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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

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

33 unique Pathogenic / Likely Pathogenic· 326 VUS of 580 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — POLG2

Authoritative clinical overview · Recommended first read

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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 OE?0.72 (0.50–1.06)

0≤0.351.4

Missense OE?1.06 (0.96–1.17)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

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

This gene — mechanism propensity

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 · 94% 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.1

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 haplo2

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

References

ClinVar Variant Classifications

580 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic12

VUS326

Likely Benign166

Benign20

Conflicting30

Pathogenic

Likely Pathogenic

326

VUS

166

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	1	0	0	21
Likely Pathogenic	11	1	0	0	12
VUS	17	288	17	4	326
Likely Benign	0	8	58	100	166
Benign	0	2	16	2	20
Conflicting	—				30
Total	48	300	91	106	575

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap POLG2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →