POLG

Summary

POLG (DNA polymerase gamma, catalytic subunit, HGNC:9179) is a protein-coding gene on chromosome 15q26.1, encoding DNA polymerase subunit gamma-1 (P54098). Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). It is a selective cancer dependency (DepMap: 22.4% of cell lines).

Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 5428 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (Definitive, GenCC) — +10 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 3,211 total — 160 pathogenic, 142 likely-pathogenic
• Phenotypes (HPO): 298
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 22.4% of screened cell lines
• MANE Select transcript: NM_002693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9179
Approved symbol	POLG
Name	DNA polymerase gamma, catalytic subunit
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	POLG1, POLGA
Ensembl gene	ENSG00000140521
Ensembl biotype	protein_coding
OMIM	174763
Entrez	5428

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 9 protein_coding, 9 nonsense_mediated_decay, 7 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000268124, ENST00000442287, ENST00000526314, ENST00000526398, ENST00000526573, ENST00000526671, ENST00000528881, ENST00000530292, ENST00000530715, ENST00000532363, ENST00000532584, ENST00000533857, ENST00000631044, ENST00000635831, ENST00000635986, ENST00000636530, ENST00000636774, ENST00000636812, ENST00000636937, ENST00000637042, ENST00000637238, ENST00000637264, ENST00000637307, ENST00000637711, ENST00000666746, ENST00000670281, ENST00000672071, ENST00000672695, ENST00000672923

RefSeq mRNA: 2 — MANE Select: NM_002693 NM_001126131, NM_002693

CCDS: CCDS10350

Canonical transcript exons

ENST00000268124 — 23 exons

Exon	Start	End
ENSE00000943530	89333096	89333913
ENSE00003794945	89334673	89334824
ENSE00003993898	89323404	89323511
ENSE00003993899	89319228	89319350
ENSE00003993900	89320766	89321012
ENSE00003993901	89327167	89327349
ENSE00003993902	89316320	89316827
ENSE00003993903	89321962	89322015
ENSE00003993904	89326912	89327063
ENSE00003993905	89318541	89318749
ENSE00003993906	89330081	89330276
ENSE00003993907	89321125	89321260
ENSE00003993908	89323815	89323901
ENSE00003993909	89326612	89326738
ENSE00003993910	89322742	89322902
ENSE00003993911	89328943	89329110
ENSE00003993912	89317376	89317536
ENSE00003993913	89328685	89328831
ENSE00003993914	89325450	89325686
ENSE00003993915	89328456	89328535
ENSE00003993916	89318931	89319099
ENSE00003993917	89321736	89321853
ENSE00003993918	89324107	89324227

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.6405 / max 416.4947, expressed in 1816 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151439	29.6405	1816

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.43	gold quality
tibial nerve	UBERON:0001323	96.12	gold quality
lower esophagus mucosa	UBERON:0035834	96.10	gold quality
transverse colon	UBERON:0001157	96.04	gold quality
body of stomach	UBERON:0001161	95.94	gold quality
right lobe of thyroid gland	UBERON:0001119	95.84	gold quality
body of pancreas	UBERON:0001150	95.83	gold quality
metanephros cortex	UBERON:0010533	95.79	gold quality
spleen	UBERON:0002106	95.78	gold quality
apex of heart	UBERON:0002098	95.76	gold quality
minor salivary gland	UBERON:0001830	95.63	gold quality
body of uterus	UBERON:0009853	95.63	gold quality
cardia of stomach	UBERON:0001162	95.49	gold quality
skin of abdomen	UBERON:0001416	95.47	gold quality
fundus of stomach	UBERON:0001160	95.43	gold quality
left lobe of thyroid gland	UBERON:0001120	95.34	gold quality
lymph node	UBERON:0000029	95.24	gold quality
upper lobe of left lung	UBERON:0008952	95.24	gold quality
stomach	UBERON:0000945	95.23	gold quality
skin of leg	UBERON:0001511	95.23	gold quality
pylorus	UBERON:0001166	95.21	gold quality
lower esophagus	UBERON:0013473	95.19	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.16	gold quality
mouth mucosa	UBERON:0003729	95.15	gold quality
tongue squamous epithelium	UBERON:0006919	95.13	gold quality
small intestine	UBERON:0002108	95.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.04	gold quality
right ovary	UBERON:0002118	95.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3, MYC, NFE2L2, NRF1

miRNA regulators (miRDB)

24 targeting POLG, 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-4682	100.00	68.89	1258
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-4424	98.91	70.33	1145
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-5007-5P	97.95	64.71	614
HSA-MIR-4642	97.52	67.60	916
HSA-MIR-3130-3P	94.98	66.97	574

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 22.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis (PMID:11897778)
• Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. (PMID:12210792)
• recessive POLG mutations in compound heterozygote patients with progressive external ophthalmoplegia presenting with sensory ataxic neuropathy (PMID:12565911)
• DNA polymerase-gamma has a role in regulating mitochondrial DNA (PMID:12645575)
• mtDNA polymerase POLG and various other as yet unidentified proteins copurify with mtDNA nucleoids (PMID:12686611)
• human DNA polymerase gamma has roles as a reverse transcriptase and other RNA-associated catalytic activities involved in mitochondrial DNA replication (PMID:12857740)
• The POLG gene polymorphism should be considered as a possible contributing factor in patients with unexplained subfertility and normal spermiograms. (PMID:14688158)
• The authors report on a patient homozygous for a recessive missense mutation in POLG who presented with a multisystem disorder without progressive external ophthalmoplegia; the clinical picture overlapped with the MERRF syndrome (PMID:14694057)
• effect of N2-deoxyguanosine and N6-deoxyadenosine adducts derived from BaP 7,8-diol 9,10-epoxide and dA adducts from benzo[c]phenanthrene 3,4-diol 1,2-epoxide on DNA replication by exonuclease-deficient human mitochondrial DNA polymerase (PMID:14729924)
• 2 new heterozygous missense transitions (C2794T, G3151C)were found in the POLG gene in a family with an autosomal recessive syndrome: progressive external ophthalmoplegia, polyneuropathy, ataxia, sensorineural hearing loss, and affective disorders. (PMID:14745080)
• authors propose that replication stalling is the principal cause of deletion formation (PMID:15181170)
• a trinucleotide repeat has expanded from a shorter sequence present in the common ancestor of Old and New World monkeys (PMID:15181541)
• Cosegregation of parkinsonism and POLG mutations suggests that when defective, this gene can underlie mendelian transmission of parkinsonism. (PMID:15351195)
• The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. (PMID:15477547)
• Under our conditions, our study does not confirm any relationship between the polymorphic CAG repeat in the POLG gene and male infertility. (PMID:15650046)
• POLG mutations in four patients with hepatocerebral syndrome and mtDNA depletion in liver, who fulfilled criteria for Alpers syndrome (PMID:15929042)
• We found Alzheimer pathology associated with POLG1 mutation, multiple mtDNA deletions, and APOE4/4 and progressive external ophthalmoplegia. (PMID:15981013)
• Reduced polymerase activity and loss of accessory subunit interaction are responsible for the depletion and deletion of mitochondrial DNA observed in patients with the A467T mutation in the POLG catalytic subunit. (PMID:16024923)
• Mitochondrial DNA polymerase-gamma W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. (PMID:16080118)
• POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (PMID:16130100)
• The Alpers phenotype in this patient was a consequence of a single-copy gene dose of the A467T allele, and selective elimination of transcripts bearing the E873stop mutation. (PMID:16181814)
• the functional human holoenzyme contains two subunits of the processivity factor and one catalytic subunit, thereby forming a heterotrimer (PMID:16263719)
• Dnaja3 is crucial for mitochondrial biogenesis through its chaperone activity on Polga and has a role in preventing dilated cardiomyopathy (PMID:16327803)
• Human mitochondrial DNA polymerase, encoded by POLG, contains a polyglutamine tract encoded by a CAG microsatellite repeat (PMID:16392637)
• POLG molecular defects were found in 25% of patients with multiple mtDNA deletions and mitochondrial disease in this study. (PMID:16401742)
• Review of DNA polymerase gamma in mitochondrial DNA replication and repair and disease (PMID:16464011)
• Non-normozoospermic men had twice as many nucleotide substitutions than normozoospermic men, however, there were no significant differences in the frequencies of nucleotide substitution and POLgamma genotypes in the two groups of men (PMID:16487403)
• endogenous error mediated by DNA pol gamma constitutes the primary source of mitochondrial point mutations (PMID:16490220)
• A467T and W748S substitutions in POLG now constitutes the most rapid and sensitive test available for confirming the clinical diagnosis of Alpers syndrome. (PMID:16545482)
• Identification of five new POLG mutations in Alpers and summary of the A467T and W748S linker mutations as the most common mutations in Alpers syndrome (PMID:16545482)
• findings, in agreement with other studies from Italy and France, suggest that, at least in these countries, the POLG1 CAG-repeat polymorphisms do not contribute to oligozoospermia (PMID:16553026)
• shares a high level of structural similarity to class IIa aminoacyl tRNA synthetases, and forms a dimer in the crystal (PMID:16574152)
• POLG mutations can segregate with premaature ovarian failure and parkinsonism and demonstrates that the Y955C mutation can lead to mtDNA depletion. (PMID:16595552)
• Causative POLG1 mutations were identified in approximately 10% of progressive external ophthalmoplegia cases, with two unrelated individuals harboring a novel premature stop codon mutation (1356T>G). (PMID:16682683)
• The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease. (PMID:16896309)
• the nuclear encoded DNA polymerase gamma (POLG) is a sole DNA polymerase responsible for replication and repair of the mitochondrial genome. (PMID:16929381)
• Our observations do not support a role for common POLG1 genetic variants in PD and indicate that dominant POLG1 mutations are a rare cause of parkinsonism in the general population. (PMID:16943369)
• Failure to thrive, feeding difficulties, epilepsy, psychomotor developmental delay and hypotonia-the presentations in children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene (PMID:16957900)
• Mitochondrial DNA polymerase-gamma and disease. Review. (PMID:16987890)
• analysis of replication and incorporation of 8-oxo-deoxyguanosine by the human mitochondrial DNA polymerase (PMID:17005553)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polg	ENSDARG00000060951
mus_musculus	Polg	ENSMUSG00000039176
rattus_norvegicus	Polg	ENSRNOG00000032293
drosophila_melanogaster	PolG1	FBGN0004406
caenorhabditis_elegans		WBGENE00013258

Protein

Protein identifiers

DNA polymerase subunit gamma-1 — P54098 (reviewed: P54098)

Alternative names: 3’-5’ exodeoxyribonuclease, 5’-deoxyribose-phosphate lyase, Mitochondrial DNA polymerase catalytic subunit, PolG-alpha

All UniProt accessions (17): A0A0D9SFM1, A0A1B0GTQ6, A0A1B0GTU7, A0A1B0GUT0, A0A1B0GV78, A0A1B0GV99, A0A1B0GVT8, A0A1B0GW33, A0A590UJP1, A0A590UK63, E5KNU5, H0YCD2, H0YCV2, H0YD36, H0YDF1, H0YE43, P54098

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). Replicates both heavy and light strands of the circular mtDNA genome using a single-stranded DNA template, RNA primers and the four deoxyribonucleoside triphosphates as substrates. Has 5’ -> 3’ polymerase activity. Functionally interacts with TWNK and SSBP1 at the replication fork to form a highly processive replisome, where TWNK unwinds the double-stranded DNA template prior to replication and SSBP1 covers the parental heavy strand to enable continuous replication of the entire mitochondrial genome. A single nucleotide incorporation cycle includes binding of the incoming nucleotide at the insertion site, a phosphodiester bond formation reaction that extends the 3’-end of the primer DNA, and translocation of the primer terminus to the post-insertion site. After completing replication of a mtDNA strand, mediates 3’ -> 5’ exonucleolytic degradation at the nick to enable proper ligation. Highly accurate due to high nucleotide selectivity and 3’ -> 5’ exonucleolytic proofreading. Proficiently corrects base substitutions, single-base additions and deletions in non-repetitive sequences and short repeats, but displays lower proofreading activity when replicating longer homopolymeric stretches. Exerts exonuclease activity toward single-stranded DNA and double-stranded DNA containing 3’-terminal mispairs. When a misincorporation occurs, transitions from replication to a pro-nucleolytic editing mode and removes the missincorporated nucleoside in the exonuclease active site. Proceeds via an SN2 nucleolytic mechanism in which Asp-198 catalyzes phosphodiester bond hydrolysis and Glu-200 stabilizes the leaving group. As a result the primer strand becomes one nucleotide shorter and is positioned in the post-insertion site, ready to resume DNA synthesis. Exerts 5’-deoxyribose phosphate (dRP) lyase activity and mediates repair-associated mtDNA synthesis (gap filling) in base-excision repair pathway. Catalyzes the release of the 5’-terminal 2-deoxyribose-5-phosphate sugar moiety from incised apurinic/apyrimidinic (AP) sites to produce a substrate for DNA ligase. The dRP lyase reaction does not require divalent metal ions and likely proceeds via a Schiff base intermediate in a beta-elimination reaction mechanism.

Subunit / interactions. Heterotrimer composed of a catalytic subunit and a homodimer of accessory subunits (POLG:POLG2). Interacts with TTC3. Interacts with LIG3.

Subcellular location. Mitochondrion. Mitochondrion matrix. Mitochondrion nucleoid.

Disease relevance. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 1 (PEOA1) [MIM:157640] A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. The disease is caused by variants affecting the gene represented in this entry. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive, 1 (PEOB1) [MIM:258450] A severe form of progressive external ophthalmoplegia, a disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. It is clinically more heterogeneous than the autosomal dominant forms. The disease is caused by variants affecting the gene represented in this entry. Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) [MIM:607459] A systemic disorder resulting from mitochondrial dysfunction associated with mitochondrial depletion in skeletal muscle and peripheral nerve tissue. The clinical triad of symptoms consists of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, the phenotype varies widely, even within the same family, and can also include myopathy, seizures, and hearing loss. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial DNA depletion syndrome 4A (MTDPS4A) [MIM:203700] An autosomal recessive hepatocerebral syndrome due to mitochondrial dysfunction. The typical course of the disease includes severe developmental delay, intractable seizures, liver failure, and death in childhood. Refractory seizures, cortical blindness, progressive liver dysfunction, and acute liver failure after exposure to valproic acid are considered diagnostic features. The neuropathological hallmarks are neuronal loss, spongiform degeneration, and astrocytosis of the visual cortex. Liver biopsy results show steatosis, often progressing to cirrhosis. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial DNA depletion syndrome 4B (MTDPS4B) [MIM:613662] An autosomal recessive progressive multisystem disorder due to mitochondrial dysfunction. It is clinically characterized by chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, and muscle weakness. The disease is caused by variants affecting the gene represented in this entry. Leigh syndrome (LS) [MIM:256000] An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia with epilepsy (SCAE) [MIM:607459] An autosomal recessive syndrome characterized by headaches and/or seizures manifesting in childhood or adolescence, cerebellar and sensory ataxia, dysarthria, and myoclonus manifesting in early adulthood. Neuropathological findings include spinocerebellar degeneration associated with cortical neuronal degeneration in advanced cases. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by dideoxynucleotides such as antiviral agent zalcitabine.

Domain organisation. The polymerase domain encompasses three conserved active site motifs: Pol A (residues 887-896), Pol B (residues 943-958) and Pol C (residues 1134-1141). Binds the incoming dNTPs and undergoes an open to close coformation change to catalyze the formation of phosphodiester bond. The 3’ -> 5’ exonuclease domain comprises three conserved active site motifs: Exo I (residues 196-200), Exo II (residues 267-275) and Exo III (residues 395-403). Proofreads the newly synthesized DNA strand. The trigger loop contracts to enable correctly matched primer-template pair entry into the polymerase domain and extends to preclude the mismatched one. The accessory determinant domain (AID) interacts with POLG2 proximal monomer.

Polymorphism. The poly-Gln region seems to be polymorphic.

Similarity. Belongs to the DNA polymerase type-A family.

RefSeq proteins (2): NP_001119603, NP_002684* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001098	DNA-dir_DNA_pol_A_palm_dom	Domain
IPR002297	DNA-dir_DNA_pol_A_mt	Family
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR019760	DNA-dir_DNA_pol_A_CS	Conserved_site
IPR041336	DNApol_Exo	Domain
IPR043502	DNA/RNA_pol_sf	Homologous_superfamily
IPR047580	POLG_palm_dom	Domain

Pfam: PF18136

Catalyzed reactions (Rhea), 3 shown:

• DNA(n) + a 2’-deoxyribonucleoside 5’-triphosphate = DNA(n+1) + diphosphate (RHEA:22508)
• a 5’-end 2’-deoxyribose-2’-deoxyribonucleotide-DNA = (2E,4S)-4-hydroxypenten-2-al-5-phosphate + a 5’-end 5’-phospho-2’-deoxyribonucleoside-DNA + H(+) (RHEA:76255)
• a 3’-end 2’-deoxyribonucleotidyl-deoxyribonucleotide-DNA + H2O = a 3’-end 2’-deoxyribonucleotide-DNA + a 2’-deoxyribonucleoside 5’-phosphate + H(+) (RHEA:77911)

UniProt features (253 total): sequence variant 81, strand 54, helix 51, binding site 25, mutagenesis site 13, turn 11, region of interest 6, short sequence motif 6, compositionally biased region 2, site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8UDL	ELECTRON MICROSCOPY	2.37
9GGC	ELECTRON MICROSCOPY	2.39
8D33	ELECTRON MICROSCOPY	2.46
8G5M	ELECTRON MICROSCOPY	2.58
8G5O	ELECTRON MICROSCOPY	2.61
9Y4F	ELECTRON MICROSCOPY	2.62
8G5J	ELECTRON MICROSCOPY	2.63
9GGB	ELECTRON MICROSCOPY	2.63
8D37	ELECTRON MICROSCOPY	2.65
9GGF	ELECTRON MICROSCOPY	2.65
9GGD	ELECTRON MICROSCOPY	2.67
9GGE	ELECTRON MICROSCOPY	2.69
8G5N	ELECTRON MICROSCOPY	2.73
9IC1	ELECTRON MICROSCOPY	2.73
8G5I	ELECTRON MICROSCOPY	2.75
8G5P	ELECTRON MICROSCOPY	2.78
8G5K	ELECTRON MICROSCOPY	2.9
8D42	ELECTRON MICROSCOPY	2.91
9Y4D	ELECTRON MICROSCOPY	2.94
9IC3	ELECTRON MICROSCOPY	2.96
8G5L	ELECTRON MICROSCOPY	3
8V5D	ELECTRON MICROSCOPY	3
8V5R	ELECTRON MICROSCOPY	3
8D3R	ELECTRON MICROSCOPY	3.04
9Y4E	ELECTRON MICROSCOPY	3.05
8T7E	ELECTRON MICROSCOPY	3.08
9Y4C	ELECTRON MICROSCOPY	3.23
3IKM	X-RAY DIFFRACTION	3.24
4ZTU	X-RAY DIFFRACTION	3.3
5C51	X-RAY DIFFRACTION	3.43

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54098-F1	79.53	0.44

Functional residue map

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

Catalytic / active sites (3): 198 (exonuclease activity); 853 (critical for replication fidelity and mismatch recognition); 1102 (critical for replication fidelity and mismatch recognition)

Ligand- & substrate-binding residues (25): 306; 579; 593; 754; 763; 768; 806; 849; 863; 869; 890; 890 …

Mutagenesis-validated functional residues (13):

Position	Phenotype
198	abolishes exonuclease activity; when associated with a-200. decreases polymerase exonucleolytic proofreading by 30-fold
200	abolishes exonuclease activity; when associated with a-198. decreases polymerase exonucleolytic proofreading by 30-fold
274	unable to idle at the 5’-end of the nascent dna strand. continues dna synthesis into double-stranded dna past the 5’-end
498	decreases processive dna synthesis.
499	decreases processive dna synthesis.
501	decreases processive dna synthesis.
543–558	markedly decreases the stimulation by polg2, resulting in impaired processive dna synthesis.
549	decreases processive dna synthesis.
552	decreases processive dna synthesis.
553	decreases processive dna synthesis.
853	abolishes primer dna extention in the presence of dntps. impairs intrinsic polymerase processivity. enhances exonuclease
890	abolishes dna polymerase activity.
1135	abolishes dna polymerase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9913635	Strand-asynchronous mitochondrial DNA replication

MSigDB gene sets: 698 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, REACTOME_DNA_REPLICATION, GOMF_NUCLEASE_ACTIVITY, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GCM_NPM1, ATGCAGT_MIR217, KAUFFMANN_DNA_REPAIR_GENES, CEBPB_01, PUJANA_CHEK2_PCC_NETWORK, GCM_PSME1, GCM_PPP1CC, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, MARTINEZ_RB1_TARGETS_DN, GOMF_DNA_POLYMERASE_ACTIVITY, KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_UP

GO Biological Process (9): DNA metabolic process (GO:0006259), DNA-templated DNA replication (GO:0006261), mitochondrial DNA replication (GO:0006264), base-excision repair (GO:0006284), base-excision repair, gap-filling (GO:0006287), DNA replication proofreading (GO:0045004), DNA replication (GO:0006260), DNA repair (GO:0006281), DNA biosynthetic process (GO:0071897)

GO Molecular Function (14): protease binding (GO:0002020), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-directed DNA polymerase activity (GO:0003887), single-stranded DNA 3’-5’ DNA exonuclease activity (GO:0008310), 3’-5’ exonuclease activity (GO:0008408), 5’-deoxyribose-5-phosphate lyase activity (GO:0051575), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), hydrolase activity (GO:0016787), lyase activity (GO:0016829), DNA polymerase activity (GO:0034061), catalytic activity, acting on a nucleic acid (GO:0140640)

GO Cellular Component (6): mitochondrial chromosome (GO:0000262), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), gamma DNA polymerase complex (GO:0005760), protein-containing complex (GO:0032991), mitochondrial nucleoid (GO:0042645)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	4
DNA metabolic process	4
catalytic activity	4
DNA repair	2
DNA biosynthetic process	2
binding	2
catalytic activity, acting on DNA	2
mitochondrial matrix	2
nucleic acid metabolic process	1
DNA replication	1
DNA-templated DNA replication	1
mitochondrial DNA metabolic process	1
base-excision repair	1
DNA-templated DNA replication maintenance of fidelity	1
DNA damage response	1
nucleic acid biosynthetic process	1
enzyme binding	1
nucleic acid binding	1
DNA polymerase activity	1
3’-5’-DNA exonuclease activity	1
single-stranded DNA exodeoxyribonuclease activity	1
exonuclease activity	1
carbon-oxygen lyase activity	1
transferase activity, transferring phosphorus-containing groups	1
nucleotidyltransferase activity	1
chromosome	1
mitochondrial nucleoid	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
DNA polymerase complex	1
mitochondrial protein-containing complex	1
cellular_component	1
nucleoid	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3150 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLG	POLG2	Q9UHN1	997
POLG	TWNK	Q96RR1	996
POLG	RRM2B	Q7LG56	942
POLG	SLC25A4	P12235	942
POLG	SSBP1	Q04837	937
POLG	TFAM	Q00059	929
POLG	MPV17	P39210	921
POLG	DGUOK	P78532	918
POLG	POLQ	O75417	891
POLG	SUCLA2	Q9P2R7	886
POLG	TYMP	P19971	838
POLG	POLRMT	O00411	823
POLG	SPAG9	O60271	749
POLG	MT-CO2	P00403	736
POLG	SUCLG1	P53597	728

IntAct

116 interactions, top by confidence:

A	B	Type	Score
POLG2	POLG	psi-mi:“MI:0407”(direct interaction)	0.950
POLG	POLG2	psi-mi:“MI:0407”(direct interaction)	0.950
POLG2	POLG	psi-mi:“MI:0914”(association)	0.950
POLG	POLG2	psi-mi:“MI:0915”(physical association)	0.950
POLG2	POLG	psi-mi:“MI:0915”(physical association)	0.950
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
MGME1	POLG	psi-mi:“MI:0914”(association)	0.640
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
OTC	RTL8C	psi-mi:“MI:0914”(association)	0.530
GATC	NME4	psi-mi:“MI:0914”(association)	0.530
TSPYL6	NME4	psi-mi:“MI:0914”(association)	0.530
MGME1	WDHD1	psi-mi:“MI:0914”(association)	0.530
POLG2	GLDC	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530
SDHB	POLG	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530

BioGRID (134): POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS), POLG (Affinity Capture-MS)

ESM2 similar proteins: A0A087WRI3, A2AIP0, A2RRW4, A4D2P6, A6QPC0, A8E5W8, A8MTA8, A9JS51, E9PGG2, G3X6E2, H3BNL1, O08856, O43247, O43566, O70373, P54098, P54099, Q0VB26, Q12770, Q2TA11, Q2TBR5, Q3ZBN4, Q400G9, Q4QR77, Q5MNU5, Q5RDC3, Q6J272, Q6ZQR2, Q70EL4, Q8BL74, Q8BUM9, Q8BX43, Q8C0R7, Q8C4S8, Q8N1D5, Q8N6G2, Q8WUA4, Q8WW14, Q969Z4, Q96MK2

Diamond homologs: P15801, P54098, P54099, Q01941, Q12704, Q27607, Q91684, Q92076, Q9QYV8, Q9Y767

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
clofarabine	“down-regulates activity”	POLG	“chemical inhibition”
POLG	“form complex”	“DNA polymerase gamma”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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
Respiratory electron transport	10	13.2×	1e-06
Mitochondrial ribosome-associated quality control	7	11.9×	2e-04
Mitochondrial protein degradation	7	11.1×	2e-04
Mitochondrial translation initiation	5	8.8×	7e-03
Mitochondrial translation elongation	5	8.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
aerobic respiration	6	16.2×	3e-04
proton motive force-driven mitochondrial ATP synthesis	5	14.3×	3e-03
mitochondrial translation	6	11.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

3211 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	160
Likely pathogenic	142
Uncertain significance	1404
Likely benign	1032
Benign	66

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073559	NM_002693.3(POLG):c.2004del (p.Met669fs)	Pathogenic
1075687	NM_002693.3(POLG):c.1237_1250dup (p.Arg417fs)	Pathogenic
1076518	NM_002693.3(POLG):c.268C>T (p.Gln90Ter)	Pathogenic
13498	NM_002693.3(POLG):c.8G>C (p.Arg3Pro)	Pathogenic
13499	NM_002693.3(POLG):c.1879C>T (p.Arg627Trp)	Pathogenic
13500	NM_002693.3(POLG):c.2794C>T (p.His932Tyr)	Pathogenic
13502	NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)	Pathogenic
13504	NM_002693.3(POLG):c.2617G>T (p.Glu873Ter)	Pathogenic
13506	NM_002693.3(POLG):c.2591A>G (p.Asn864Ser)	Pathogenic
13511	NM_002693.3(POLG):c.3057G>A (p.Trp1019Ter)	Pathogenic
13514	NM_002693.3(POLG):c.1532G>A (p.Ser511Asn)	Pathogenic
13516	NM_002693.3(POLG):c.3218C>T (p.Pro1073Leu)	Pathogenic
1357431	NM_002693.3(POLG):c.3630C>G (p.Tyr1210Ter)	Pathogenic
1373955	NM_002693.3(POLG):c.1035G>A (p.Trp345Ter)	Pathogenic
1390135	NM_002693.3(POLG):c.2217C>A (p.Tyr739Ter)	Pathogenic
1398287	NM_002693.3(POLG):c.846C>G (p.Tyr282Ter)	Pathogenic
1405074	NM_002693.3(POLG):c.2753G>A (p.Trp918Ter)	Pathogenic
1409996	NM_002693.3(POLG):c.3326dup (p.Leu1109fs)	Pathogenic
1412734	NM_002693.3(POLG):c.3574G>T (p.Glu1192Ter)	Pathogenic
1421810	NM_002693.3(POLG):c.1783C>T (p.Gln595Ter)	Pathogenic
1425375	NM_002693.3(POLG):c.907G>A (p.Gly303Arg)	Pathogenic
1449732	NM_002693.3(POLG):c.3003_3013del (p.Trp1003fs)	Pathogenic
1452045	NM_002693.3(POLG):c.1720C>T (p.Arg574Trp)	Pathogenic
1453148	NM_002693.3(POLG):c.2691_2703dup (p.Leu902fs)	Pathogenic
1454099	NM_002693.3(POLG):c.3576_3580dup (p.Thr1194delinsLysTer)	Pathogenic
1454886	NM_002693.3(POLG):c.2894_2897del (p.Arg964_Leu965insTer)	Pathogenic
1455242	NM_002693.3(POLG):c.287del (p.Gly96fs)	Pathogenic
1455434	NM_002693.3(POLG):c.1457G>A (p.Trp486Ter)	Pathogenic
1457717	NM_002693.3(POLG):c.3325_3328del (p.Leu1109fs)	Pathogenic
1457770	NM_002693.3(POLG):c.1846del (p.Glu616fs)	Pathogenic

SpliceAI

4972 predictions. Top by Δscore:

Variant	Effect	Δscore
15:89305238:ACCAG:A	donor_loss	1.0000
15:89305239:CCAGG:C	donor_loss	1.0000
15:89305240:CAGGT:C	donor_loss	1.0000
15:89305241:AGGT:A	donor_loss	1.0000
15:89305242:GG:G	donor_loss	1.0000
15:89305243:G:A	donor_loss	1.0000
15:89305244:T:G	donor_loss	1.0000
15:89305336:CCCA:C	acceptor_loss	1.0000
15:89305337:CCA:C	acceptor_loss	1.0000
15:89305338:CA:C	acceptor_loss	1.0000
15:89305339:A:AC	acceptor_loss	1.0000
15:89305339:A:AG	acceptor_gain	1.0000
15:89305340:G:GG	acceptor_gain	1.0000
15:89305340:GGAT:G	acceptor_gain	1.0000
15:89305408:GT:G	donor_gain	1.0000
15:89305410:G:GG	donor_gain	1.0000
15:89305601:TCAGT:T	acceptor_loss	1.0000
15:89305602:CA:C	acceptor_loss	1.0000
15:89305603:A:AG	acceptor_gain	1.0000
15:89305603:A:C	acceptor_loss	1.0000
15:89305604:G:GA	acceptor_gain	1.0000
15:89305604:GTT:G	acceptor_gain	1.0000
15:89305604:GTTA:G	acceptor_gain	1.0000
15:89305604:GTTAC:G	acceptor_gain	1.0000
15:89305698:GGTAA:G	donor_loss	1.0000
15:89305699:G:C	donor_loss	1.0000
15:89305700:T:A	donor_loss	1.0000
15:89306005:A:AG	acceptor_gain	1.0000
15:89306006:G:GG	acceptor_gain	1.0000
15:89306006:GAA:G	acceptor_gain	1.0000

AlphaMissense

8098 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:89318619:T:A	D1135V	1.000
15:89318627:G:C	S1132R	1.000
15:89318627:G:T	S1132R	1.000
15:89318629:T:G	S1132R	1.000
15:89318728:A:G	W1099R	1.000
15:89318728:A:T	W1099R	1.000
15:89321759:A:G	W859R	1.000
15:89321759:A:T	W859R	1.000
15:89317446:C:A	K1191N	0.999
15:89317446:C:G	K1191N	0.999
15:89317449:C:A	R1190S	0.999
15:89317449:C:G	R1190S	0.999
15:89317450:C:A	R1190M	0.999
15:89317450:C:G	R1190T	0.999
15:89318610:C:G	R1138P	0.999
15:89318616:T:A	E1136V	0.999
15:89318619:T:G	D1135A	0.999
15:89318620:C:G	D1135H	0.999
15:89318704:C:G	D1107H	0.999
15:89318714:G:C	S1103R	0.999
15:89318714:G:T	S1103R	0.999
15:89318716:T:G	S1103R	0.999
15:89318964:G:C	S1080R	0.999
15:89318964:G:T	S1080R	0.999
15:89318966:T:G	S1080R	0.999
15:89320897:G:C	N950K	0.999
15:89320897:G:T	N950K	0.999
15:89321170:A:G	W897R	0.999
15:89321170:A:T	W897R	0.999
15:89321172:A:G	L896P	0.999

dbSNP variants (sampled 300 via entrez): RS1000050379 (15:89320523 T>A), RS1000091663 (15:89324652 G>A), RS1000366960 (15:89332111 C>T), RS1000501787 (15:89326203 G>A), RS1000669622 (15:89331093 C>T), RS1000829274 (15:89335204 A>G), RS1000876898 (15:89336239 G>A), RS1000909206 (15:89317138 G>A), RS1000948176 (15:89335151 A>C,G,T), RS1001007161 (15:89321680 G>GT), RS1001050063 (15:89331160 C>T), RS1001205255 (15:89330596 G>C), RS1001361742 (15:89316947 C>G,T), RS1001437048 (15:89331366 G>A), RS1001570418 (15:89325609 C>T)

Disease associations

OMIM: gene MIM:174763 | disease phenotypes: MIM:203700, MIM:258450, MIM:603041, MIM:607459, MIM:613832, MIM:613662, MIM:157640, MIM:303350, MIM:615530, MIM:540000, MIM:609053, MIM:227650, MIM:616280, MIM:209850, MIM:606369, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	Definitive	Autosomal dominant
mitochondrial DNA depletion syndrome 4a	Definitive	Autosomal recessive
sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	Definitive	Autosomal recessive
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	Strong	Autosomal recessive
mitochondrial DNA depletion syndrome 4b	Strong	Autosomal recessive
spinocerebellar ataxia with epilepsy	Supportive	Autosomal recessive
autosomal recessive progressive external ophthalmoplegia	Supportive	Autosomal recessive
autosomal dominant progressive external ophthalmoplegia	Supportive	Autosomal dominant
mitochondrial neurogastrointestinal encephalomyopathy	Supportive	Autosomal recessive
recessive mitochondrial ataxia syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR

Mondo (38): mitochondrial DNA depletion syndrome 4a (MONDO:0008758), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (MONDO:0009783), mitochondrial DNA depletion syndrome 1 (MONDO:0011283), sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (MONDO:0011835), mitochondrial DNA depletion syndrome 4b (MONDO:0013350), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (MONDO:0024528), hereditary spastic paraplegia (MONDO:0019064), mitochondrial disease (MONDO:0044970), early-onset Parkinson disease 20 (MONDO:0014233), mitochondrial DNA depletion syndrome (MONDO:0018158), MELAS syndrome (MONDO:0010789), intellectual disability (MONDO:0001071), spinocerebellar ataxia with epilepsy (MONDO:0016809), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), congenital nervous system disorder (MONDO:0002320)

Orphanet (25): Alpers-Huttenlocher syndrome (Orphanet:726), Autosomal recessive progressive external ophthalmoplegia (Orphanet:254886), Mitochondrial neurogastrointestinal encephalomyopathy (Orphanet:298), Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome (Orphanet:70595), Hereditary spastic paraplegia (Orphanet:685), Mitochondrial disease (Orphanet:68380), Atypical juvenile parkinsonism (Orphanet:391411), Mitochondrial DNA depletion syndrome (Orphanet:35698), MELAS (Orphanet:550), Spinocerebellar ataxia with epilepsy (Orphanet:254881), Autosomal dominant non-syndromic intellectual disability (Orphanet:178469), Rare hypertrophic cardiomyopathy (Orphanet:217569), Fanconi anemia (Orphanet:84), Neuromuscular disease (Orphanet:68381), Recessive mitochondrial ataxia syndrome (Orphanet:94125)

HPO phenotypes

298 total (30 of 298 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000017	Nocturia
HP:0000029	Testicular atrophy
HP:0000044	Hypogonadotropic hypogonadism
HP:0000182	Movement abnormality of the tongue
HP:0000252	Microcephaly
HP:0000298	Mask-like facies
HP:0000338	Hypomimic face
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000478	Abnormality of the eye
HP:0000479	Abnormal retinal morphology
HP:0000496	Abnormality of eye movement
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000544	External ophthalmoplegia
HP:0000565	Esotropia
HP:0000572	Visual loss
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000651	Diplopia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000136_5	Height	8.000000e-07
GCST001381_4	Menopause (age at onset)	4.000000e-13
GCST004275_1	Venlafaxine response in generalised anxiety disorder (responders vs non-responders after 24 weeks)	3.000000e-06
GCST004946_120	Schizophrenia	3.000000e-08
GCST005312_8	Menopause (age at onset)	2.000000e-19
GCST007327_124	Smoking status (ever vs never smokers)	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0004318	smoking behavior

MeSH disease descriptors (19)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065768	Lennox Gastaut Syndrome	C10.228.140.490.493.750; C16.320.495
D017241	MELAS Syndrome	C05.651.460.620.520; C10.228.140.163.100.535; C10.228.140.300.275.500; C10.668.491.500.500.500; C14.907.253.329.500; C16.320.565.189.535; C18.452.132.100.535; C18.452.648.189.535; C18.452.660.560.620.520
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
D009468	Neuromuscular Diseases	C10.668
D011115	Polyneuropathies	C10.668.829.800
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C537968	Camptocormia (supp.)
C563802	Fanconi Anemia, Complementation Group I (supp.)
C563575	Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 1 (supp.)
C564926	Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Recessive (supp.)
C564395	Spinocerebellar Ataxia with Epilepsy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2732 (SINGLE PROTEIN), CHEMBL3430903 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 27,632 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL922	ADEFOVIR DIPIVOXIL	4	27,632

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3087374	Toxicity	3	valproic acid	Toxic liver disease

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2307441	POLG		0.00	0
rs3087374	FANCI, POLG	3	4.00	1	valproic acid
rs61752783	POLG		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — DNA polymerases

ChEMBL bioactivities

9 potent at pChembl≥5 of 16 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.30	IC50	500	nM	CHEMBL483492
6.10	Kd	800	nM	DEOXYGUANOSINE TRIPHOSPHATE
6.01	Ki	970	nM	ADEFOVIR DIPIVOXIL
5.96	Kd	1100	nM	DEOXYCYTIDINE TRIPHOSPHATE
5.82	IC50	1500	nM	CHEMBL2092833
5.70	IC50	2000	nM	CHEMBL2092835
5.52	IC50	3000	nM	CHEMBL3126408
5.46	IC50	3500	nM	CHEMBL2092834
5.22	Kd	6000	nM	ACYCLOVIR TRIPHOSPHATE

PubChem BioAssay actives

9 with measured affinity, of 110 total; 9 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
[[(2S,3R,5S)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-fluorooxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53489: Compound was evaluated for the inhibition of cellular DNA polymerase (gamma)	ic50	0.5000	uM
[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	357985: Binding affinity to exonuclase deficient human recombinant DNA polymerase gamma E200A mutant	kd	0.8000	uM
Adefovir Dipivoxil	2095788: Binding affinity to human DNA polymerase gamma assessed as inhibition constant	ki	0.9700	uM
[[(2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	2139936: Binding affinity to human DNA polymerase gamma assessed as dissociation constant	kd	1.1000	uM
[[(2S,3R,5S)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53489: Compound was evaluated for the inhibition of cellular DNA polymerase (gamma)	ic50	1.5000	uM
[[(2S,3R,5S)-5-(4-amino-2-oxopyrimidin-1-yl)-3-fluorooxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53489: Compound was evaluated for the inhibition of cellular DNA polymerase (gamma)	ic50	2.0000	uM
(3S,6Z,8E,11S)-3-[(1E,3E,5E)-7-(dimethylamino)-2,5-dimethylhepta-1,3,5-trienyl]-9,11-dimethyl-4,12-dioxa-20-thia-21-azabicyclo[16.2.1]henicosa-1(21),6,8,18-tetraene-5,13-dione	1073658: Inhibition of DNA polymerase-gamma (unknown origin) assessed as incorporation of Br(d)UTP by colorimetric analysis	ic50	3.0000	uM
[[(2S,3R,5S)-5-(2,4-dioxopyrimidin-1-yl)-3-fluorooxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53489: Compound was evaluated for the inhibition of cellular DNA polymerase (gamma)	ic50	3.5000	uM
[2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	357985: Binding affinity to exonuclase deficient human recombinant DNA polymerase gamma E200A mutant	kd	6.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	3
Sunitinib	affects response to substance, decreases expression, increases expression	2
Leflunomide	decreases expression	2
Air Pollutants	affects expression, affects cotreatment, increases abundance, increases oxidation	2
Benzo(a)pyrene	decreases methylation, increases mutagenesis	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Valproic Acid	increases response to substance	2
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
1,12-benzoperylene	increases expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
CPG-oligonucleotide	decreases expression	1
pyranicin	decreases activity	1
ICG 001	decreases expression	1
(+)-JQ1 compound	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Amphotericin B	increases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Carbamazepine	affects expression	1
Chloramphenicol	increases expression	1
Diazinon	increases methylation	1
Diclofenac	affects expression	1
Doxorubicin	increases expression	1
Fluorouracil	affects response to substance	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Thiram	increases expression	1

ChEMBL screening assays

33 unique, capped per target: 30 binding, 2 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000070	Binding	Inhibition of human DNA polymerase gamma	Anti-AIDS agents, 1. Isolation and characterization of four new tetragalloylquinic acids as a new class of HIV reverse transcriptase inhibitors from tannic acid. — J Nat Prod
CHEMBL4394397	ADMET	Inhibition of human DNA polymerase-gamma assessed as reduction in [3H]dTTP incorporation in to activated calf thymus DNA substrate at 100 uM by scintillation counting method relative to control	Synthesis and Anti-HCV Activities of 4’-Fluoro-2’-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4’-Fluoro-2’- C-methyluridine 5’-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection. — J Med Chem
CHEMBL6194223	Functional	Inhibition of human POLG using DNA-dependant DNA polymerase activity assay (POLG) ( DNA polymerase gamma (Abcam))	Data for DCP probe JNJ-8003

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C1D0	SJCRH30 POLG Y955C	Cancer cell line	Male
CVCL_D7Y0	Ubigene A-549 POLG KO	Cancer cell line	Male
CVCL_DQ62	PG64SV.2	Induced pluripotent stem cell	Female
CVCL_E4VS	KOLF2.1J POLG 17.1kbdel DEL/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT02427178	PHASE1	WITHDRAWN	MNGIE Allogeneic Hematopoietic Stem Cell Transplant Safety Study
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT03034512	Not specified	TERMINATED	Alpers Huttenlocher Natural History Study
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford