Mitochondrial DNA depletion syndrome: genes and variants
Mitochondrial DNA depletion syndrome is linked to 1 analyzed protein (POLG). 26 DNA variants are known to cause it; 53 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: mitochondrial DNA depletion syndrome 1; mitochondrial DNA depletion syndrome 4a; Mitochondrial DNA depletion syndrome 4b
Genes linked to Mitochondrial DNA depletion syndrome
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.
26 disease-causing and 53 uncertain variants in POLG are linked to Mitochondrial DNA depletion syndrome.
Where Mitochondrial DNA depletion syndrome variants cluster
- POLG Pol B (positions 943–958): 3 of 26 disease-causing changes, 8.9× more than its size predicts.
Known disease-causing variants in Mitochondrial DNA depletion syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| POLG A957V | 957 | Pol B | Disease-causing (★★) |
| POLG A957P | 957 | Pol B | Disease-causing (★★) |
| POLG R807P | 807 | Disease-causing (★★) | |
| POLG T851A | 851 | Disease-causing (★★) | |
| POLG A862T | 862 | Trigger loop | Disease-causing (★★) |
| POLG R869Q | 869 | Disease-causing (★★) | |
| POLG H932Y | 932 | Disease-causing (★★) | |
| POLG Y955C | 955 | Pol B | Disease-causing (★★) |
| POLG H1134Y | 1134 | Pol C | Disease-causing (★★) |
| POLG G426S | 426 | Disease-causing (★★) | |
| POLG G737R | 737 | Disease-causing (★★) | |
| POLG R853Q | 853 | Disease-causing (★★) | |
| POLG T914P | 914 | Disease-causing (★★) | |
| POLG P1073L | 1073 | Disease-causing (★★) | |
| POLG N864S | 864 | Trigger loop | Disease-causing (★★) |
| POLG V1106A | 1106 | Disease-causing (★★) | |
| POLG R227W | 227 | Disease-causing (★★) | |
| POLG R232H | 232 | Disease-causing (★★) | |
| POLG R627W | 627 | Disease-causing (★★) | |
| POLG W748S | 748 | Disease-causing (★★) | |
| POLG G1051R | 1051 | Disease-causing (★★) | |
| POLG R1096G | 1096 | Disease-causing (★★) | |
| POLG L244P | 244 | Disease-causing (★★) | |
| POLG Q308H | 308 | Disease-causing (★) | |
| POLG M919V | 919 | Disease-causing (★) | |
| POLG A467T | 467 | Disease-causing |
Uncertain variants in Mitochondrial DNA depletion syndrome that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| POLG R853W | 853 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R853Q at the same position is pathogenic; REVEL 0.881 |
Which prediction tools work for Mitochondrial DNA depletion syndrome
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: 100 out of 100
- PolyPhen-2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 95 out of 100
- SIFT: 94 out of 100
Same protein, different disease
- Progressive sclerosing poliodystrophy is also caused by POLG variants; they fall partly in the same places as the Mitochondrial DNA depletion syndrome variants (77 disease-causing).
- Progressive external ophthalmoplegia with mitochondrial DNA deletions is also caused by POLG variants; they fall mostly in different places as the Mitochondrial DNA depletion syndrome variants (17 disease-causing).
- Mitochondrial disease is also caused by POLG variants; they fall partly in the same places as the Mitochondrial DNA depletion syndrome variants (6 disease-causing).
Diseases related to Mitochondrial DNA depletion syndrome
- Hereditary spastic paraplegia, also linked to POLG
- Progressive sclerosing poliodystrophy, 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 Mitochondrial DNA depletion syndrome?
In CATVariant, Mitochondrial DNA depletion syndrome is linked to 1 analyzed protein: POLG (DNA polymerase subunit gamma-1).
How many genetic variants are linked to Mitochondrial DNA depletion syndrome?
115 variants: 26 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 53 are of uncertain significance or have conflicting reports.
Which uncertain variants in Mitochondrial DNA depletion syndrome look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example POLG R853W. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Mitochondrial DNA depletion syndrome?
Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 1.00, based on 23 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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