POLD3

Summary

POLD3 (DNA polymerase delta 3, accessory subunit, HGNC:20932) is a protein-coding gene on chromosome 11q13.4, encoding DNA polymerase delta subunit 3 (Q15054). Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

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.

Source: NCBI Gene 10714 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 122 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 68 total — 1 likely-pathogenic
• GTEx eGene: eQTL in 10 tissues, sQTL in 33 (q < 0.05)
• Phenotypes (HPO): 35
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.41 (moderately constrained)
• MANE Select transcript: NM_006591

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20932
Approved symbol	POLD3
Name	DNA polymerase delta 3, accessory subunit
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	P66, KIAA0039, P68, PPP1R128
Ensembl gene	ENSG00000077514
Ensembl biotype	protein_coding
OMIM	611415
Entrez	10714

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000263681

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 2, TSL 4: 2

ENST00000263681, ENST00000524752, ENST00000527458, ENST00000528481, ENST00000530163, ENST00000530511, ENST00000531615, ENST00000532497, ENST00000532784, ENST00000532954, ENST00000935603, ENST00001053955, ENST00001089244, ENST00001108603, ENST00001117496, ENST00001117497, ENST00001117498, ENST00001129415, ENST00001136700

RefSeq mRNA: 2 — MANE Select: NM_006591 NM_001363597, NM_006591

CCDS: CCDS8233, CCDS86228

Canonical transcript exons

ENST00000263681 — 12 exons

Exon	Start	End
ENSE00001039036	74625408	74625573
ENSE00001039037	74620017	74620089
ENSE00001039041	74629217	74629323
ENSE00001039046	74618537	74618804
ENSE00001299884	74640564	74643076
ENSE00002198152	74592582	74592718
ENSE00003472241	74634583	74634695
ENSE00003546052	74611499	74611538
ENSE00003553153	74636197	74636275
ENSE00003563921	74594061	74594116
ENSE00003601709	74612878	74613010
ENSE00003655011	74604692	74604794

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 92.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.1491 / max 227.7270, expressed in 1734 samples.

Highest expression (Bgee): secondary oocyte, ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, sperm, ganglionic eminence.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLD3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 10 tissues and its splicing (sQTL) in 33 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 43 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	sqtl	6.9e-34	-0.83	11:74598497:C:T
Artery Tibial	sqtl	5.2e-25	-0.67	11:74596656:G:GAATAT
Cells Cultured fibroblasts	sqtl	5.3e-19	-0.62	11:74596656:G:GAATAT
Colon Transverse	sqtl	2.8e-18	-0.72	11:74596656:G:GAATAT
Skin Sun Exposed Lower leg	sqtl	1.4e-15	-0.56	11:74596656:G:GAATAT
Breast Mammary Tissue	sqtl	7.8e-15	-0.66	11:74598497:C:T
Skin Not Sun Exposed Suprapubic	sqtl	6.4e-14	-0.56	11:74596656:G:GAATAT
Adipose Visceral Omentum	sqtl	3.4e-13	-0.54	11:74596656:G:GAATAT
Nerve Tibial	sqtl	3.4e-11	-0.49	11:74600440:C:T
Ovary	sqtl	5.6e-11	-0.98	11:74596656:G:GAATAT
Esophagus Gastroesophageal Junction	sqtl	1.2e-10	-0.64	11:74596656:G:GAATAT
Pituitary	sqtl	2.3e-09	-0.88	11:74596656:G:GAATAT
Stomach	sqtl	4.1e-08	-0.63	11:74597974:A:G
Small Intestine Terminal Ileum	sqtl	6.8e-08	+0.82	11:74586913:A:G
Lung	sqtl	9.6e-08	-0.46	11:74590147:T:C
Uterus	sqtl	3.5e-07	+0.98	11:74596656:G:GAATAT
Minor Salivary Gland	sqtl	3.9e-07	-0.84	11:74584690:C:T
Esophagus Muscularis	sqtl	6.2e-07	-0.45	11:74568961:T:C
Esophagus Mucosa	sqtl	1.7e-06	-0.39	11:74596656:G:GAATAT
Adrenal Gland	sqtl	2.2e-06	-0.60	11:74595743:G:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
115855	11.8269	1730
115854	0.2606	79
115853	0.0617	20

Top tissues by expression

showing 100 of 291 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	92.28	gold quality
ventricular zone	UBERON:0003053	91.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.81	gold quality
sperm	CL:0000019	90.15	gold quality
ganglionic eminence	UBERON:0004023	89.40	gold quality
embryo	UBERON:0000922	88.79	gold quality
oocyte	CL:0000023	88.49	gold quality
male germ cell	CL:0000015	88.37	gold quality
rectum	UBERON:0001052	88.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.59	gold quality
monocyte	CL:0000576	87.44	gold quality
mononuclear cell	CL:0000842	87.31	gold quality
leukocyte	CL:0000738	86.91	gold quality
nephron tubule	UBERON:0001231	86.50	gold quality
bronchial epithelial cell	CL:0002328	86.15	gold quality
right uterine tube	UBERON:0001302	85.96	gold quality
epithelium of bronchus	UBERON:0002031	85.88	gold quality
esophagus squamous epithelium	UBERON:0006920	85.73	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.60	gold quality
bronchus	UBERON:0002185	85.35	gold quality
testis	UBERON:0000473	85.11	gold quality
body of pancreas	UBERON:0001150	84.87	gold quality
right testis	UBERON:0004534	84.82	gold quality
left testis	UBERON:0004533	84.49	gold quality
calcaneal tendon	UBERON:0003701	84.39	gold quality
vermiform appendix	UBERON:0001154	84.32	gold quality
superficial temporal artery	UBERON:0001614	84.22	silver quality
colonic mucosa	UBERON:0000317	83.98	gold quality
pancreas	UBERON:0001264	83.93	gold quality
colonic epithelium	UBERON:0000397	83.92	gold quality
cartilage tissue	UBERON:0002418	83.71	gold quality
body of uterus	UBERON:0009853	83.62	gold quality
bone marrow	UBERON:0002371	83.58	gold quality
smooth muscle tissue	UBERON:0001135	83.55	gold quality
caecum	UBERON:0001153	83.50	gold quality
adult mammalian kidney	UBERON:0000082	83.42	gold quality
bone marrow cell	CL:0002092	83.38	gold quality
tonsil	UBERON:0002372	83.25	gold quality
gall bladder	UBERON:0002110	83.24	gold quality
blood	UBERON:0000178	83.16	gold quality
endometrium	UBERON:0001295	83.16	gold quality
large intestine	UBERON:0000059	83.03	gold quality
islet of Langerhans	UBERON:0000006	83.02	gold quality
sigmoid colon	UBERON:0001159	82.99	gold quality
colon	UBERON:0001155	82.98	gold quality
epithelium of esophagus	UBERON:0001976	82.95	gold quality
intestine	UBERON:0000160	82.91	gold quality
caput epididymis	UBERON:0004358	82.91	gold quality
gingival epithelium	UBERON:0001949	82.87	silver quality
small intestine Peyer’s patch	UBERON:0003454	82.77	gold quality
kidney epithelium	UBERON:0004819	82.74	gold quality
transverse colon	UBERON:0001157	82.68	gold quality
nasal cavity epithelium	UBERON:0005384	82.65	gold quality
adrenal tissue	UBERON:0018303	82.59	gold quality
kidney	UBERON:0002113	82.58	gold quality
uterus	UBERON:0000995	82.44	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.42	gold quality
mucosa of transverse colon	UBERON:0004991	82.40	gold quality
trabecular bone tissue	UBERON:0002483	82.26	gold quality
cortical plate	UBERON:0005343	82.22	gold quality
endometrium epithelium	UBERON:0004811	82.20	silver quality
small intestine	UBERON:0002108	82.18	gold quality
myometrium	UBERON:0001296	82.06	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.92	gold quality
amniotic fluid	UBERON:0000173	81.91	gold quality
gingiva	UBERON:0001828	81.88	gold quality
ectocervix	UBERON:0012249	81.79	gold quality
lower esophagus	UBERON:0013473	81.65	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.64	gold quality
ovary	UBERON:0000992	81.55	gold quality
stromal cell of endometrium	CL:0002255	81.49	gold quality
mucosa of stomach	UBERON:0001199	81.48	gold quality
tendon	UBERON:0000043	81.43	gold quality
female reproductive system	UBERON:0000474	81.35	gold quality
squamous epithelium	UBERON:0006914	81.34	gold quality
esophagus	UBERON:0001043	81.27	gold quality
cortex of kidney	UBERON:0001225	81.23	gold quality
lymph node	UBERON:0000029	81.21	gold quality
epididymis	UBERON:0001301	81.14	gold quality
urinary bladder	UBERON:0001255	81.11	gold quality
endocervix	UBERON:0000458	81.09	gold quality
left uterine tube	UBERON:0001303	81.09	gold quality
pylorus	UBERON:0001166	81.05	gold quality
esophagus mucosa	UBERON:0002469	80.90	gold quality
right ovary	UBERON:0002118	80.89	gold quality
left ovary	UBERON:0002119	80.80	gold quality
minor salivary gland	UBERON:0001830	80.52	gold quality
vagina	UBERON:0000996	80.51	gold quality
popliteal artery	UBERON:0002250	80.47	gold quality
tibial artery	UBERON:0007610	80.47	gold quality
corpus epididymis	UBERON:0004359	80.39	gold quality
upper lobe of left lung	UBERON:0008952	80.38	gold quality
biceps brachii	UBERON:0001507	80.32	silver quality
left ventricle myocardium	UBERON:0006566	80.26	gold quality
body of stomach	UBERON:0001161	80.20	gold quality
mouth mucosa	UBERON:0003729	80.20	gold quality
peritoneum	UBERON:0002358	80.16	gold quality
omental fat pad	UBERON:0010414	80.15	gold quality
cauda epididymis	UBERON:0004360	80.13	gold quality
upper lobe of lung	UBERON:0008948	80.09	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.22

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 65 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Kidney	tissue	40.2	medium
Choroid plexus	tissue	21.7
Cerebral cortex	tissue	18.2	low
Testis	tissue	18.1	high
Hypothalamus	tissue	17.3
Cerebellum	tissue	17.3	medium
Basal ganglia	tissue	17.2	low
Nucleus accumbens	tissue	17.2
Amygdala	tissue	16.5
Midbrain	tissue	16.5
Medulla oblongata	tissue	16.1
Rectum	tissue	15.7	high
Spinal cord	tissue	15.7
Pons	tissue	15.6
Occipital cortex	tissue	15.6
Colon	tissue	15.3	high
Putamen	tissue	15.1
Thalamus	tissue	15.1
Substantia nigra	tissue	14.9
Hippocampal formation	tissue	14.9
Endometrium 1	tissue	14.7	high
Hippocampus	tissue	14.4	low
Retrosplenial cortex	tissue	14.4
Postcentral gyrus	tissue	14.2
Duodenum	tissue	14.0	high
Tonsil	tissue	13.9	medium
Smooth muscle	tissue	13.8	medium
Stomach 1	tissue	13.6	medium
Fallopian tube	tissue	13.6	medium
Appendix	tissue	13.6	high
Thymus	tissue	13.4
Thyroid gland	tissue	13.2	medium
Locus coeruleus	tissue	13.2
Lymph node	tissue	12.9	high
Small intestine	tissue	12.9	medium
Retina	tissue	12.8
Gallbladder	tissue	12.7	high
Ovary	tissue	12.2	medium
Esophagus	tissue	11.9	high
Urinary bladder	tissue	11.2	high
Skin 1	tissue	10.4	high
Lung	tissue	10.2	medium
Spleen	tissue	10.2	medium
Epididymis	tissue	10.1
Placenta	tissue	10.1	medium
Pancreas	tissue	9.7	low
Bone marrow	tissue	9.5	high
Breast	tissue	9.4	medium
Tongue	tissue	8.7
Cervix	tissue	8.5	medium
Seminal vesicle	tissue	8.5	medium
Heart muscle	tissue	7.7	low
Vagina	tissue	7.2	high
Prostate	tissue	7.2	low
Adipose tissue	tissue	7.0	not detected
Skeletal muscle	tissue	6.9	low
Liver	tissue	6.3	low
Parathyroid gland	tissue	6.2	low
Salivary gland	tissue	5.4	low
Adrenal gland	tissue	5.3	low

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Corpus callosum, genu (white matter) (19.7), White matter (19.7), Cerebellar white matter (18.2), Lateral funiculus (white matter) (18.2), Parieto-temporal junction (white matter) (18.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting POLD3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 131 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481

Functional genomics

gnomAD constraint: pLI 0.996, LOEUF 0.41, missense Z 0.402 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000263681 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
11:74,592,659–74,618,589	119 / 175.0	0.68	no
11:74,618,590–74,640,763	385 / 370.5	1.04	no
DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): CAL-120 (-2.813), KP-N-YN (-2.752), SW1463 (-2.693), Hs 683 (-2.638), Panc 08.13 (-2.605), JHOM-1 (-2.566), C8166 (-2.54), HCC1143 (-2.524), SNU-308 (-2.514), HCC38 (-2.477), LOU-NH91 (-2.472), MFE-280 (-2.454), NCI-H460 (-2.454), Panc 04.03 (-2.438), NCI-H209 (-2.438).

Literature-anchored findings (GeneRIF, showing 22)

• show that there is a direct interaction between p66 and PCNA in living cells during DNA replication. The dominant negative effect upon growth resulting from expression of p66 sub-domains confirms that the p66-PCNA interaction is essential in vivo. (PMID:16000169)
• POLD3, plays a crucial role in the efficient recycling of PCNA during dissociation-association cycles of pol delta during elongation phase of DNA replication. (PMID:17932049)
• Taken together, the results provide evidence that concurrent phosphorylation events in p66 may positively and negatively regulate its activity and interactions with other components of the replisome during the cell cycle. (PMID:18157942)
• 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 winged helix-turn-helix N-terminal domain in p66 (PMID:18818516)
• Serine-458, located in the proliferating cell nuclear antigen (PCNA)-interacting motif of Poldelta(p68), is a phosphorylation site for protein kinase A (PKA); p68 mutation results in decreased p68 affinity for PCNA as well as processivity of Poldelta. (PMID:22148433)
• We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 x 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 x 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 x 10(-10)). (PMID:22634755)
• Pol delta3 is the predominant form of Pol delta at sites of UV damage as a result of p12 degradation; results show that Pol delta at the DNA damage site is the Pol delta trimer lacking p12 regardless of the cell cycle phase (PMID:22801543)
• Findings provide evidence for the novel concept that Pol delta3 has a role in lagging strand synthesis, and that both forms of Pol delta3 and 4 may participate in DNA replication in higher eukaryotic cells. (PMID:24035200)
• In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. (PMID:24310611)
• POLD3 is SUMOylated by SUMO2 in response to replication stress and could play an important role in the regulation of cellular response to DNA replication stress. (PMID:25497329)
• Studies indicate that DNA polymerase delta 3 (Pol delta3) exhibits significant differences in properties with a major impact on cellular processes in genomic surveillance, DNA replication and DNA repair. (PMID:26916162)
• Data suggest that relatively high affinity binding of PolD3-RIR motif to Rev1-C-terminal domain displaces subunits from PolN, Pol-iota, or PolK from Rev1 complex and promotes formation of Rev1/PolZ4 assembly with PCNA for translesion DNA replication. (PMID:26982350)
• data support Poldelta contributing to translesion synthesis in vivo and suggest that the mutagenesis resulting from loss of Poldelta proofreading activity may in part be explained by enhanced lesion bypass (PMID:27185888)
• findings demonstrate a key role of POLD1 and POLD3 in genome stability and S-phase progression revealing RNA-DNA hybrids-dependent effects for POLD3 that might be partly due to its Pol zeta interaction. (PMID:27974823)
• The mitotic DNA synthesis is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to common fragile sites in early mitosis. (PMID:27984745)
• 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)
• ROS-induced telomeric R-loops promote repair of telomeric DSBs through CSB-RAD52-POLD3-mediated BIR, a previously unknown pathway protecting telomeres from ROS. ROS-induced telomeric SSBs may not only give rise to DSBs indirectly, but also promote DSB repair by inducing R-loops, revealing an unexpected interplay between distinct ROS-induced DNA lesions. (PMID:31777915)
• Polymerase delta promotes chromosomal rearrangements and imprecise double-strand break repair. (PMID:33077594)
• Interaction of CCND2, CDKN1A, and POLD3 Variants in Mexican Patients with Colorectal Cancer. (PMID:35786622)
• Interaction of human HelQ with DNA polymerase delta halts DNA synthesis and stimulates DNA single-strand annealing. (PMID:36718939)
• POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment. (PMID:37030525)

Cross-species orthologs

0 orthologs

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915217) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 18 distinct phenotype terms.

Mouse phenotype (MP)	Records
small testis	1
seminiferous tubule degeneration	1
absent egg cylinders	1
increased circulating insulin level	1
spontaneous chromosome breakage	1
decreased testis weight	1
decreased male germ cell number	1
arrest of male meiosis	1
abnormal embryonic tissue physiology	1
abnormal trophoblast giant cell proliferation	1
embryonic lethality between implantation and somite formation, complete penetrance	1
preweaning lethality, complete penetrance	1
decreased inner cell mass proliferation	1
embryonic lethality prior to organogenesis	1
prenatal lethality prior to heart atrial septation	1
increased male germ cell apoptosis	1
impaired double-strand DNA break repair	1
decreased telomere length	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	P84798	82.9%	Diamond
Mus musculus	Q9EQ28	81.6%	Diamond
Gallus gallus	Q5ZK28	59.2%	Diamond
Thermochaetoides thermophila DSM 1495	G0S636	57.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CHRDL2	protein-coding	25884
LIPT2-AS1	ncRNA	100287896
LIPT2	protein-coding	387787
MIR4696	ncRNA	100616402

Protein

Protein identifiers

DNA polymerase delta subunit 3 — Q15054 (reviewed: Q15054)

Alternative names: DNA polymerase delta subunit C, DNA polymerase delta subunit p66, DNA polymerase delta subunit p68

All UniProt accessions (6): E9PM91, E9PNC0, E9PRK3, H0YD46, H0YEX7, Q15054

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. Required for optimal Pol-delta activity. Stabilizes the Pol-delta complex and plays a major role in Pol-delta stimulation by PCNA. 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. In this context, POLD3, along with PCNA and RFC1-replication factor C complex, is required to recruit POLD1, the catalytic subunit of the polymerase delta complex, to DNA damage sites. 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 tetrameric DNA polymerase zeta complex. Along with POLD2, 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. 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 this complex, directly interacts with POLD2. 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. Directly interacts with PCNA, as do POLD1 and POLD4; this interaction stimulates Pol-delta polymerase activity. POLD3 phosphorylation at Ser-458 impairs PCNA binding. Component of the DNA polymerase zeta complex (POLZ), which consists of REV3L, MAD2L2, POLD2 and POLD3, with REV3L bearing DNA polymerase catalytic activity. The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2. Interacts with REV1 (via C-terminal domain).

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Ubiquitinated, but not targeted to the proteasome. Sumoylated. Sumoylation with SUMO3 may be predominant. Phosphorylation at Ser-458 is catalyzed in vitro by PKA. It is thought to decrease the affinity for PCNA and Pol-delta4 processivity. Can also be phosphorylated in vitro by CDK1-cyclin-A complex, as well as CDK2-cyclin-A and CDK2-cyclin-E complexes. PCNA interferes with CDK-cyclin phosphorylation.

Disease relevance. Immunodeficiency 122 (IMD122) [MIM:620869] An autosomal recessive, severe immunologic disorder characterized by recurrent viral and bacterial infections of the respiratory tract and skin, appearing in early infancy. Additional clinical features include poor overall growth, global developmental delay with poor motor skills, impaired intellectual development, and poor or absent speech acquisition. Some patients have diffuse skin rash, erythroderma, sensorineural hearing loss, lymphadenopathy, dysmorphic facial features, and tooth abnormalities. Death in early childhood may occur. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The PIP-box mediates the interaction with PCNA.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15054-1	1	yes
Q15054-2	2
Q15054-3	3

RefSeq proteins (2): NP_001350526, NP_006582* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019038	POLD3	Family
IPR041913	POLD3_sf	Homologous_superfamily

Pfam: PF09507

UniProt features (52 total): modified residue 8, helix 8, mutagenesis site 6, compositionally biased region 5, region of interest 5, cross-link 5, strand 5, sequence variant 4, splice variant 2, initiator methionine 1, chain 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

9 structures by resolution:

PDB	Title	Method	Resolution (Å)
1U76	Crystal structure of hPCNA bound to residues 452-466 of the DNA polymerase-delta-p66 …	X-RAY DIFFRACTION	2.6
3E0J	X-ray structure of the complex of regulatory subunits of human DNA polymerase delta	X-RAY DIFFRACTION	3
6TNY	Processive human polymerase delta holoenzyme	ELECTRON MICROSCOPY	3.08
9EKB	Cryo-EM structure of apo-form human DNA polymerase delta	ELECTRON MICROSCOPY	3.65
6TNZ	Human polymerase delta-FEN1-PCNA toolbelt	ELECTRON MICROSCOPY	4.05
6S1M	Human polymerase delta holoenzyme Conformer 1	ELECTRON MICROSCOPY	4.27
6S1N	Human polymerase delta holoenzyme Conformer 2	ELECTRON MICROSCOPY	4.86
6S1O	Human polymerase delta holoenzyme Conformer 3	ELECTRON MICROSCOPY	8.1
2N1G	Structure of C-terminal domain of human polymerase Rev1 in complex with PolD3 RIR-motif	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15054-F1	63.65	0.32

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

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 (13)

Type	Positions
N-acetylalanine	2
Phosphothreonine	277, 411
Phosphoserine	307, 407, 409, 413, 458
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo)	258, 433
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	258, 261, 433

Mutagenesis-validated functional residues (6)

Position	Phenotype
258	partially loss of sumoylation. complete loss of sumoylation; when associated with r-433.
325	no effect on sumoylation.
433	partially loss of sumoylation. complete loss of sumo3-sumoylation; when associated with r-285.
456–466	complete loss of pcna binding.
458	partial loss of pcna binding (60% of wild-type) and strong decrease of pcna stimulation of pol-delta4 polymerase activity.
459–463	complete loss of pcna binding.

Function

Pathways and Gene Ontology

Reactome pathways

18 curated (TAS) of 43; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

43 pathways:

ID	Pathway	Evidence
R-HSA-5696400	Dual Incision in GG-NER	curated
R-HSA-6782135	Dual incision in TC-NER	curated
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER	curated
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER	curated
R-HSA-5685942	HDR through Homologous Recombination (HRR)	curated
R-HSA-5358606	Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	curated
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	curated
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair	curated
R-HSA-69091	Polymerase switching	curated
R-HSA-174411	Polymerase switching on the C-strand of the telomere	curated
R-HSA-174414	Processive synthesis on the C-strand of the telomere	curated
R-HSA-69183	Processive synthesis on the lagging strand	curated
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex	curated
R-HSA-69166	Removal of the Flap Intermediate	curated
R-HSA-174437	Removal of the Flap Intermediate from the C-strand	curated
R-HSA-9968295	Somatic hypermutation of immunoglobulin genes by error-prone mismatch repair (MMR)	curated
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis	curated
R-HSA-5656169	Termination of translesion DNA synthesis	curated
R-HSA-73884	Base Excision Repair	—
R-HSA-1640170	Cell Cycle	—
R-HSA-69278	Cell Cycle, Mitotic	—
R-HSA-73886	Chromosome Maintenance	—
R-HSA-73893	DNA Damage Bypass	—
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-69306	DNA Replication	—
R-HSA-69190	DNA strand elongation	—
R-HSA-180786	Extension of Telomeres	—
R-HSA-5696399	Global Genome Nucleotide Excision Repair (GG-NER)	—
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	—
R-HSA-5693538	Homology Directed Repair	—
R-HSA-69186	Lagging Strand Synthesis	—
R-HSA-69109	Leading Strand Synthesis	—
R-HSA-5358508	Mismatch Repair	—
R-HSA-5696398	Nucleotide Excision Repair	—
R-HSA-110373	Resolution of AP sites via the multiple-nucleotide patch replacement pathway	—
R-HSA-73933	Resolution of Abasic Sites (AP sites)	—
R-HSA-69242	S Phase	—
R-HSA-9968297	Somatic hypermutation of immunoglobulin genes by error-prone base excision repair (BER)	electronic
R-HSA-69239	Synthesis of DNA	—
R-HSA-157579	Telomere Maintenance	—
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)	—
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	—

MSigDB gene sets: 397 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, E2F_Q4, REACTOME_DNA_REPLICATION, E2F4DP1_01, GOBP_CELLULAR_RESPONSE_TO_UV, FISCHER_G1_S_CELL_CYCLE, CROONQUIST_NRAS_SIGNALING_DN, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, DITTMER_PTHLH_TARGETS_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_DNA_DAMAGE_TOLERANCE, RIZKI_TUMOR_INVASIVENESS_3D_DN

GO Biological Process (11): DNA synthesis involved in DNA repair (GO:0000731), DNA-templated DNA replication (GO:0006261), DNA strand elongation involved in DNA replication (GO:0006271), nucleotide-excision repair, DNA gap filling (GO:0006297), mismatch repair (GO:0006298), error-prone translesion synthesis (GO:0042276), DNA biosynthetic process (GO:0071897), DNA synthesis involved in UV-damage excision repair (GO:1904161), DNA replication (GO:0006260), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (3): protein-macromolecule adaptor activity (GO:0030674), DNA-directed DNA polymerase activity (GO:0003887), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), zeta DNA polymerase complex (GO:0016035), delta DNA polymerase complex (GO:0043625), nucleus (GO:0005634), nuclear lumen (GO:0031981)

Reactome top-level categories

14 top-level categories:

Category	Pathways
DNA Damage Bypass	2
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
Somatic hypermutation of immunoglobulin genes	2
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

27 GO namespaces:

Category	Terms
DNA metabolic process	4
DNA repair	2
DNA biosynthetic process	2
DNA replication	2
cellular anatomical structure	2
DNA polymerase complex	2
DNA-templated DNA replication	1
DNA strand elongation	1
DNA synthesis involved in DNA replication	1
nucleotide-excision repair	1
translesion synthesis	1
nucleic acid biosynthetic process	1
DNA synthesis involved in DNA repair	1
UV-damage excision repair	1
DNA damage response	1
cellular response to stress	1
protein binding	1
molecular adaptor activity	1
DNA polymerase activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear replisome	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1
nucleus	1
intracellular organelle lumen	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
DNA biosynthetic process	BP	direct assay
DNA-templated DNA replication	BP	direct assay
error-prone translesion synthesis	BP	direct assay
nucleotide-excision repair, DNA gap filling	BP	mutant phenotype
delta DNA polymerase complex	CC	direct assay
nucleoplasm	CC	direct assay
zeta DNA polymerase complex	CC	direct assay
protein-macromolecule adaptor activity	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,084 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLD3	POLD2	P49005	973
POLD3	POLD1	P28340	959
POLD3	POLD4	Q9HCU8	954
POLD3	PCNA	P12004	859
POLD3	LIG1	P18858	692
POLD3	REV3L	O60673	690
POLD3	MUS81	Q96NY9	684
POLD3	MAD2L2	Q9UI95	670
POLD3	REV1	Q9UBZ9	655
POLD3	RAD51	Q06609	639
POLD3	RAD52	P43351	631
POLD3	EME1	Q96AY2	623
POLD3	POLE2	P56282	593
POLD3	SLX4	Q8IY92	585
POLD3	EXO1	Q9UQ84	535

IntAct

Human interaction partners of POLD3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

6 partners by confidence:

Partner	Interaction type	MIscore	Records
POLD1	association	0.900	1
POLD2	direct interaction	0.890	5
PCNA	direct interaction	0.870	7
AGMAT	physical association	0.400	1
ZGRF1	physical association	0.400	1
ESYT2	association	0.350	1

BioGRID (152 interactions; top human partners by supporting records): PCNA (Affinity Capture-MS; 11 records), SPRTN (Affinity Capture-MS; 6 records), POLD1 (Affinity Capture-MS; 5 records), POLD2 (Affinity Capture-MS; 5 records), REV1 (Co-crystal Structure; 4 records), MAD2L2 (Affinity Capture-Western; 3 records), APP (Reconstituted Complex; 2 records), CCNF (Affinity Capture-MS; 2 records), POLA1 (Co-fractionation; 2 records), RPA1 (Co-fractionation; 2 records), AGMAT (Affinity Capture-MS), AHSA1 (Affinity Capture-MS), ALPI (Affinity Capture-MS), APLNR (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
PRKACA	down-regulates	POLD3	phosphorylation
POLD3	“form complex”	“DNA polymerase delta”	binding

Protein complexes (CORUM) (9)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

9 complexes by size:

Complex	Subunits	Members
★ RC complex, S-phase-specific	23	POLD4, POLE2, POLE4, CCNA2, CDK2, POLD2, POLD3, RFC2, POLE, RFC1, RFC5, RPA3, LIG1, PARP1, POLA1, POLD1, RFC3, RPA2, POLA2, POLE3, RFC4, RPA1, TOP1
★ DNA synthesome complex, breast cancer MCF7 cells	23	POLA2, POLD3, POLE4, PRIM1, RFC1, RPA1, PCNA, POLD4, POLE2, POLE3, RFC4, TOP1, POLA1, RFC2, RFC3, RFC5, RPA2, RPA3, TOP2A, POLD1, POLD2, POLE, PRIM2
★ DNA synthesome complex, breast cancer cells	20	POLD3, POLE4, RFC2, RFC3, POLA2, POLE3, LIG1, PARP1, PCNA, POLD2, PRIM1, PRIM2, RFC1, RFC4, POLD4, POLE, POLE2, RFC5, POLA1, POLD1
★ RC complex, G2/M-phase-specific	19	CCNB1, POLA1, POLA2, POLD2, RPA1, RPA2, CDK1, POLD3, RFC1, RFC2, RPA3, POLD1, POLD4, POLE, POLE3, PARP1, POLE2, POLE4, TOP1
★ DNA synthesome complex, leukemia cells	19	PCNA, POLD1, RFC5, TOP2A, POLD4, PRIM1, PRIM2, RFC2, RPA2, TOP1, POLD2, POLD3, RPA1, POLA1, POLA2, RFC1, RFC3, RFC4, RPA3
★ DNA synthesome core complex	14	PCNA, POLA2, POLD1, POLD2, POLD3, POLD4, PRIM2, RFC1, POLA1, PRIM1, RFC2, RFC3, RFC4, RFC5
DNA polymerase zeta	4	MAD2L2, POLD2, POLD3, REV3L
★ DNA polymerase delta	4	POLD1, POLD2, POLD3, POLD4
★ DNA polymerase delta, trimeric form	3	POLD1, POLD2, POLD3

Disease & clinical

Genetic variants

Variant evidence for POLD3: 68 ClinVar records (1 pathogenic / likely pathogenic); 14 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	51
Likely benign	1
Benign	5

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3250357	NM_006591.3(POLD3):c.1118A>C (p.Lys373Thr)	Likely pathogenic	criteria provided, single submitter	5

Per-variant reference — Sugi Variant

Explore POLD3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 1,108):

Position(s)	Effect	Δscore	Sites
11:74592727	donor_gain	1.0000
11:74604684	acceptor_gain	1.0000
11:74612876–74612877	acceptor_loss	1.0000	5
11:74613011–74613012	donor_loss	1.0000	4
11:74618528	acceptor_gain	1.0000
11:74618535–74618536	acceptor_loss	1.0000	6
11:74625574–74625575	donor_loss	1.0000	4
11:74592681	donor_gain	0.9900
11:74592738–74592739	donor_gain	0.9900	2
11:74592914	donor_gain	0.9900

AlphaMissense

714 missense substitutions predicted likely pathogenic (of 3,073 scored), across 173 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D118	8	0.988	0.998
H99	8	0.986	0.997
S102	8	0.960	1.000
D16	8	0.937	0.983
D110	8	0.933	0.983
F463	8	0.926	0.974
S27	8	0.916	0.999
N9	8	0.911	0.986
N35	8	0.902	0.994
F462	8	0.896	0.989
H33	8	0.877	0.974
D11	8	0.841	0.953
F239	8	0.803	0.925
K38	7	0.973	1.000
F115	7	0.962	0.988
M40	7	0.957	0.994
F13	7	0.955	0.989
W25	7	0.937	0.998
F132	7	0.927	0.976
Q104	7	0.922	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.07e-06
Kidney Chromophobe (TCGA)	unfavorable	0.000224

Disease associations

OMIM: gene MIM:611415 | disease phenotypes: MIM:620869

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
immunodeficiency 122	Strong	Autosomal recessive
hearing loss disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
immunodeficiency 122	Limited	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Primary immunodeficiency or monogenic inflammatory bowel disease	amber

Mondo (2): immunodeficiency 122 (MONDO:0971151), hearing loss disorder (MONDO:0005365)

HPO phenotypes

35 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000958	Dry skin
HP:0001019	Erythroderma
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001880	Increased total eosinophil count
HP:0001999	Abnormal facial shape
HP:0002007	Frontal bossing
HP:0002110	Bronchiectasis
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002783	Recurrent lower respiratory tract infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0003212	Increased circulating IgE concentration
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004429	Recurrent viral infections
HP:0004430	Severe combined immunodeficiency
HP:0005359	Aplasia of the thymus
HP:0005403	Decreased total T cell count
HP:0006297	Enamel hypoplasia
HP:0008404	Nail dystrophy
HP:0010975	Abnormal total B cell count
HP:0011968	Feeding difficulties
HP:0031430	Oligoclonal T cell expansion
HP:0032126	Decreased unswitched memory B cell proportion
HP:0040218	Reduced total natural killer cell count
HP:0410243	Abnormal circulating IgM concentration
HP:0410377	Decreased naive CD8+ T cell proportion
HP:0410378	Decreased naive CD4+ T cell proportion
HP:0500093	Food allergy

GWAS associations

14 associations:

Study	Trait	p-value
GCST007856_36	Colorectal cancer or advanced adenoma	1e-20
GCST007856_54	Colorectal cancer or advanced adenoma	1e-18
GCST005235_1	Hand grip strength	5e-13
GCST002919_11	Colorectal cancer	8e-11
GCST001544_2	Colorectal cancer	4e-10
GCST006630_6	Diastolic blood pressure	6e-10
GCST005830_91	Hand grip strength	9e-10
GCST010276_12	Renal underexcretion gout	4e-7
GCST003017_16	Colorectal cancer	1e-6
GCST009869_59	Colorectal cancer	1e-6
GCST007552_14	Colorectal cancer	3e-6
GCST007856_6	Colorectal cancer or advanced adenoma	3e-6
GCST003791_6	Response to metformin (IC50)	6e-6
GCST003253_9	Microalbuminuria	9e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0006941	grip strength measurement
EFO:0006336	diastolic blood pressure

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2260 (SINGLE PROTEIN), CHEMBL2363042 (PROTEIN FAMILY)

PharmGKB: 1 entry (CPIC guideline: no)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.80	Kd	1.573	nM	CHEMBL3752910
8.80	ED50	1.573	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149915: Binding affinity to human POLD3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0016	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases reaction, decreases expression, decreases methylation	4
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	affects cotreatment, increases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Cyclosporine	increases expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
4-biphenylamine	decreases expression, decreases reaction	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	increases abundance, increases expression	1
sulindac sulfide	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Troglitazone	decreases expression	1
Acetaminophen	increases expression	1
Glyphosate	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Azathioprine	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652957	Binding	Binding affinity to human POLD3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Cellosaurus cell lines

233 cell lines: 232 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0336	Huh-7	Cancer cell line	Male
CVCL_2957	Huh-7D12	Cancer cell line	Male
CVCL_4W53	Huh7S1	Cancer cell line	Male
CVCL_7927	Huh-7.5	Cancer cell line	Male
CVCL_A0TI	Huh-7.5 Tet-On	Cancer cell line	Male
CVCL_A5AV	Huh7.93	Cancer cell line	Male
CVCL_B7TI	HUH7-R	Cancer cell line	Male
CVCL_B7TJ	HUH7-R-LUC	Cancer cell line	Male
CVCL_C0FW	CHUSJi001-A	Induced pluripotent stem cell	Male
CVCL_C2UW	Huh-7.5 STAT1 KO #1	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00205881	Phase 4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	Phase 4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	Phase 4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	Phase 4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	Phase 4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	Phase 3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	Phase 3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	Phase 3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	Phase 3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	Phase 2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	Phase 2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	Phase 2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	Phase 2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	Phase 2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	Phase 2	WITHDRAWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	Phase 2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	Phase 2	UNKNOWN	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	Phase 2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	Phase 2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	Phase 2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	Phase 2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	Phase 1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	Phase 1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	Phase 1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	Phase 1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	Phase 1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	Phase 1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	Phase 1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	Phase 1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	Phase 1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	Phase 2/3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	Phase 2/3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	Phase 2/3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	Phase 2/3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	Phase 1/2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	Phase 1/2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	Phase 1/2	ACTIVE_NOT_RECRUITING	A Phase I/II Clinical Trial With SENS-501 in Children Suffering From Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	Phase 1/2	ACTIVE_NOT_RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	Phase 1/2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	Early Phase 1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss
NCT03300687	Early Phase 1	COMPLETED	First in Human Safety Study of FX-322 in Adults Undergoing Cochlear Implantation
NCT04777669	Early Phase 1	UNKNOWN	Removing Background Talker Noise for Cochlear Implant Users
NCT06025032	Early Phase 1	WITHDRAWN	a Study in Subjects With Otoferlin Mutation-related Hearing Loss Using RNA Base-eDiting Therapy(SOUND)
NCT00001668	Not specified	COMPLETED	Endolymphatic Sac Tumors in a Population of Patients With Von Hippel-Lindau Disease:The Natural History and Pathobiology, and a Prospective Non-Randomized Clinical Trial of Hearing Preservation Surgery in Patients With Early Stage Endolymphatic Sac Tumors
NCT00001782	Not specified	COMPLETED	Areas of Brain Responsible for Understanding American Sign Language
NCT00013468	Not specified	COMPLETED	Early Diagnosis of Steroid-Responsive & No-Responsive Hearing Loss
NCT00016471	Not specified	COMPLETED	A Genetic Analysis of Usher Syndrome in Ashkenazi Jews
NCT00018486	Not specified	COMPLETED	Epidemiology of Hearing Loss in Diabetic and Non-Diabetic Veterans
NCT00106743	Not specified	COMPLETED	Natural History and Genetic Studies of Usher Syndrome
NCT00110604	Not specified	COMPLETED	The Effect of Folic Acid on Atherosclerosis, Cognitive Performance and Hearing
NCT00126113	Not specified	COMPLETED	The Performance-Perceptual Test as a Counseling Tool
NCT00260663	Not specified	COMPLETED	The Hearing Aid Effectiveness After Aural Rehabilitation (HEAR) Trial
NCT00371436	Not specified	COMPLETED	Progressive Intervention Program for Tinnitus Management
NCT00371449	Not specified	COMPLETED	Predicting Success With Hearing Aids
NCT00371839	Not specified	COMPLETED	Clinical Applications for Time-Compressed Speech Tests
NCT00400413	Not specified	COMPLETED	Neuroanatomy of Reading in Congenital Deafness.
NCT00438334	Not specified	COMPLETED	Real-World Benefit From Directional Hearing Aids
NCT00451503	Not specified	COMPLETED	Evaluation of Middle Ear Implantation
NCT00484224	Not specified	UNKNOWN	Audiological Disturbances in Vitiligo
NCT00511381	Not specified	COMPLETED	Genetic Testing in Detection of Late-Onset Hearing Loss

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for POLD3 across ~30M SureChEMBL compounds — explore on Sugi Predict.