POLG

Chr 15ARAD

DNA polymerase gamma, catalytic subunit

Also known as: MIRAS, MTDPS4A, MTDPS4B, PEO, POLG1, POLGA, PolG-alpha, SANDO

NCBI Gene: 5428 ENSG00000140521 UniProt: P54098 OMIM: 174763

The encoded protein is the catalytic subunit of mitochondrial DNA polymerase, which replicates mitochondrial DNA. Mutations cause a spectrum of mitochondrial disorders including Alpers-Huttenlocher syndrome, progressive external ophthalmoplegia, sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO), and mitochondrial DNA depletion syndromes, inherited in both autosomal recessive and autosomal dominant patterns. The pathogenic mechanism involves defective mitochondrial DNA replication leading to mitochondrial DNA depletion or deletions.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 4A (Alpers type)MIM #203700

Mitochondrial DNA depletion syndrome 4B (MNGIE type)MIM #613662

Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE)MIM #607459

Progressive external ophthalmoplegia, autosomal dominant 1MIM #157640

Progressive external ophthalmoplegia, autosomal recessive 1MIM #258450

UniProtSensory ataxic neuropathy dysarthria and ophthalmoparesis

UniProtLeigh syndrome

UniProtSpinocerebellar ataxia with epilepsy

Clinical highlights

Management implications

Valproate is CONTRAINDICATED — it can precipitate fatal hepatotoxicity in POLG-related disease.Never use valproate in known or suspected POLG-related disease; choose alternative anti-seizure medication.

POLG: valproate contraindicated

Gene-disease validity (ClinGen)

Leigh syndrome · ARLimitednot for standalone diagnostic reporting

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

121

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.56

LOEUF

LOF

Mechanism· G2P

Treatment implicationsContraindication

POLG-related mitochondrial disease (Alpers-Huttenlocher, ataxia-neuropathy, MELAS-like)

Never use valproate in known or suspected POLG-related disease; choose alternative anti-seizure medication.

Valproate is CONTRAINDICATED — it can precipitate fatal hepatotoxicity in POLG-related disease.

Avoid

valproate / valproic acid (risk of fatal hepatotoxicity)

FDA valproate labeling; Saneto & Cohen; Stewart et al. 2010, Hepatology. Confirm with a neurologist and current guidelines. Functional class (GOF/LOF) is from published functional/segregation data, never inferred from the variant. As of 2026-07. Curated from the clinical genetics/neurology literature (cited per gene). Decision-support, not prescribing.