POLG — DNA polymerase gamma, catalytic subunit

25 sources retrieved · Most recent: April 2026 · Index updated 16 days ago

351PubMed Papers

27Diseases

0Drugs

373Pathogenic Variants

RESEARCH IMPACT

Highly StudiedTrendingVariant-Rich

CLINICAL

OMIM Disease Gene

DATA QUALITY

✓ Experimental GO Evidence✓ Swiss-Prot Reviewed

base-excision repair, gap-fillingprotease bindingDNA bindingchromatin bindingmitochondrial DNA depletion syndrome 4asensory ataxic neuropathy, dysarthria, and ophthalmoparesisprogressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1Sensory ataxic neuropathy - dysarthria - ophthalmoparesis

✦AI Summary

POLG encodes the catalytic subunit of DNA polymerase gamma, the sole enzyme responsible for mitochondrial DNA (mtDNA) replication in mammals 1. The enzyme exhibits 5' to 3' polymerase activity and 3' to 5' exonuclease proofreading activity, ensuring highly accurate mtDNA replication 2. POLG functions as part of a heterotrimer complex with two accessory subunits (POLγB), forming a processive replisome that replicates both heavy and light strands of the circular mitochondrial genome 2. The enzyme also possesses 5'-deoxyribose phosphate lyase activity, participating in mitochondrial base-excision repair pathways 3. POLG mutations are among the most common causes of inherited mitochondrial diseases, affecting up to 2% of the population 1. These mutations cause a spectrum of disorders including Alpers-Huttenlocher syndrome, progressive external ophthalmoplegia, ataxia neuropathy spectrum disorders, and mitochondrial DNA depletion syndromes 4 5. Disease mechanisms involve mtDNA mutations accumulating over time, promoting apoptosis particularly in rapidly dividing tissues 6. Clinical manifestations typically include neuropathy, seizures, hepatopathy, myopathy, and sensory ataxia, with symptom onset ranging from infancy to adulthood 5 7. Recent therapeutic advances include small-molecule activators that can restore function to mutant POLG variants by binding allosteric sites unaffected by disease mutations 2.

Sources cited

POLG encodes mitochondrial DNA polymerase and mutations affect 2% of population causing inherited mitochondrial disorders

PMID: 30451971

POLG functions as heterotrimer with polymerase activity and small-molecule activators can restore mutant function

PMID: 40205042

POLG has 5'-deoxyribose phosphate lyase activity and participates in base-excision repair

PMID: 37679327

POLG mutations cause spectrum of disorders including Alpers syndrome and progressive external ophthalmoplegia

PMID: 18546365

Clinical manifestations include neuropathy, seizures, hepatopathy, myopathy with broad age range of onset

PMID: 21880868

mtDNA mutations from POLG deficiency accumulate and promote apoptosis in rapidly dividing tissues

PMID: 16020738

Adult-onset sensory ataxia and neuropathy are clinical manifestations of POLG mutations

PMID: 36703500

mitochondrial DNA depletion syndrome 4aOpen Targets

0.85Strong

sensory ataxic neuropathy, dysarthria, and ophthalmoparesisOpen Targets

0.83Strong

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1Open Targets

0.83Strong

Sensory ataxic neuropathy - dysarthria - ophthalmoparesisOpen Targets

0.83Strong

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1Open Targets

0.83Strong

mitochondrial neurogastrointestinal encephalomyopathyOpen Targets

0.77Strong

Alpers syndromeOpen Targets

0.77Strong

spinocerebellar ataxia with epilepsyOpen Targets

0.68Moderate

mitochondrial DNA depletion syndromeOpen Targets

0.67Moderate

autosomal dominant progressive external ophthalmoplegiaOpen Targets

0.62Moderate

autosomal recessive progressive external ophthalmoplegiaOpen Targets

0.60Moderate

Fanconi anemiaOpen Targets

0.58Moderate

mitochondrial diseaseOpen Targets

0.57Moderate

Fanconi anemia complementation group IOpen Targets

0.57Moderate

autism spectrum disorderOpen Targets

0.57Moderate

Leigh syndromeOpen Targets

0.56Moderate

genetic disorderOpen Targets

0.55Moderate

mitochondrial DNA depletion syndrome 1Open Targets

0.54Moderate

neurodegenerative diseaseOpen Targets

0.53Moderate

hereditary spastic paraplegiaOpen Targets

0.53Moderate

Leigh syndromeUniProt

Mitochondrial DNA depletion syndrome 4AUniProt

Mitochondrial DNA depletion syndrome 4BUniProt

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 1UniProt

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive, 1UniProt

Sensory ataxic neuropathy dysarthria and ophthalmoparesisUniProt

Spinocerebellar ataxia with epilepsyUniProt

NM_002693.3(POLG):c.3313G>C (p.Ala1105Pro)Likely pathogenic

not provided|Mitochondrial disease|Progressive sclerosing poliodystrophy|not specified

★★★☆2021→ Residue 1105

NM_002693.3(POLG):c.3286C>T (p.Arg1096Cys)Likely pathogenic

★★★☆2021→ Residue 1096

NM_002693.3(POLG):c.3523C>T (p.Gln1175Ter)Likely pathogenic

Progressive sclerosing poliodystrophy|Mitochondrial disease

★★★☆2021→ Residue 1175

NM_002693.3(POLG):c.3550G>A (p.Asp1184Asn)Pathogenic

not provided|Mitochondrial disease|Progressive sclerosing poliodystrophy|Inborn genetic diseases|Progressive sclerosing poliodystrophy;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Mitochondrial DNA depletion syndrome 4b|POLG-related disorder

★★★☆2021→ Residue 1184

NM_002693.3(POLG):c.3643+2T>CPathogenic

not provided|Progressive sclerosing poliodystrophy|Mitochondrial disease|6 conditions

★★★☆2021

NM_002693.3(POLG):c.3573G>T (p.Lys1191Asn)Likely pathogenic

not provided|Progressive sclerosing poliodystrophy|Mitochondrial disease|POLG-related disorder

★★★☆2021→ Residue 1191

NM_002693.3(POLG):c.3609_3612dup (p.Gly1205fs)Likely pathogenic

not provided|Mitochondrial disease|Progressive sclerosing poliodystrophy

★★★☆2021→ Residue 1205

NM_002693.3(POLG):c.3630dup (p.Gly1211fs)Likely pathogenic

Mitochondrial disease

★★★☆2021→ Residue 1211

NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)Pathogenic

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1|not provided|Progressive sclerosing poliodystrophy|POLG-related disorder|Mitochondrial disease|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis|Hereditary spastic paraplegia|Inborn genetic diseases|Tip-toe gait|6 conditions

★★☆☆2026→ Residue 737

NM_002693.3(POLG):c.1399G>A (p.Ala467Thr)Pathogenic

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis|Spinocerebellar ataxia with epilepsy|Progressive sclerosing poliodystrophy|not provided|Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1|POLG-related disorder|Mitochondrial disease|Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Mitochondrial DNA depletion syndrome 4b|Tip-toe gait|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Neurodevelopmental delay|Hereditary spastic paraplegia|Inborn genetic diseases|Intellectual disability|See cases

★★☆☆2026→ Residue 467

NM_002693.3(POLG):c.2827C>T (p.Arg943Cys)Pathogenic

Progressive sclerosing poliodystrophy|not provided|Possible mitochondrial disorder - nuclear genes

★★☆☆2026→ Residue 943

NM_002693.3(POLG):c.922C>T (p.Gln308Ter)Pathogenic

not provided|Progressive sclerosing poliodystrophy

★★☆☆2026→ Residue 308

NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)Pathogenic

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1|Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic|Progressive sclerosing poliodystrophy|Mitochondrial DNA depletion syndrome 4b|not provided|POLG-related disorder|Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Mitochondrial disease|Hereditary spastic paraplegia|Inborn genetic diseases|Mitochondrial DNA depletion syndrome|6 conditions

★★☆☆2026→ Residue 848

NM_002693.3(POLG):c.2740A>C (p.Thr914Pro)Pathogenic

POLG-related disorder|not provided|Progressive sclerosing poliodystrophy|Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|Tip-toe gait|Mitochondrial DNA depletion syndrome 4b|Progressive sclerosing poliodystrophy;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Mitochondrial DNA depletion syndrome 4b|6 conditions

★★☆☆2026→ Residue 914

NM_002693.3(POLG):c.2897T>G (p.Leu966Arg)Pathogenic

not provided|Progressive sclerosing poliodystrophy|Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|POLG-related disorder

★★☆☆2026→ Residue 966

NM_002693.3(POLG):c.2674dup (p.Asp892fs)Pathogenic

Progressive sclerosing poliodystrophy|Mitochondrial DNA depletion syndrome 4b;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive sclerosing poliodystrophy;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

★★☆☆2026→ Residue 892

NM_002693.3(POLG):c.1433+1G>APathogenic

not provided|Progressive sclerosing poliodystrophy|Progressive sclerosing poliodystrophy;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Mitochondrial DNA depletion syndrome 4b|POLG-related disorder

★★☆☆2026

NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)Pathogenic

★★☆☆2026→ Residue 852

NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)Pathogenic

Progressive sclerosing poliodystrophy|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis|Spinocerebellar ataxia with epilepsy|not provided|POLG-related disorder|not specified|Mitochondrial disease|Mitochondrial DNA depletion syndrome 4b|Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1|Inborn genetic diseases|Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy;Mitochondrial DNA depletion syndrome 4b|6 conditions|Acute rhabdomyolysis

★★☆☆2026→ Residue 748

NM_002693.3(POLG):c.1880G>A (p.Arg627Gln)Pathogenic

not provided|Progressive sclerosing poliodystrophy|POLG-related disorder

★★☆☆2026→ Residue 627

MCM3Protein interaction100%POLE3Protein interaction100%SSBP1Protein interaction100%POLA2Protein interaction99%PRIM2Protein interaction99%PRIM1Protein interaction99%

Lung

100%

Liver

87%

Bone Marrow

72%

Ovary

72%

Heart

65%

Brain

51%

Click a node to explore

PROTEIN STRUCTURE

Preparing viewer…

PDB8UDL · 2.37 Å · EM

View on RCSB

LOEUFⓘ

0.85LoF Tolerant

pLIⓘ

0.00Tolerant

Observed/Expected LoF0.72 [0.62–0.85]

#892of 20,598
Most Researched351 · top 5%
#150of 5,498
Most Pathogenic Variants373 · top 5%
#7,315of 17,882
Most Constrained (LOEUF)0.85

Genes detectedPOLG

Sources retrieved25 papers

Response time—

POLG-related disorders and their neurological manifestations.

PMID: 30451971

Nat Rev Neurol · 2019

1.00

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

PMID: 18546365

Hum Mutat · 2008

0.90

Small molecules restore mutant mitochondrial DNA polymerase activity.

PMID: 40205042

Nature · 2025

0.80

Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.

PMID: 38643274

Cell Death Dis · 2024

0.76

Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.

PMID: 40404629

Nat Commun · 2025

0.72

Loading gene record…

25 sources retrieved · Most recent: April 2026 · Index updated 16 days ago

351PubMed Papers

27Diseases

0Drugs

373Pathogenic Variants

RESEARCH IMPACT

Highly StudiedTrendingVariant-Rich

CLINICAL

OMIM Disease Gene

DATA QUALITY

✓ Experimental GO Evidence✓ Swiss-Prot Reviewed

✦AI Summary

Sources cited

POLG encodes mitochondrial DNA polymerase and mutations affect 2% of population causing inherited mitochondrial disorders

PMID: 30451971

POLG functions as heterotrimer with polymerase activity and small-molecule activators can restore mutant function

PMID: 40205042

POLG has 5'-deoxyribose phosphate lyase activity and participates in base-excision repair

PMID: 37679327

POLG mutations cause spectrum of disorders including Alpers syndrome and progressive external ophthalmoplegia

PMID: 18546365

Clinical manifestations include neuropathy, seizures, hepatopathy, myopathy with broad age range of onset

PMID: 21880868

mtDNA mutations from POLG deficiency accumulate and promote apoptosis in rapidly dividing tissues

PMID: 16020738

Adult-onset sensory ataxia and neuropathy are clinical manifestations of POLG mutations

PMID: 36703500

mitochondrial DNA depletion syndrome 4aOpen Targets

0.85Strong

sensory ataxic neuropathy, dysarthria, and ophthalmoparesisOpen Targets

0.83Strong

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1Open Targets

0.83Strong

Sensory ataxic neuropathy - dysarthria - ophthalmoparesisOpen Targets

0.83Strong

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1Open Targets

0.83Strong

mitochondrial neurogastrointestinal encephalomyopathyOpen Targets

0.77Strong

Alpers syndromeOpen Targets

0.77Strong

spinocerebellar ataxia with epilepsyOpen Targets

0.68Moderate

mitochondrial DNA depletion syndromeOpen Targets

0.67Moderate

autosomal dominant progressive external ophthalmoplegiaOpen Targets

0.62Moderate

autosomal recessive progressive external ophthalmoplegiaOpen Targets

0.60Moderate

Fanconi anemiaOpen Targets

0.58Moderate

mitochondrial diseaseOpen Targets

0.57Moderate

Fanconi anemia complementation group IOpen Targets

0.57Moderate

autism spectrum disorderOpen Targets

0.57Moderate

Leigh syndromeOpen Targets

0.56Moderate

genetic disorderOpen Targets

0.55Moderate

mitochondrial DNA depletion syndrome 1Open Targets

0.54Moderate

neurodegenerative diseaseOpen Targets

0.53Moderate

hereditary spastic paraplegiaOpen Targets

0.53Moderate

Leigh syndromeUniProt

Mitochondrial DNA depletion syndrome 4AUniProt

Mitochondrial DNA depletion syndrome 4BUniProt

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 1UniProt

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive, 1UniProt

Sensory ataxic neuropathy dysarthria and ophthalmoparesisUniProt

Spinocerebellar ataxia with epilepsyUniProt

NM_002693.3(POLG):c.3313G>C (p.Ala1105Pro)Likely pathogenic

not provided|Mitochondrial disease|Progressive sclerosing poliodystrophy|not specified

★★★☆2021→ Residue 1105

NM_002693.3(POLG):c.3286C>T (p.Arg1096Cys)Likely pathogenic

★★★☆2021→ Residue 1096

NM_002693.3(POLG):c.3523C>T (p.Gln1175Ter)Likely pathogenic

Progressive sclerosing poliodystrophy|Mitochondrial disease

★★★☆2021→ Residue 1175

NM_002693.3(POLG):c.3550G>A (p.Asp1184Asn)Pathogenic

★★★☆2021→ Residue 1184

NM_002693.3(POLG):c.3643+2T>CPathogenic

not provided|Progressive sclerosing poliodystrophy|Mitochondrial disease|6 conditions

★★★☆2021

NM_002693.3(POLG):c.3573G>T (p.Lys1191Asn)Likely pathogenic

not provided|Progressive sclerosing poliodystrophy|Mitochondrial disease|POLG-related disorder

★★★☆2021→ Residue 1191

NM_002693.3(POLG):c.3609_3612dup (p.Gly1205fs)Likely pathogenic

not provided|Mitochondrial disease|Progressive sclerosing poliodystrophy

★★★☆2021→ Residue 1205

NM_002693.3(POLG):c.3630dup (p.Gly1211fs)Likely pathogenic

Mitochondrial disease

★★★☆2021→ Residue 1211

NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)Pathogenic

★★☆☆2026→ Residue 737

NM_002693.3(POLG):c.1399G>A (p.Ala467Thr)Pathogenic

★★☆☆2026→ Residue 467

NM_002693.3(POLG):c.2827C>T (p.Arg943Cys)Pathogenic

Progressive sclerosing poliodystrophy|not provided|Possible mitochondrial disorder - nuclear genes

★★☆☆2026→ Residue 943

NM_002693.3(POLG):c.922C>T (p.Gln308Ter)Pathogenic

not provided|Progressive sclerosing poliodystrophy

★★☆☆2026→ Residue 308

NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)Pathogenic

★★☆☆2026→ Residue 848

NM_002693.3(POLG):c.2740A>C (p.Thr914Pro)Pathogenic

★★☆☆2026→ Residue 914

NM_002693.3(POLG):c.2897T>G (p.Leu966Arg)Pathogenic

★★☆☆2026→ Residue 966

NM_002693.3(POLG):c.2674dup (p.Asp892fs)Pathogenic

★★☆☆2026→ Residue 892

NM_002693.3(POLG):c.1433+1G>APathogenic

★★☆☆2026

NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)Pathogenic

★★☆☆2026→ Residue 852

NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)Pathogenic

★★☆☆2026→ Residue 748

NM_002693.3(POLG):c.1880G>A (p.Arg627Gln)Pathogenic

not provided|Progressive sclerosing poliodystrophy|POLG-related disorder

★★☆☆2026→ Residue 627

MCM3Protein interaction100%POLE3Protein interaction100%SSBP1Protein interaction100%POLA2Protein interaction99%PRIM2Protein interaction99%PRIM1Protein interaction99%

Lung

100%

Liver

87%

Bone Marrow

72%

Ovary

72%

Heart

65%

Brain

51%

Click a node to explore

PROTEIN STRUCTURE

Preparing viewer…

PDB8UDL · 2.37 Å · EM

View on RCSB

LOEUFⓘ

0.85LoF Tolerant

pLIⓘ

0.00Tolerant

Observed/Expected LoF0.72 [0.62–0.85]

#892of 20,598
Most Researched351 · top 5%
#150of 5,498
Most Pathogenic Variants373 · top 5%
#7,315of 17,882
Most Constrained (LOEUF)0.85

Genes detectedPOLG

Sources retrieved25 papers

Response time—

POLG-related disorders and their neurological manifestations.

PMID: 30451971

Nat Rev Neurol · 2019

1.00

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

PMID: 18546365

Hum Mutat · 2008

0.90

Small molecules restore mutant mitochondrial DNA polymerase activity.

PMID: 40205042

Nature · 2025

0.80

Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.

PMID: 38643274

Cell Death Dis · 2024

0.76

Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.

PMID: 40404629

Nat Commun · 2025

0.72