PRIMPOL

Summary

PRIMPOL (primase and DNA directed polymerase, HGNC:26575) is a protein-coding gene on chromosome 4q35.1, encoding DNA-directed primase/polymerase protein (Q96LW4). DNA primase and DNA polymerase required to tolerate replication-stalling lesions by bypassing them.

This gene encodes a DNA primase-polymerase that belongs to a superfamily of archaeao-eukaryotic primases. Members of this family have primase activity, catalyzing the synthesis of short RNA primers that serve as starting points for DNA synthesis, as well as DNA polymerase activity. The encoded protein facilitates DNA damage tolerance by mediating uninterrupted fork progression after UV irradiation and reinitiating DNA synthesis. An allelic variant in this gene is associated with myopia 22. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 201973 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopia 22, autosomal dominant (Limited, GenCC)
• Clinical variants (ClinVar): 86 total
• Phenotypes (HPO): 3
• MANE Select transcript: NM_152683

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26575
Approved symbol	PRIMPOL
Name	primase and DNA directed polymerase
Location	4q35.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33167
Ensembl gene	ENSG00000164306
Ensembl biotype	protein_coding
OMIM	615421
Entrez	201973

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 33 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000314970, ENST00000503752, ENST00000506278, ENST00000508001, ENST00000509002, ENST00000509538, ENST00000510864, ENST00000512658, ENST00000512834, ENST00000515152, ENST00000515774, ENST00000868776, ENST00000868777, ENST00000868778, ENST00000868779, ENST00000868780, ENST00000868781, ENST00000868782, ENST00000868783, ENST00000868784, ENST00000868785, ENST00000868786, ENST00000868787, ENST00000868788, ENST00000868789, ENST00000868790, ENST00000868791, ENST00000939781, ENST00000939782, ENST00000939783, ENST00000939784, ENST00000966669, ENST00000966670, ENST00000966671, ENST00000966672, ENST00000966673, ENST00000966674, ENST00000966675, ENST00000966676

RefSeq mRNA: 14 — MANE Select: NM_152683 NM_001300767, NM_001300768, NM_001345891, NM_001345892, NM_001345893, NM_001345894, NM_001345895, NM_001345896, NM_001345897, NM_001345898, NM_001345899, NM_001345900, NM_001345901, NM_152683

CCDS: CCDS3837, CCDS75211, CCDS75212

Canonical transcript exons

ENST00000314970 — 14 exons

Exon	Start	End
ENSE00001083276	184685409	184685498
ENSE00001150506	184682248	184682336
ENSE00001199600	184678232	184678394
ENSE00001214785	184657082	184657320
ENSE00001214794	184652023	184652100
ENSE00002020859	184649738	184649908
ENSE00003470435	184694522	184694952
ENSE00003500256	184661774	184661903
ENSE00003583918	184659340	184659437
ENSE00003627667	184685576	184685684
ENSE00003654849	184672173	184672460
ENSE00003675377	184665917	184666064
ENSE00003681973	184691499	184691581
ENSE00003694717	184691666	184691712

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 92.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2535 / max 270.4276, expressed in 1769 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50839	10.2684	1760
50838	0.8022	507
50840	0.1829	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	92.94	gold quality
cerebellar cortex	UBERON:0002129	92.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.48	gold quality
calcaneal tendon	UBERON:0003701	92.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.66	gold quality
oviduct epithelium	UBERON:0004804	91.40	gold quality
cerebellum	UBERON:0002037	91.20	gold quality
adenohypophysis	UBERON:0002196	91.04	gold quality
right uterine tube	UBERON:0001302	90.84	gold quality
right ovary	UBERON:0002118	90.03	gold quality
left ovary	UBERON:0002119	89.79	gold quality
pituitary gland	UBERON:0000007	89.61	gold quality
tibial nerve	UBERON:0001323	89.43	gold quality
body of uterus	UBERON:0009853	89.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.98	gold quality
mucosa of transverse colon	UBERON:0004991	88.95	gold quality
secondary oocyte	CL:0000655	88.93	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.80	gold quality
spleen	UBERON:0002106	88.42	gold quality
ventricular zone	UBERON:0003053	88.28	gold quality
ovary	UBERON:0000992	88.18	gold quality
endocervix	UBERON:0000458	87.98	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.75	gold quality
transverse colon	UBERON:0001157	87.64	gold quality
apex of heart	UBERON:0002098	87.50	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.43	gold quality
lower esophagus	UBERON:0013473	87.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.38	gold quality
mucosa of stomach	UBERON:0001199	87.14	gold quality
rectum	UBERON:0001052	86.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting PRIMPOL, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-342-3P	96.44	67.48	1344

Literature-anchored findings (GeneRIF, showing 40)

• Identification of a novel missense variant of the CCDC111 gene in a high myopia family. (PMID:23579484)
• PRIMPOL depletion results in increased spontaneous DNA damage and defects in the restart of stalled replication forks. (PMID:24126761)
• Primpol is proposed to facilitate replication fork progression by acting as a translesion DNA polymerase or as a specific DNA primase reinitiating downstream of lesions that block synthesis during DNA replication. (PMID:24207056)
• PrimPol is an important player in replication fork progression in eukaryotic cells. (PMID:24267451)
• Although PrimPol’s primase activity is required to restore wild-type replication fork rates in irradiated PrimPol-/- cells, the polymerase activity is sufficient to maintain regular replisome progression in unperturbed cells. (PMID:24682820)
• Data suggest that PrimPol exhibits fidelity that is 1.7-fold more accurate with magnesium as cofactor compared to manganese; activity of PrimPol is increased 400-1000-fold by manganese compared to magnesium based on steady-state kinetic parameters. (PMID:25255211)
• The data establishes that a point mutation identified in PrimPol from patients with high myopia results in a major disruption of the catalytic and replication activities associated with human PrimPol thus establishing a link between replication stress and high myopia. (PMID:25262353)
• The authors propose a mechanism whereby single-stranded DNA binding proteins greatly restrict the contribution of PrimPol to DNA replication at stalled forks, thus reducing the mutagenic potential of PrimPol during genome replication. (PMID:25550423)
• PrimPol tolerates DNA lesions, involving template and primer dislocations that can be operating during both mitochondrial and nuclear DNA replication. PrimPol could also operate as a translesion synthesis partner during DNA-directed RNA synthesis. (PMID:25746449)
• The molecular mechanism of polymerization and nucleoside reverse transcriptase inhibitor incorporation by human PrimPol have been described. (PMID:26552983)
• Implicate PrimPol in promoting restart of DNA synthesis downstream of, but closely coupled to, G4 replication impediments. (PMID:26626482)
• Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation (PMID:26627254)
• Data suggest that, during genetic transcription, Prim-Pol-alpha-cat binds the DNA/RNA junction at 5prime-terminus of RNA primer (or initiating NTP, nucleoside-triphosphate). (PMID:26710848)
• findings establish that PolDIP2 can regulate the translesion synthesis polymerase and primer extension activities of PrimPol (PMID:26984527)
• PrimPol shows the ability to synthesize DNA opposite ultraviolet (UV) lesions; however, unexpectedly, the active-site cleft of the enzyme is constrained, which precludes the bypass of UV-induced DNA lesions by conventional translesion synthesis. (PMID:27819052)
• The ability of human PrimPol to discriminate against ribonucleotides (rNTPs) and to incorporate the triphosphates of four nucleoside analog drugs in the presence of Mn2+or Mg2+ was studied. (PMID:27989484)
• These new findings supports the existence of a functional PrimPol/RPA association that allows repriming at the exposed ssDNA regions formed in the leading strand upon replicase stalling. (PMID:28396594)
• Data propose that it is highly likely that PrimPol plays the same roles in mitochondria as in cell nucleus by repriming DNA replication to allow replication to be completed in an efficient and timely manner. Also, a range of PrimPol mutations have been found in cancer cells and other conditions suggesting possible connections to human diseases. [review] (PMID:28408491)
• RPA serves to stimulate the primase activity of PrimPol. (PMID:28534480)
• Growing evidence suggests that the main biological function of human PrimPol during replication of chromosomal DNA is a repriming of stalled replication downstream of DNA damage or naturally occurring obstacles. However, the mechanisms that regulate the repriming by PrimPol in cells are yet to be understood. PrimPol in cells are yet to be understood. [review] (PMID:28754021)
• Active PrimPol can be purified from E. coli and human suspension cell line in high quantities and the activity of the purified enzyme is similar in both expression systems. (PMID:28902865)
• Description of the sequential substrate interactions of human PrimPol during primer synthesis, and the relevance of the Zn finger-containing domain at each individual step. (PMID:29608762)
• the properties of PrimPol as a TLS polymerase in the presence of different metal ions in vitro (PMID:30098578)
• PrimPol is required for the maintenance of efficient nuclear and mitochondrial DNA replication in human cells. (PMID:30715459)
• A cancer-associated point mutation disables the steric gate of human PrimPol. (PMID:30718533)
• PrimPol active site requires a specific motif A (DxE) to favor the use of Mn(2+) ions in order to achieve optimal incoming nucleotide stabilization (PMID:30889508)
• The WRNIP1-mediated reduction in the amount of PrimPol was suppressed by treatment of the cells with proteasome inhibitors, suggesting that WRNIP1 is involved in the degradation of PrimPol via the proteasome. (PMID:31061318)
• REVIEW: Mechanism of DNA primer synthesis by human PrimPol (PMID:31627881)
• Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro. (PMID:32191790)
• PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts. (PMID:33203852)
• The deubiquitinase USP36 Regulates DNA replication stress and confers therapeutic resistance through PrimPol stabilization. (PMID:33237263)
• Strand Displacement Activity of PrimPol. (PMID:33261049)
• The DNA ligands Arg47 and Arg76 are crucial for catalysis by human PrimPol. (PMID:33571927)
• PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks. (PMID:34128550)
• Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase. (PMID:34188055)
• Motif WFYY of human PrimPol is crucial to stabilize the incoming 3’-nucleotide during replication fork restart. (PMID:34302490)
• Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells. (PMID:34624216)
• BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage. (PMID:34645815)
• Human PrimPol Discrimination against Dideoxynucleotides during Primer Synthesis. (PMID:34680882)
• PRIMPOL competes with RAD51 to resolve G-quadruplex-induced replication stress via its interaction with RPA. (PMID:36647718)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	primpol	ENSDARG00000033273
mus_musculus	Primpol	ENSMUSG00000038225
rattus_norvegicus	Primpol	ENSRNOG00000022320

Protein

Protein identifiers

DNA-directed primase/polymerase protein — Q96LW4 (reviewed: Q96LW4)

Alternative names: Coiled-coil domain-containing protein 111

All UniProt accessions (5): A0A5S6SZ32, D6R908, D6R971, Q96LW4, H0Y9N8

UniProt curated annotations — full annotation on UniProt →

Function. DNA primase and DNA polymerase required to tolerate replication-stalling lesions by bypassing them. Required to facilitate mitochondrial and nuclear replication fork progression by initiating de novo DNA synthesis using dNTPs and acting as an error-prone DNA polymerase able to bypass certain DNA lesions. Shows a high capacity to tolerate DNA damage lesions such as 8oxoG and abasic sites in DNA. Provides different translesion synthesis alternatives when DNA replication is stalled: able to synthesize DNA primers downstream of lesions, such as ultraviolet (UV) lesions, R-loops and G-quadruplexes, to allow DNA replication to continue. Can also realign primers ahead of ‘unreadable lesions’ such as abasic sites and 6-4 photoproduct (6-4 pyrimidine-pyrimidinone), thereby skipping the lesion. Repriming avoids fork degradation while leading to accumulation of internal ssDNA gaps behind the forks. Also able to incorporate nucleotides opposite DNA lesions such as 8oxoG, like a regular translesion synthesis DNA polymerase. Also required for reinitiating stalled forks after UV damage during nuclear DNA replication. Required for mitochondrial DNA (mtDNA) synthesis and replication, by reinitiating synthesis after UV damage or in the presence of chain-terminating nucleotides. Prevents APOBEC family-mediated DNA mutagenesis by repriming downstream of abasic site to prohibit error-prone translesion synthesis. Has non-overlapping function with POLH. In addition to its role in DNA damage response, also required to maintain efficient nuclear and mitochondrial DNA replication in unperturbed cells.

Subunit / interactions. Interacts with RPA1; leading to recruitment to chromatin and stimulate DNA primase activity. Interacts with SSBP1. Interacts with POLDIP2; leading to enhance DNA polymerase activity.

Subcellular location. Nucleus. Mitochondrion matrix. Chromosome.

Disease relevance. Myopia 22, autosomal dominant (MYP22) [MIM:615420] A refractive error of the eye, in which parallel rays from a distant object come to focus in front of the retina, vision being better for near objects than for far. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Can act both with Mn(2+) and Mg(2+) as cofactor in vitro, but Mn(2+) is the preferred cofactor in vivo. The polymerase activity incorporates correct dNTPs with much higher efficiency with Mn(2+) than with Mg(2+). The fidelity is slightly more accurate when Mg(2+) is the cofactor compared to Mn(2+). In the presence of Mn(2+), a conformational transition step from non-productive to productive PRIMPOL:DNA complexes limits the enzymatic turnover, whereas in the presence of Mg(2+), the chemical step becomes rate limiting.

Domain organisation. The zinc knuckle motif binds zinc and is required for the DNA primase activity. It facilitates the binding and selection of the 5’-nucleotide of the newly synthesized primer and the recognition of preferred initiation sites. The RPA1-binding motifs (RBM) mediate interaction with RPA1 and are essential for recruitment to chromatin. The interaction is primarily mediated by RPA1-binding motif 1, which binds to the basic cleft of RPA1, with motif 2 plays a supporting role in RPA1-binding. The presence of an Asp-Aaa-Glu (DxE) motif in the metal-binding active site favors the use of Mn(2+) ions to achieve optimal incoming nucleotide stabilization, especially required during primer synthesis. Glu-116 is required to stabilize the incoming nucleotide at the 3’-site.

Similarity. Belongs to the eukaryotic-type primase small subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96LW4-1	1	yes
Q96LW4-2	2

RefSeq proteins (14): NP_001287696, NP_001287697, NP_001332820, NP_001332821, NP_001332822, NP_001332823, NP_001332824, NP_001332825, NP_001332826, NP_001332827, NP_001332828, NP_001332829, NP_001332830, NP_689896* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002755	DNA_primase_S	Family
IPR044917	PRIMPOL	Family

Pfam: PF01896, PF03121

Enzyme classification (BRENDA):

• EC 2.7.7.102 — DNA primase AEP (BRENDA: 9 organisms, 25 substrates, 3 inhibitors, 8 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DNTP	5–198	3
5’-CTTCTTCTGTGC-3’	0.2	1
ATP	0.15	1
DATP	0.032	1
NTP	27.5	1

Catalyzed reactions (Rhea), 1 shown:

• DNA(n) + a 2’-deoxyribonucleoside 5’-triphosphate = DNA(n+1) + diphosphate (RHEA:22508)

UniProt features (68 total): strand 16, mutagenesis site 13, helix 12, binding site 11, region of interest 3, sequence variant 3, short sequence motif 3, chain 1, modified residue 1, splice variant 1, sequence conflict 1, coiled-coil region 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5N8A	X-RAY DIFFRACTION	1.28
5N85	X-RAY DIFFRACTION	2
7JLG	X-RAY DIFFRACTION	2.07
7JL8	X-RAY DIFFRACTION	2.1
5L2X	X-RAY DIFFRACTION	2.2
7JKL	X-RAY DIFFRACTION	2.38
7JKP	X-RAY DIFFRACTION	2.59
7JK1	X-RAY DIFFRACTION	2.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96LW4-F1	74.72	0.53

Functional residue map

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

Ligand- & substrate-binding residues (11): 114–116; 114; 116; 165–169; 288–291; 297; 419; 426; 446; 451; 76

Post-translational modifications (1): 255

Mutagenesis-validated functional residues (13):

Position	Phenotype
89	does not affect dna primase activity.
89	reduced dna primase activity.
114–116	in axa; abolished dna primase and polymerase activities.
114	abolishes dna primase and polymerase activities.
169	abolishes dna primase and polymerase activities.
280	abolished mn(2+) dna primase activity.
419	abolished zinc-binding, leading to altered translesion synthesis; when associated with a-426.
419	in mutant ch; abolished dna primase activity and impaired ability to restart stalled forks; when associated with y-426.
426	abolished zinc-binding, leading to altered translesion synthesis; when associated with a-419.
426	abolishes dna primase activity, while it increases dna polymerase activity.
426	in mutant ch; abolished dna primase activity and impaired ability to restart stalled forks; when associated with g-419.
519–522	abolished interaction with rpa1, impairing recruitment to chromatin and reducing dna primase activity; when associated w
551–554	abolished interaction with rpa1, impairing recruitment to chromatin and reducing dna primase activity; when associated w

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GOBP_DNA_DAMAGE_TOLERANCE, GOMF_DNA_POLYMERASE_ACTIVITY, chr4q35, GOBP_RESPONSE_TO_UV, GOBP_DNA_DAMAGE_RESPONSE, GOBP_RESPONSE_TO_RADIATION, GOBP_DNA_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOCC_RNA_POLYMERASE_COMPLEX, GOBP_ERROR_PRONE_TRANSLESION_SYNTHESIS, FISCHER_DREAM_TARGETS

GO Biological Process (11): mitochondrial DNA replication (GO:0006264), DNA replication, synthesis of primer (GO:0006269), response to UV (GO:0009411), translesion synthesis (GO:0019985), replication fork processing (GO:0031297), error-prone translesion synthesis (GO:0042276), mitochondrial DNA repair (GO:0043504), R-loop processing (GO:0062176), DNA-templated DNA replication (GO:0006261), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (10): chromatin binding (GO:0003682), DNA-directed DNA polymerase activity (GO:0003887), DNA-directed RNA polymerase activity (GO:0003899), zinc ion binding (GO:0008270), manganese ion binding (GO:0030145), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), DNA polymerase activity (GO:0034061), metal ion binding (GO:0046872)

GO Cellular Component (6): DNA-directed RNA polymerase complex (GO:0000428), nucleus (GO:0005634), replication fork (GO:0005657), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
DNA-templated DNA replication	2
mitochondrial DNA metabolic process	2
RNA biosynthetic process	2
binding	2
transition metal ion binding	2
intracellular membrane-bounded organelle	2
response to light stimulus	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	1
DNA-templated DNA replication maintenance of fidelity	1
translesion synthesis	1
DNA repair	1
chromatin remodeling	1
DNA replication	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
DNA polymerase activity	1
5’-3’ RNA polymerase activity	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
nucleotidyltransferase activity	1
DNA biosynthetic process	1
catalytic activity, acting on DNA	1
cation binding	1
RNA polymerase complex	1
chromosome	1
cellular anatomical structure	1
cytoplasm	1
intracellular organelle lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

868 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRIMPOL	POLDIP2	Q9Y2S7	849
PRIMPOL	SMARCAL1	Q9NZC9	713
PRIMPOL	REV1	Q9UBZ9	710
PRIMPOL	ZRANB3	Q5FWF4	708
PRIMPOL	POLL	Q9UGP5	696
PRIMPOL	HLTF	Q14527	688
PRIMPOL	REV3L	O60673	684
PRIMPOL	POLM	Q9NP87	660
PRIMPOL	PRIM1	P49642	654
PRIMPOL	TENT4A	Q5XG87	640
PRIMPOL	SSBP1	Q04837	630
PRIMPOL	RPA1	P27694	628
PRIMPOL	TWNK	Q96RR1	626
PRIMPOL	POLRMT	O00411	614
PRIMPOL	DNA2	P51530	607

IntAct

28 interactions, top by confidence:

A	B	Type	Score
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
RPA1	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.620
RPA1	PRIMPOL	psi-mi:“MI:0407”(direct interaction)	0.620
NAV1	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.560
CDKN2D	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.560
PSMA1	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.560
MPP1	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.560
PRIMPOL	RPA2	psi-mi:“MI:0914”(association)	0.510
PRIMPOL	RPA2	psi-mi:“MI:0403”(colocalization)	0.510
PRIMPOL	ECI2	psi-mi:“MI:0914”(association)	0.350
NAV1	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.000
CDKN2D	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.000
PSMA1	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.000
MPP1	PRIMPOL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (40): C10orf2 (Affinity Capture-MS), NEURL4 (Affinity Capture-MS), HERC2 (Affinity Capture-MS), ECI2 (Affinity Capture-MS), C4orf29 (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS), PRIMPOL (Affinity Capture-MS), PRIMPOL (Affinity Capture-MS), PRIMPOL (Affinity Capture-MS), SMARCAL1 (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), RFWD3 (Affinity Capture-MS), TIPIN (Affinity Capture-MS), CLSPN (Affinity Capture-MS), PRIMPOL (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q2TTB3, A0JMR6, A4IIA7, F4JNY0, F6RRD7, I3XHK1, O60934, O88622, P14629, P28715, P79457, Q08DZ8, Q12789, Q17RS7, Q1LWH4, Q28I29, Q32PL8, Q3B7T1, Q4R7Q1, Q5FWP4, Q5M954, Q5QJC2, Q5RA37, Q5RCV3, Q5ZIN2, Q66J91, Q6GQV7, Q6NVF4, Q6P1E7, Q6P1H6, Q6P256, Q6P7W5, Q76CY8, Q7TP65, Q86W56, Q8BMI4, Q8C0W1, Q8C5W4, Q8GT06, Q8IXW5

Diamond homologs: A0A3Q2TTB3, Q08DZ8, Q32PL8, Q6P1E7, Q96LW4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	72
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3032 predictions. Top by Δscore:

Variant	Effect	Δscore
4:184652017:TTACA:T	acceptor_loss	1.0000
4:184652018:TACA:T	acceptor_loss	1.0000
4:184652020:CA:C	acceptor_loss	1.0000
4:184652021:A:AG	acceptor_gain	1.0000
4:184652021:A:T	acceptor_loss	1.0000
4:184652022:G:GA	acceptor_loss	1.0000
4:184652022:G:GG	acceptor_gain	1.0000
4:184652022:GA:G	acceptor_gain	1.0000
4:184652022:GAGGT:G	acceptor_gain	1.0000
4:184652096:TCCAG:T	donor_loss	1.0000
4:184652097:CCAG:C	donor_loss	1.0000
4:184652098:CAGG:C	donor_loss	1.0000
4:184652101:G:A	donor_loss	1.0000
4:184652102:T:G	donor_loss	1.0000
4:184659339:GGAC:G	acceptor_gain	1.0000
4:184665915:A:AG	acceptor_gain	1.0000
4:184665916:G:GG	acceptor_gain	1.0000
4:184665916:GT:G	acceptor_gain	1.0000
4:184665916:GTAT:G	acceptor_gain	1.0000
4:184685407:A:AG	acceptor_gain	1.0000
4:184685408:G:GA	acceptor_gain	1.0000
4:184685408:GTA:G	acceptor_gain	1.0000
4:184685496:G:GT	donor_gain	1.0000
4:184685680:ATAAT:A	donor_gain	1.0000
4:184685681:TAAT:T	donor_gain	1.0000
4:184685682:AAT:A	donor_gain	1.0000
4:184685682:AATGT:A	donor_loss	1.0000
4:184685683:AT:A	donor_gain	1.0000
4:184685684:TGTA:T	donor_loss	1.0000
4:184685685:G:GG	donor_gain	1.0000

AlphaMissense

3719 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:184666044:T:C	F179S	0.997
4:184678250:G:C	R288T	0.997
4:184678251:A:C	R288S	0.997
4:184678251:A:T	R288S	0.997
4:184691539:T:C	C446R	0.997
4:184678250:G:T	R288I	0.996
4:184685463:T:A	V384D	0.996
4:184685644:T:C	C419R	0.996
4:184691554:T:C	C451R	0.996
4:184685587:T:A	W400R	0.995
4:184685587:T:C	W400R	0.995
4:184685644:T:A	C419S	0.995
4:184685645:G:C	C419S	0.995
4:184691539:T:A	C446S	0.995
4:184691540:G:C	C446S	0.995
4:184691554:T:A	C451S	0.995
4:184691555:G:C	C451S	0.995
4:184661844:T:C	F117L	0.994
4:184661846:T:A	F117L	0.994
4:184661846:T:G	F117L	0.994
4:184666004:T:C	F166L	0.993
4:184666006:C:A	F166L	0.993
4:184666006:C:G	F166L	0.993
4:184666007:A:C	S167R	0.993
4:184666009:C:A	S167R	0.993
4:184666009:C:G	S167R	0.993
4:184666013:C:G	H169D	0.993
4:184678256:T:C	F290S	0.993
4:184685665:C:G	H426D	0.993
4:184659356:C:A	A66D	0.992

dbSNP variants (sampled 300 via entrez): RS1000002401 (4:184654170 T>C), RS1000024343 (4:184653395 C>G), RS1000037394 (4:184678796 A>G), RS1000154738 (4:184693129 C>T), RS10001960 (4:184658191 A>G), RS1000241542 (4:184671971 A>C), RS1000263692 (4:184675306 A>T), RS1000281647 (4:184656049 G>A), RS1000334269 (4:184656351 C>G), RS10003354 (4:184668628 G>A), RS1000401498 (4:184675097 T>C,G), RS10004250 (4:184665396 C>T), RS1000425173 (4:184693331 G>A), RS1000445309 (4:184690123 T>A), RS1000493001 (4:184650206 C>G)

Disease associations

OMIM: gene MIM:615421 | disease phenotypes: MIM:615420

GenCC curated gene-disease

Disease	Classification	Inheritance
myopia 22, autosomal dominant	Limited	Autosomal dominant

Mondo (1): myopia 22, autosomal dominant (MONDO:0014177)

Orphanet (0):

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0007663	Reduced visual acuity
HP:0011003	High myopia

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs113420705	CASP3, PRIMPOL		0.00	0

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Testosterone	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases methylation	1
Okadaic Acid	decreases expression	1
Acrylamide	increases expression	1
Particulate Matter	increases abundance, decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TG58	HAP1 PRIMPOL (-) 1	Cancer cell line	Male
CVCL_TG59	HAP1 PRIMPOL (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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