POLD2

Summary

POLD2 (DNA polymerase delta 2, accessory subunit, HGNC:9176) is a protein-coding gene on chromosome 7p13, encoding DNA polymerase delta subunit 2 (P49005). Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. It is a common-essential gene (DepMap: required in 97.7% of cancer cell lines).

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.

Source: NCBI Gene 5425 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-severe combined immunodeficiency due to polymerase delta deficiency (Moderate, GenCC)
• Clinical variants (ClinVar): 398 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_006230

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9176
Approved symbol	POLD2
Name	DNA polymerase delta 2, accessory subunit
Location	7p13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106628
Ensembl biotype	protein_coding
OMIM	600815
Entrez	5425

Gene structure

Transcript identifiers

Ensembl transcripts: 111 — 61 protein_coding, 38 retained_intron, 10 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000223361, ENST00000406581, ENST00000418438, ENST00000433715, ENST00000436400, ENST00000436844, ENST00000452185, ENST00000456038, ENST00000461116, ENST00000463464, ENST00000464871, ENST00000467469, ENST00000470867, ENST00000481104, ENST00000481763, ENST00000489883, ENST00000496539, ENST00000610533, ENST00000698945, ENST00000698946, ENST00000698947, ENST00000698948, ENST00000698949, ENST00000698950, ENST00000698951, ENST00000698952, ENST00000698953, ENST00000698954, ENST00000698955, ENST00000698956, ENST00000698957, ENST00000698958, ENST00000698959, ENST00000698960, ENST00000698961, ENST00000698962, ENST00000698963, ENST00000698964, ENST00000698965, ENST00000698966, ENST00000698967, ENST00000698968, ENST00000698969, ENST00000698970, ENST00000698971, ENST00000698972, ENST00000698973, ENST00000698974, ENST00000698975, ENST00000698976, ENST00000698977, ENST00000698978, ENST00000698979, ENST00000698980, ENST00000698981, ENST00000698982, ENST00000698983, ENST00000698984, ENST00000698985, ENST00000698986, ENST00000698987, ENST00000698988, ENST00000698989, ENST00000698990, ENST00000698991, ENST00000698992, ENST00000698993, ENST00000698994, ENST00000881299, ENST00000881300, ENST00000881301, ENST00000881302, ENST00000881303, ENST00000881304, ENST00000881305, ENST00000881306, ENST00000881307, ENST00000881308, ENST00000881309, ENST00000881310, ENST00000881311, ENST00000881312, ENST00000881313, ENST00000881314, ENST00000881315, ENST00000881316, ENST00000881317, ENST00000881318, ENST00000881319, ENST00000881320, ENST00000881321, ENST00000881322, ENST00000881323, ENST00000931682, ENST00000931683, ENST00000931684, ENST00000931685, ENST00000931686, ENST00000931687, ENST00000931688, ENST00000964228, ENST00000964229, ENST00000964230, ENST00000964231, ENST00000964232, ENST00000964233, ENST00000964234, ENST00000964235, ENST00000964236, ENST00000964237, ENST00000964238

RefSeq mRNA: 3 — MANE Select: NM_006230 NM_001127218, NM_001256879, NM_006230

CCDS: CCDS5477

Canonical transcript exons

ENST00000610533 — 11 exons

Exon	Start	End
ENSE00000680769	44116430	44116510
ENSE00000680772	44116817	44117015
ENSE00000680774	44117133	44117247
ENSE00001761884	44116115	44116272
ENSE00003557682	44121834	44122109
ENSE00003727843	44123511	44123548
ENSE00003730786	44114680	44114945
ENSE00003975291	44115766	44115893
ENSE00003975308	44115295	44115396
ENSE00003975316	44117619	44117742
ENSE00003975338	44117943	44118064

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.4872 / max 130.8352, expressed in 1777 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83847	19.6425	1775
83845	0.8447	565

Top tissues by expression

301 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.31	gold quality
apex of heart	UBERON:0002098	97.22	gold quality
ventricular zone	UBERON:0003053	97.20	gold quality
right lobe of liver	UBERON:0001114	96.95	gold quality
lower esophagus mucosa	UBERON:0035834	96.88	gold quality
right atrium auricular region	UBERON:0006631	96.82	gold quality
body of pancreas	UBERON:0001150	96.80	gold quality
left ovary	UBERON:0002119	96.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.67	gold quality
esophagus mucosa	UBERON:0002469	96.57	gold quality
skin of abdomen	UBERON:0001416	96.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.51	gold quality
ganglionic eminence	UBERON:0004023	96.49	gold quality
ectocervix	UBERON:0012249	96.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.47	gold quality
adenohypophysis	UBERON:0002196	96.43	gold quality
left uterine tube	UBERON:0001303	96.41	gold quality
gastrocnemius	UBERON:0001388	96.41	gold quality
skin of leg	UBERON:0001511	96.41	gold quality
right ovary	UBERON:0002118	96.36	gold quality
esophagus	UBERON:0001043	96.32	gold quality
cerebellar hemisphere	UBERON:0002245	96.30	gold quality
cerebellar cortex	UBERON:0002129	96.20	gold quality
tibial nerve	UBERON:0001323	96.18	gold quality
popliteal artery	UBERON:0002250	96.14	gold quality
lower esophagus	UBERON:0013473	96.14	gold quality
cardiac atrium	UBERON:0002081	96.13	gold quality
tibial artery	UBERON:0007610	96.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.13	gold quality
heart left ventricle	UBERON:0002084	96.06	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	21.87
E-HCAD-10	yes	17.83
E-MTAB-8271	yes	6.56
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, E2F4, JUN, MYC, NFIC, SP1, TFAP2A, TP53, TP63, TP73

miRNA regulators (miRDB)

1 targeting POLD2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3934-3P	99.76	65.51	1351

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 14)

• the interaction of PCNA with DNA polymerase delta is mediated through the small subunit of the enzyme (PMID:11986310)
• The association of PDIP38 with pol delta was shown to occur in calf thymus tissue and mammalian cell extracts by GST-PDIP38 pull-down and coimmunoprecipitation experiments. (PMID:12522211)
• As a first step towards understanding the functional importance of their regulatory subunit interactions, the three-dimensional structure of the p50-p66 heterodimer of human Pol delta has been solved using X-ray crystallography. (PMID:18765914)
• the crystal structure of p50*p66(N) complex featuring oligonucleotide binding and phosphodiesterase domains in p50 (PMID:18818516)
• Results suggest that POLD2 and KSP37 might be potential prognostic biomarkers. (PMID:21079801)
• DNA polymerase delta catalytic subunit p125 induced by mutant type p53 is associated with hepatocellular carcinoma invasion. (PMID:21372597)
• The results show that the FF483-484 amino acids in the human Poleta (designated F1 motif) are necessary for the interaction of this polymerase with POLD2, the B subunit of the replicative DNA polymerase delta, both in vitro and in vivo. (PMID:25662213)
• Inhibition of DNA polymerases a, delra and e by AFP promoter-driven artificial microRNAs may lead to effective growth arrest of AFP-positive HCC cells,as novel strategy for gene therapy (PMID:25924900)
• The proofreading activity of DNA polymerase delta plays a role in shunting DNA mismatch repair to an EXO1-dependent excision pathway as opposed to directly participating in gap formation via its 3’-5’ exonuclease activity. (PMID:28934474)
• The role in cellular processes (DNA replication, DNA repair, homologous recombination) and cell cycle regulation of 2 forms of human DNA polymerase delta: delta3 and delta4 was reviewed. (REVIEW) (PMID:31326365)
• In patients from 2 independent pedigrees, we have identified what we believe to be a novel syndrome with reduced functionality of the polymerase delta complex caused by germline biallelic mutations in POLD1 or POLD2 as the underlying etiology of a previously unknown autosomal-recessive syndrome that combines replicative stress, neurodevelopmental abnormalities, and immunodeficiency. (PMID:31449058)
• ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics. (PMID:31954770)
• Polymerase delta promotes chromosomal rearrangements and imprecise double-strand break repair. (PMID:33077594)
• Exome sequencing reveals novel rare variants in Iranian familial multiple sclerosis: The importance of POLD2 in the disease pathogenesis. (PMID:34116171)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pold2	ENSDARG00000095046
mus_musculus	Pold2	ENSMUSG00000020471
rattus_norvegicus	Pold2	ENSRNOG00000014098
drosophila_melanogaster	PolD2	FBGN0027903
caenorhabditis_elegans		WBGENE00008722

Protein

Protein identifiers

DNA polymerase delta subunit 2 — P49005 (reviewed: P49005)

Alternative names: DNA polymerase delta subunit p50

All UniProt accessions (16): P49005, A0A087WWF6, A0A8V8TMJ0, A0A8V8TMJ5, A0A8V8TMK0, A0A8V8TMZ6, A0A8V8TN02, A0A8V8TN07, A0A8V8TNY7, A0A8V8TPA1, A0A8V8TPA6, A0A8V8TPB6, C9IZD2, C9JHC7, C9JLE1, H7C1B3

UniProt curated annotations — full annotation on UniProt →

Function. Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. 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. 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. 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. Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR). 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 DNA polymerase zeta complex. Along with POLD3, dramatically increases the efficiency and processivity of DNA synthesis of the DNA polymerase zeta complex compared to the minimal zeta complex, consisting of only REV3L and REV7.

Subunit / interactions. Component of both the DNA polymerase delta and DNA polymerase zeta complexes. Component of the tetrameric DNA polymerase delta complex (Pol-delta4), which consists of POLD1/p125, POLD2/p50, POLD3/p66/p68 and POLD4/p12, with POLD1 bearing DNA polymerase and 3’ to 5’ proofreading exonuclease activities. Within Pol-delta4, directly interacts with POLD1, POLD3 and POLD4. Following stress caused by DNA damaging agents or by replication stress, POLD4 is degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3), which consists of POLD1, POLD2 and POLD3. Pol-delta3 is the major form occurring at S phase replication sites, as well as DNA damage sites. Also observed as a dimeric complex with POLD2 (Pol-delta2 complex). Pol-delta2 is relatively insensitive to the PCNA stimulation (2-5-fold) compared to Pol-delta4 that is stimulated by over 50-fold. Contrary to the other components of Pol-delta4, does not directly interact with PCNA. As POLD1 and POLD4, directly interacts with WRNIP1; this interaction stimulates DNA polymerase delta-mediated DNA synthesis, independently of the presence of PCNA. This stimulation may be due predominantly to an increase of initiation frequency and also to increased processivity. Directly interacts with POLDIP2 and POLDIP3. Directly interacts with KCTD13/PDIP1; in the presence of PCNA, this interaction may stimulate DNA polymerase activity. Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3, with REV3L bearing DNA polymerase catalytic activity. Interacts with KCTD10.

Subcellular location. Nucleus.

Similarity. Belongs to the DNA polymerase delta/II small subunit family.

RefSeq proteins (3): NP_001120690, NP_001243808, NP_006221* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007185	DNA_pol_a/d/e_bsu	Domain
IPR024826	DNA_pol_delta/II_ssu	Family
IPR040663	DNA_pol_D_N	Domain
IPR041863	PolD2_C	Domain

Pfam: PF04042, PF18018

UniProt features (47 total): strand 22, helix 11, turn 4, modified residue 3, mutagenesis site 3, sequence variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
3E0J	X-RAY DIFFRACTION	3
6TNY	ELECTRON MICROSCOPY	3.08
9EKB	ELECTRON MICROSCOPY	3.65
6TNZ	ELECTRON MICROSCOPY	4.05
6S1M	ELECTRON MICROSCOPY	4.27
6S1N	ELECTRON MICROSCOPY	4.86
6S1O	ELECTRON MICROSCOPY	8.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49005-F1	89.42	0.75

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 1, 15, 257

Mutagenesis-validated functional residues (3):

Position	Phenotype
217	loss of pold3-binding in a yeast two-hybrid assay.
224	loss of pold3-binding in a yeast two-hybrid assay.
231	loss of pold3-binding in a yeast two-hybrid assay.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174414	Processive synthesis on the C-strand of the telomere
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
R-HSA-5358606	Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-69091	Polymerase switching
R-HSA-69166	Removal of the Flap Intermediate
R-HSA-69183	Processive synthesis on the lagging strand

MSigDB gene sets: 270 (showing top): REACTOME_DNA_REPLICATION, MODULE_52, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_DNA_DAMAGE_TOLERANCE, MODULE_16, KAUFFMANN_DNA_REPAIR_GENES, KEGG_HOMOLOGOUS_RECOMBINATION, MODULE_118, GOCC_NUCLEAR_REPLICATION_FORK, MUELLER_PLURINET, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, KEGG_MISMATCH_REPAIR

GO Biological Process (8): DNA replication (GO:0006260), DNA-templated DNA replication (GO:0006261), DNA strand elongation involved in DNA replication (GO:0006271), DNA repair (GO:0006281), error-prone translesion synthesis (GO:0042276), DNA biosynthetic process (GO:0071897), DNA metabolic process (GO:0006259), DNA damage response (GO:0006974)

GO Molecular Function (2): DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), zeta DNA polymerase complex (GO:0016035), delta DNA polymerase complex (GO:0043625)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	2
Mismatch Repair	2
Global Genome Nucleotide Excision Repair (GG-NER)	2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2
Lagging Strand Synthesis	2
DNA Damage Bypass	1
Extension of Telomeres	1
Processive synthesis on the C-strand of the telomere	1
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Leading Strand Synthesis	1
Processive synthesis on the lagging strand	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	3
DNA replication	2
DNA polymerase complex	2
DNA biosynthetic process	1
DNA-templated DNA replication	1
DNA strand elongation	1
DNA synthesis involved in DNA replication	1
DNA damage response	1
translesion synthesis	1
nucleic acid biosynthetic process	1
nucleic acid metabolic process	1
cellular response to stress	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear replisome	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

1715 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLD2	POLD3	Q15054	999
POLD2	POLD1	P28340	999
POLD2	REV3L	O60673	995
POLD2	MAD2L2	Q9UI95	991
POLD2	POLD4	Q9HCU8	927
POLD2	POLDIP2	Q9Y2S7	907
POLD2	KCTD13	Q8WZ19	829
POLD2	POLE2	P56282	828
POLD2	REV1	Q9UBZ9	828
POLD2	FEN1	P39748	796
POLD2	KCTD10	Q9H3F6	786
POLD2	POLA2	Q14181	784
POLD2	POLE4	Q9NR33	757
POLD2	POLA1	P09884	744
POLD2	TNFAIP1	Q13829	724

IntAct

71 interactions, top by confidence:

A	B	Type	Score
POLD1	POLD2	psi-mi:“MI:0914”(association)	0.910
POLD2	POLD1	psi-mi:“MI:0407”(direct interaction)	0.910
POLD1	POLD2	psi-mi:“MI:0407”(direct interaction)	0.910
POLD2	POLD1	psi-mi:“MI:0914”(association)	0.910
POLD1	POLD2	psi-mi:“MI:0915”(physical association)	0.910
POLD2	POLD1	psi-mi:“MI:0915”(physical association)	0.910
POLD4	POLD1	psi-mi:“MI:0914”(association)	0.900
POLD2	POLD3	psi-mi:“MI:0407”(direct interaction)	0.890
POLD3	POLD2	psi-mi:“MI:0915”(physical association)	0.890
POLD2	POLD3	psi-mi:“MI:0915”(physical association)	0.890
POLD2	POLD4	psi-mi:“MI:0915”(physical association)	0.790
POLD4	POLD2	psi-mi:“MI:0407”(direct interaction)	0.790
POLD2	POLD4	psi-mi:“MI:0407”(direct interaction)	0.790
PCNA	POLD2	psi-mi:“MI:0915”(physical association)	0.680
PCNA	POM121C	psi-mi:“MI:0914”(association)	0.550
ERP44	MEX3A	psi-mi:“MI:0914”(association)	0.530
AMZ1	SUSD5	psi-mi:“MI:0914”(association)	0.530
GPR37	ATE1	psi-mi:“MI:0914”(association)	0.530

BioGRID (113): POLD2 (Affinity Capture-MS), POLD2 (Affinity Capture-Western), OSBPL9 (Co-fractionation), POLA2 (Co-fractionation), POLD2 (Co-fractionation), POLD2 (Co-fractionation), POLD2 (Synthetic Growth Defect), POLD2 (Two-hybrid), POLD2 (Affinity Capture-MS), POLD2 (Affinity Capture-MS), POLD2 (Affinity Capture-MS), POLD2 (Affinity Capture-MS), POLH (Two-hybrid), POLH (Reconstituted Complex), REV3L (Affinity Capture-MS)

ESM2 similar proteins: A2VCW9, A5WVX1, A7SBF0, A8E657, D3ZVK1, F4JWP9, I0IUP3, O16216, O35654, O48520, O89043, O93610, P0CN24, P0CN25, P17571, P33611, P49004, P49005, Q0J7N5, Q13057, Q14181, Q2UM43, Q3UJK4, Q4WN24, Q58D13, Q5B5L3, Q5RCH4, Q5VQ69, Q652P4, Q6AU07, Q6AXY4, Q6DE00, Q6ING7, Q6NUA1, Q7RZA2, Q7ZWC4, Q8AVL0, Q8GWT4, Q8K224, Q95TS5

Diamond homologs: O35654, O48520, O93610, P46957, P49004, P49005, P87324, Q6AXY4, Q9LRE5, Q9W088

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POLD2	“form complex”	“DNA polymerase delta”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Processive synthesis on the C-strand of the telomere	5	112.0×	4e-08
PCNA-Dependent Long Patch Base Excision Repair	5	76.3×	3e-07
Gap-filling DNA repair synthesis and ligation in GG-NER	5	64.6×	6e-07
Gap-filling DNA repair synthesis and ligation in TC-NER	5	26.2×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
DNA synthesis involved in DNA repair	5	95.5×	6e-07
DNA-templated DNA replication	5	57.3×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

398 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	217
Likely benign	141
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

1972 predictions. Top by Δscore:

Variant	Effect	Δscore
7:44115761:GTTAC:G	donor_loss	1.0000
7:44115763:TACCT:T	donor_loss	1.0000
7:44115765:CC:C	donor_loss	1.0000
7:44116428:A:AC	donor_gain	1.0000
7:44116429:C:CA	donor_gain	1.0000
7:44116429:CG:C	donor_gain	1.0000
7:44116429:CGCT:C	donor_gain	1.0000
7:44116435:G:C	donor_gain	1.0000
7:44116463:AACAG:A	donor_gain	1.0000
7:44116506:TTGGC:T	acceptor_gain	1.0000
7:44116507:TGGC:T	acceptor_gain	1.0000
7:44116508:GGC:G	acceptor_gain	1.0000
7:44116508:GGCCT:G	acceptor_loss	1.0000
7:44116509:GC:G	acceptor_gain	1.0000
7:44116510:CC:C	acceptor_gain	1.0000
7:44116511:C:CC	acceptor_gain	1.0000
7:44116511:CTGGA:C	acceptor_loss	1.0000
7:44116512:T:A	acceptor_loss	1.0000
7:44116516:A:AC	acceptor_gain	1.0000
7:44116812:CATA:C	donor_loss	1.0000
7:44116813:ATAC:A	donor_loss	1.0000
7:44116815:A:AT	donor_loss	1.0000
7:44116816:CCT:C	donor_loss	1.0000
7:44117011:CAAAC:C	acceptor_gain	1.0000
7:44117012:AAACC:A	acceptor_loss	1.0000
7:44117013:AACC:A	acceptor_loss	1.0000
7:44117014:ACC:A	acceptor_loss	1.0000
7:44117016:C:CG	acceptor_loss	1.0000
7:44117017:T:A	acceptor_loss	1.0000
7:44117617:AC:A	donor_gain	1.0000

