Progressive sclerosing poliodystrophy: genes and variants

Genes linked to Progressive sclerosing poliodystrophy

• POLG: DNA polymerase subunit gamma-1

  It replicates and repairs mitochondrial DNA and is therefore essential for maintaining mitochondrial genome copy number and integrity. Pathogenic variants cause a broad spectrum including Alpers syndrome, progressive external ophthalmoplegia, epilepsy, ataxia, neuropathy, and liver disease.

  77 disease-causing and 1,009 uncertain variants in POLG are linked to Progressive sclerosing poliodystrophy.

Where Progressive sclerosing poliodystrophy variants cluster

• POLG Pol B (positions 943–958): 8 of 77 disease-causing changes, 8.1× more than its size predicts.
• POLG Pol C (positions 1134–1141): 4 of 77 disease-causing changes, 8.1× more than its size predicts.
• POLG Pol A (positions 887–896): 4 of 77 disease-causing changes, 6.4× more than its size predicts.

Known disease-causing variants in Progressive sclerosing poliodystrophy

Showing 60 of 77.

Uncertain variants in Progressive sclerosing poliodystrophy that look disease-causing

Which prediction tools work for Progressive sclerosing poliodystrophy

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 99 out of 100
• PolyPhen-2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 96 out of 100
• phyloP: 90 out of 100

Same protein, different disease

• Mitochondrial DNA depletion syndrome is also caused by POLG variants; they fall in the same places as the Progressive sclerosing poliodystrophy variants (26 disease-causing).
• Progressive external ophthalmoplegia with mitochondrial DNA deletions is also caused by POLG variants; they fall partly in the same places as the Progressive sclerosing poliodystrophy variants (17 disease-causing).
• Mitochondrial disease is also caused by POLG variants; they fall in the same places as the Progressive sclerosing poliodystrophy variants (6 disease-causing).
• Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis is also caused by POLG variants; they fall partly in the same places as the Progressive sclerosing poliodystrophy variants (6 disease-causing).

Diseases related to Progressive sclerosing poliodystrophy

• Hereditary spastic paraplegia, also linked to POLG
• Mitochondrial DNA depletion syndrome, also linked to POLG
• Fanconi anemia, also linked to POLG
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, also linked to POLG
• Mitochondrial disease, also linked to POLG
• Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, also linked to POLG
• Possible mitochondrial disorder - nuclear genes, also linked to POLG
• Mitochondrial DNA maintenance disorder, also linked to POLG
• Mitochondrial neurogastrointestinal encephalomyopathy, also linked to POLG

Frequently asked questions

Which genes are linked to Progressive sclerosing poliodystrophy?

In CATVariant, Progressive sclerosing poliodystrophy is linked to 1 analyzed protein: POLG (DNA polymerase subunit gamma-1).

How many genetic variants are linked to Progressive sclerosing poliodystrophy?

1,094 variants: 77 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,009 are of uncertain significance or have conflicting reports.

Which uncertain variants in Progressive sclerosing poliodystrophy look disease-causing?

12 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example POLG R1138C, POLG R1096L, POLG A467D, POLG T851S and POLG E1136D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Progressive sclerosing poliodystrophy?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 56 disease-causing and 16 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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