POLG2

Chr 17ARAD

DNA polymerase gamma 2, accessory subunit

Also known as: HP55, MTDPS16, MTDPS16A, MTDPS16B, MTPOLB, PEOA4, POLG-BETA, POLGB

NCBI Gene: 11232ENSG00000256525UniProt: Q9UHN1

This gene encodes the processivity subunit of the mitochondrial DNA polymerase gamma. The encoded protein forms a heterotrimer containing one catalytic subunit and two processivity subunits. This protein enhances DNA binding and promotes processive DNA synthesis. Mutations in this gene result in autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions.[provided by RefSeq, Sep 2009]

Primary Disease Associations & Inheritance

?Mitochondrial DNA depletion syndrome 16 (hepatic type)MIM #618528
AR
?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type)MIM #619425
AR
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4MIM #610131
AD
195
ClinVar variants
6
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— POLG2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
6 Pathogenic / Likely Pathogenic· 111 VUS of 195 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.06LOEUF
pLI 0.000
Z-score 1.32
OE 0.72 (0.50–1.06)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.35Z-score
OE missense 1.06 (0.96–1.17)
270 obs / 254.4 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.72 (0.50–1.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.06 (0.96–1.17)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 19 / 26.3Missense obs/exp: 270 / 254.4Syn Z: -0.34

ClinVar Variant Classifications

195 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic5
VUS111
Likely Benign74
Benign2
Conflicting2
1
Pathogenic
5
Likely Pathogenic
111
VUS
74
Likely Benign
2
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
0
0
1
Likely Pathogenic
4
0
1
0
5
VUS
4
98
7
2
111
Likely Benign
0
2
22
50
74
Benign
0
0
1
1
2
Conflicting
—2
Total91003153195

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

POLG2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Mitochondrial DNA depletion syndrome 16 (hepatic type)

MIM #618528

Molecular basis of disorder known

Autosomal recessive

?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type)

MIM #619425

Molecular basis of disorder known

Autosomal recessive

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

MIM #610131

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — POLG2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mitochondrial DNA maintenance defects.
El-Hattab AW et al.·Biochim Biophys Acta Mol Basis Dis
2017Review
Autophagy deficiency abolishes liver mitochondrial DNA segregation.
Tostes K et al.·Autophagy
2022
POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature.
Borsche M et al.·Cerebellum
2024Review
Perampanel as precision therapy in rare genetic epilepsies.
Nissenkorn A et al.·Epilepsia
2023
Consequences of compromised mitochondrial genome integrity.
Gustafson MA et al.·DNA Repair (Amst)
2020Review
Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome.
Hoff KE et al.·PLoS One
2018
A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2 -Related Mitochondrial Disorder.
Rossi V et al.·Am J Med Genet A
2025Case report
Mitochondrial DNA homeostasis impairment and dopaminergic dysfunction: A trembling balance.
Manini A et al.·Ageing Res Rev
2022Review
Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1.
Ferraris S et al.·Arch Neurol
2008Case report
Model organisms in POLG-related disorders: insights from yeast to multicellular systems.
Casas RB et al.·Cell Death Dis
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mitochondrial DiseasesMitochondrial EncephalomyopathyMitochondrial Encephalopathy

Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

RECRUITING
NCT04802707Phase PHASE2Kenneth Myers, MDStarted 2021-10-18
deoxycytidine and deoxythymidine

External Resources

Links to major genomics databases and tools