POLG2

Chr 17ARAD

DNA polymerase gamma 2, accessory subunit

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

NCBI Gene: 11232 ENSG00000256525 UniProt: Q9UHN1 OMIM: 604983

The encoded protein serves as the processivity subunit of mitochondrial DNA polymerase gamma, enhancing DNA binding and promoting efficient replication of mitochondrial DNA. Mutations cause progressive external ophthalmoplegia with mitochondrial DNA deletions (autosomal dominant inheritance) and mitochondrial DNA depletion syndromes affecting liver and neuro-ophthalmic systems (autosomal recessive inheritance). This gene shows very low constraint against loss-of-function variants, indicating tolerance to such mutations in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 1.063 OMIM phenotypes

Clinical Summary— POLG2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 261 VUS of 492 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

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

-0.35Z-score

OE missense 1.06 (0.96–1.17)

270 obs / 254.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.72 (0.50–1.06)

0≤0.351.4

Missense OE1.06 (0.96–1.17)

0≤0.61.4

Synonymous OE1.04

0≤1.21.6

LoF obs/exp: 19 / 26.3Missense obs/exp: 270 / 254.4Syn Z: -0.34

0.5378th %ile

GOF

0.2796th %ile

LOF

0.4332th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 68% of P/LP variants are LoF

DN1 literature citation

Literature Evidence

DNPOLG2 disease variants: analyses reveal a dominant negative heterodimer, altered mitochondrial localization and impaired respiratory capacity.PMID:26123486

LOFAlthough the WT component of p55 dimers within the mitochondria of an individual heterozygous for POLG2 cannot easily be determined, the failure of our mixing experiments to reveal a dominant negative effect in vitro suggests that the phenotype of the affected heterozygote may be due to simple haploPMID:16685652

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.