# NM_001953.5(TYMP):c.163_164del (p.Arg55fs)

https://sugi.bio/variant/tymp-p-arg55fs

## Summary

**TYMP p.Arg55fs (c.163_164del)** is classified **Likely pathogenic** in TYMP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-21). Associated with mitochondrial neurogastrointestinal encephalomyopathy.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TYMP gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to mitochondrial neurogastrointestinal encephalomyopathy.

*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) |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |
| 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/0009920/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TYMP](https://sugi.bio/atlas/gene/TYMP/) |
| Protein change (HGVS p.) | p.Arg55fs |
| Coding change (HGVS c.) | c.163_164del |
| MANE Select transcript | [NM_001953](https://www.ncbi.nlm.nih.gov/nuccore/NM_001953) |
| Variant type | Deletion |
| Location | chr22:50529546-50529547 (GRCh38) |
| ClinVar | [VCV4814986](https://www.ncbi.nlm.nih.gov/clinvar/variation/4814986/) |

**All HGVS expressions:** `LRG_727:g.5539_5540del`, `LRG_727t1:c.163_164del`, `LRG_727t2:c.163_164del`, `NC_000022.10:g.50967975_50967976del`, `NC_000022.11:g.50529546_50529547del`, `NG_011860.1:g.5539_5540del`, `NG_016235.1:g.1893_1894del`, `NM_001113755.3:c.163_164del`, `NM_001113756.3:c.163_164del`, `NM_001257988.1:c.163_164del`, `NM_001257989.1:c.163_164del`, `NM_001953.5:c.163_164del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.444, GERP -0.352 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.518, pLI 7.118e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

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

**TYMP** population constraint: LOEUF 1.518, pLI 7.118e-20, missense-Z -3.4365; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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}

Residue **55** lies in an α-helix.

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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-21.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-06-21 |

## Associated conditions {#conditions}

[mitochondrial neurogastrointestinal encephalomyopathy](https://sugi.bio/atlas/disease/mitochondrial-neurogastrointestinal-encephalomyopathy/).

**Reported phenotype names (ClinVar):** Mitochondrial neurogastrointestinal encephalomyopathy, Mitochondrial neurogastrointestinal encephalopathy syndrome, MNGIE syndrome, Thymidine phosphorylase deficiency.

## Similar variants {#similar}

Related TYMP variant pages (same residue, condition, or type): [TYMP p.Ala135fs](/variant/tymp-p-ala135fs), [TYMP p.Ala3_Leu4insTer](/variant/tymp-p-ala3-leu4inster), [TYMP p.Arg55Lys](/variant/tymp-p-arg55lys), [TYMP p.Gln24fs](/variant/tymp-p-gln24fs), [TYMP p.Arg55Thr](/variant/tymp-p-arg55thr), [TYMP p.Arg55=](/variant/tymp-p-arg55), [TYMP c.1301-1G>A](/variant/tymp-c-1301-minus-1g-a), [TYMP c.418-1G>A](/variant/tymp-c-418-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4814986). 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.*