA replication and DNA repair. Additionally, a co-IP assay has shown that POLD2 co-immunoprecipitates with POLD1, the catalytic subunit of DNA polymerase delta that has also been implicated in non-severe combined immunodeficiency due to polymerase delta deficiency. In summary, this curation reached a level of Limited due to the small number of published patients. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the SCID-CID GCEP on February 16, 2023. It was reevaluated on February 16, 2026. As a result of this reevaluation, the classification did not change.

non-severe combined immunodeficiency due to polymerase delta deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0800145

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLD2 variants in ClinVar

2 Conditions Cataloged

not providedTotal: 329

not specifiedTotal: 77

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006230.4. 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			6 clinvar	84 clinvar	4 clinvar	94
missense			168 clinvar	2 clinvar		170
nonsense			4 clinvar			4
start loss						0
frameshift			6 clinvar			6
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	189	86	4	279

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 178 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006230.4	RefSeq	NP_006221.3	10	MANE Select
ENST00000610533.6	Ensembl	ENSP00000480186.2	10	MANE Select
NM_001127218.3	RefSeq	NP_001120690.1	10	Standard
NM_001256879.2	RefSeq	NP_001243808.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide excision repair - Homo sapiens (human)
Pyrimidine metabolism - Homo sapiens (human)
Base excision repair - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
Mismatch repair - Homo sapiens (human)

Biological Process

telomere maintenance
DNA replication
DNA strand elongation involved in DNA replication
transcription-coupled nucleotide-excision repair
nucleotide-excision repair, DNA incision, 5'-to lesion

Molecular Function

DNA binding
DNA-directed DNA polymerase activity
protein binding

Cellular Component

nucleus
nucleoplasm
delta DNA polymerase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000406581
Coding exons: 10
Length: 9672
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125747
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.65	212	291	0.729	0.0000177	3027
Missense (PolyPhen)		58	88.961	0.65197		945
Synonymous	0.581	118	126	0.934	0.00000806	981
Loss of Function	2.66	9	22.7	0.397	0.00000123	238

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As a component of the trimeric and tetrameric DNA polymerase delta complexes (Pol-delta3 and Pol-delta4, respectively), plays a role in high fidelity genome replication, including in lagging strand synthesis, and repair (PubMed:12403614, PubMed:16510448, PubMed:19074196, PubMed:20334433, PubMed:24035200). Pol-delta3 and Pol-delta4 are characterized by the absence or the presence of POLD4. They exhibit differences in catalytic activity. Most notably, Pol- delta3 shows higher proofreading activity than Pol-delta4 (PubMed:19074196, PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may also be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated (PubMed:24035200). Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation (PubMed:20227374). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR) (PubMed:24310611). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites performed by Pol-delta4, independently of DNA polymerase zeta (REV3L) or eta (POLH). Facilitates abasic site bypass by DNA polymerase delta by promoting extension from the nucleotide inserted opposite the lesion. Also involved in TLS as a component of the POLZ complex. Along with POLD3, dramatically increases the efficiency and processivity of DNA synthesis of the minimal DNA polymerase zeta complex, consisting of only REV3L and REV7 (PubMed:24449906). {ECO:0000269|PubMed:12403614, ECO:0000269|PubMed:16510448, ECO:0000269|PubMed:19074196, ECO:0000269|PubMed:20227374, ECO:0000269|PubMed:20334433, ECO:0000269|PubMed:24035200, ECO:0000269|PubMed:24310611, ECO:0000269|PubMed:24449906}.;

Recessive Scores

pRec: 0.224

Intolerance Scores

LoFtool: 0.639
RVIS EVS: -0.91
RVIS percentile EVS: 9.9

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium