# c.1069A>G

https://sugi.bio/variant/tymp-c-1069a-g

## Summary

**TYMP c.1069A>G** is classified **Benign** in TYMP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-01-14). Associated with mitochondrial DNA depletion syndrome 1.

**At a glance:** Benign · review: No assertion criteria · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TYMP gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to mitochondrial DNA depletion syndrome 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | TYMP is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Mitochondrial neurogastrointestinal encephalomyopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- External ophthalmoplegia — Very frequent (99-80%)
- Vomiting — Very frequent (99-80%)
- Dysphagia — Very frequent (99-80%)
- Nausea — Very frequent (99-80%)
- Gastroesophageal reflux — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Leukoencephalopathy — Very frequent (99-80%)
- Gastrointestinal dysmotility — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024787/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TYMP](https://sugi.bio/atlas/gene/TYMP/) |
| Coding change (HGVS c.) | c.1069A>G |
| MANE Select transcript | [NM_001953](https://www.ncbi.nlm.nih.gov/nuccore/NM_001953) |
| Variant type | Variation |
| ClinVar | [VCV223008](https://www.ncbi.nlm.nih.gov/clinvar/variation/223008/) |

## Gene constraint & dosage {#gene-context}

**TYMP** population constraint: LOEUF 1.518, pLI 7.118e-20, missense-Z -3.4365; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.82, 90% of residues very-high.

**4 experimental structure(s)** (PDB): [1UOU](https://www.rcsb.org/structure/1UOU), [2J0F](https://www.rcsb.org/structure/2J0F), [2WK5](https://www.rcsb.org/structure/2WK5), [2WK6](https://www.rcsb.org/structure/2WK6).

## What this gene does {#gene-function}

*Describes the biological roles of TYMP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TYMP's established molecular role includes thymidine phosphorylase activity.


### Pathways affected {#pathways}

TYMP participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Pyrimidine catabolism](https://reactome.org/content/detail/R-HSA-73621) | other |
| [Pyrimidine salvage](https://reactome.org/content/detail/R-HSA-73614) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** thymidine phosphorylase activity, protein homodimerization activity.

**Biological process:** pyrimidine nucleoside metabolic process.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-01-14.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneReviews | Benign | no assertion criteria provided | literature only | 2016-01-14 |

## Associated conditions {#conditions}

[mitochondrial DNA depletion syndrome 1](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome-1/).

**Reported phenotype names (ClinVar):** Mitochondrial DNA depletion syndrome 1, Mitochondrial neurogastrointestinal encephalomyopathy syndrome, Mitochondrial DNA Depletion Syndrome, MNGIE Form, Mitochondrial DNA depletion syndrome 1 (MNGIE type), Mitochondrial Neurogastrointestinal Encephalopathy Disease, MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, TYMP-RELATED, MNGIE, TYMP-RELATED, POLIP SYNDROME, POLYNEUROPATHY, OPHTHALMOPLEGIA, LEUKOENCEPHALOPATHY, AND INTESTINAL PSEUDOOBSTRUCTION.

## Similar variants {#similar}

Related TYMP variant pages (same residue, condition, or type): [TYMP c.52_53delCT](/variant/tymp-c-52-53delct), [TYMP c.972T>C](/variant/tymp-c-972t-c), [TYMP c.1301-1G>A](/variant/tymp-c-1301-minus-1g-a), [TYMP c.214+1G>T](/variant/tymp-c-214-plus-1g-t), [TYMP c.417+1G>A](/variant/tymp-c-417-plus-1g-a), [TYMP c.418-1G>A](/variant/tymp-c-418-minus-1g-a), [TYMP c.646+1G>A](/variant/tymp-c-646-plus-1g-a), [TYMP c.647-1G>A](/variant/tymp-c-647-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 223008). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*