AlphaMissense

3260 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:44116863:C:A	G245V	0.999
7:44114885:G:T	A437D	0.998
7:44115342:A:T	V401D	0.998
7:44116144:G:C	N330K	0.998
7:44116144:G:T	N330K	0.998
7:44116244:C:A	G297V	0.998
7:44116443:A:G	L283P	0.998
7:44116452:T:A	D280V	0.998
7:44116878:C:G	R240P	0.998
7:44116926:C:T	G224E	0.998
7:44116947:A:G	L217P	0.998
7:44116214:G:T	P307H	0.997
7:44116235:T:C	D300G	0.997
7:44116250:A:C	M295R	0.997
7:44116434:A:G	L286P	0.997
7:44116453:C:A	D280Y	0.997
7:44116453:C:G	D280H	0.997
7:44116863:C:T	G245D	0.997
7:44116864:C:G	G245R	0.997
7:44116875:A:T	V241D	0.997
7:44116926:C:A	G224V	0.997
7:44116927:C:A	G224W	0.997
7:44116938:T:A	D220V	0.997
7:44114902:G:C	F431L	0.996
7:44114902:G:T	F431L	0.996
7:44114903:A:G	F431S	0.996
7:44114904:A:G	F431L	0.996
7:44114912:A:T	V428D	0.996
7:44115330:C:T	G405D	0.996
7:44115777:G:T	P379H	0.996

dbSNP variants (sampled 300 via entrez): RS1000097122 (7:44115028 C>T), RS1000215120 (7:44122322 G>A), RS1000277471 (7:44121614 C>A,T), RS1001100722 (7:44116741 C>A,T), RS1001164351 (7:44122415 C>T), RS1002225027 (7:44116355 G>A,T), RS1002824949 (7:44117835 G>A,C), RS1002860650 (7:44122980 C>G,T), RS1003040343 (7:44124153 C>G,T), RS1003113212 (7:44119267 C>T), RS1003328478 (7:44125671 A>G), RS1003623272 (7:44125406 G>A), RS1004238527 (7:44118771 G>A), RS1004958209 (7:44125725 G>A), RS1005377821 (7:44125931 C>T)

Disease associations

OMIM: gene MIM:600815 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
non-severe combined immunodeficiency due to polymerase delta deficiency	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
non-severe combined immunodeficiency due to polymerase delta deficiency	Limited	AR

Mondo (1): non-severe combined immunodeficiency due to polymerase delta deficiency (MONDO:0800145)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363042 (PROTEIN FAMILY), CHEMBL2763 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
Hydrogen Peroxide	affects cotreatment, decreases reaction, increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
bisphenol A	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenate	decreases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
chromium histidinate	decreases reaction, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Coumestrol	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	increases expression	1
Guanine	affects binding, decreases activity	1
Ivermectin	decreases expression	1
Mercury	affects expression	1
Methapyrilene	increases methylation	1
Oxygen	decreases expression	1
Quercetin	decreases expression	1
Quinic Acid	affects cotreatment, increases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697345	Binding	Inhibition of POLD2 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.