POLG

Chr 15ARAD

DNA polymerase gamma, catalytic subunit

Also known as: MDP1, MIRAS, MTDPS4A, MTDPS4B, PEO, POLG1, POLGA, PolG-alpha

NCBI Gene: 5428 ENSG00000140521 UniProt: P54098

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]

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

586

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— POLG

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

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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

83 Pathogenic / Likely Pathogenic· 288 VUS of 586 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.56LOEUF

pLI 0.000

Z-score 4.54

OE 0.40 (0.29–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

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.

-0.74Z-score

OE missense 1.08 (1.01–1.14)

770 obs / 714.2 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.0.40 (0.29–0.56)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (1.01–1.14)

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.1.13

0≤1.21.6

LoF obs/exp: 27 / 67.1Missense obs/exp: 770 / 714.2Syn Z: -1.77

ClinVar Variant Classifications

586 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic50

VUS288

Likely Benign207

Benign1

Conflicting7

Pathogenic

Likely Pathogenic

288

VUS

207

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	4	17	0	33
Likely Pathogenic	23	17	10	0	50
VUS	2	252	32	2	288
Likely Benign	0	7	92	108	207
Benign	0	0	1	0	1
Conflicting	—				7
Total	37	280	152	110	586

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

View in ClinVar →

Protein Context — Lollipop Plot

POLG · protein map & ClinVar variants

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

Gene2Phenotype Curations

POLG-related progressive external ophthalmoplegia

definitive

ADUndeterminedAltered Gene Product Structure

Eye

G2P ↗

missense variantinframe deletioninframe insertion

POLG-related mitochondrial ataxia syndrome

definitive

ARLoss Of FunctionAbsent Gene Product

Eye

G2P ↗

POLG-related mitochondrial DNA depletion syndrome, Alpers type

definitive

ARUndeterminedAltered Gene Product Structure

Dev. DisordersEye

G2P ↗

missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

POLYMERASE, DNA, GAMMA; POLG

MIM #174763 · *

Mitochondrial DNA depletion syndrome 4A (Alpers type)

MIM #203700