# NM_017952.6(PTCD3):c.1746_1747dup (p.Phe583fs)

https://sugi.bio/variant/ptcd3-p-phe583fs

## Summary

**PTCD3 p.Phe583fs (c.1746_1747dup)** is classified **Pathogenic** in PTCD3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-02-08). Ultra-rare (popmax 0.0245%, eas); Associated with combined oxidative phosphorylation deficiency 51.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1573859565 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0245%, eas)

## For patients & families {#patients}

This is a change in the PTCD3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to combined oxidative phosphorylation deficiency 51.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025815/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PTCD3](https://sugi.bio/atlas/gene/PTCD3/) |
| Protein change (HGVS p.) | p.Phe583fs |
| Coding change (HGVS c.) | c.1746_1747dup |
| MANE Select transcript | [NM_017952](https://www.ncbi.nlm.nih.gov/nuccore/NM_017952) |
| dbSNP | [rs1573859565](https://www.ncbi.nlm.nih.gov/snp/rs1573859565/) |
| Variant type | Microsatellite |
| Location | chr2:86134952-86134953 (GRCh38) |
| ClinVar | [VCV982043](https://www.ncbi.nlm.nih.gov/clinvar/variation/982043/) |

**All HGVS expressions:** `NC_000002.11:g.86362076CT[3]`, `NC_000002.12:g.86134953CT[3]`, `NM_017952.6:c.1746_1747dup`

## 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 0.407, GERP 1.17, phastCons 0.974 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.132, pLI 8.3863e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 24**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0245%** (eas) · FAF95 0.0137% · FAF99 0.0106% · 11/44,880 in the highest group · 11/1,614,134 alleles overall — ultra-rare (popmax 0.0245%, eas).

*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}

**PTCD3** population constraint: LOEUF 1.132, pLI 8.3863e-21, missense-Z -0.058174. *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):

- **Leigh syndrome** — Limited (AR)

## Protein context {#protein}

Residue **583** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 79.48, 43% of residues very-high.

**86 experimental structure(s)** (PDB): [3J9M](https://www.rcsb.org/structure/3J9M), [6NU2](https://www.rcsb.org/structure/6NU2), [6NU3](https://www.rcsb.org/structure/6NU3), [6RW4](https://www.rcsb.org/structure/6RW4), [6RW5](https://www.rcsb.org/structure/6RW5), [6VLZ](https://www.rcsb.org/structure/6VLZ).

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

*Describes the biological roles of PTCD3 (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:** PTCD3's established molecular role includes RNA binding.


### Pathways affected {#pathways}

PTCD3 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial ribosome-associated quality control](https://reactome.org/content/detail/R-HSA-9937383) | curated |
| [Mitochondrial translation termination](https://reactome.org/content/detail/R-HSA-5419276) | curated |
| [Mitochondrial translation elongation](https://reactome.org/content/detail/R-HSA-5389840) | electronic |
| [Mitochondrial translation initiation](https://reactome.org/content/detail/R-HSA-5368286) | electronic |

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

**Molecular function:** RNA binding, rRNA binding, ribosomal small subunit binding.

**Biological process:** mitochondrial translation.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-02-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2024-02-08 |

## Associated conditions {#conditions}

[combined oxidative phosphorylation deficiency 51](https://sugi.bio/atlas/disease/combined-oxidative-phosphorylation-deficiency-51/).

**Reported phenotype names (ClinVar):** Combined oxidative phosphorylation deficiency 51.

## Similar variants {#similar}

Related PTCD3 variant pages (same residue, condition, or type): [PTCD3 p.Leu95fs](/variant/ptcd3-p-leu95fs), [PTCD3 p.Arg524Leu](/variant/ptcd3-p-arg524leu), [PTCD3 c.1630-1G>A](/variant/ptcd3-c-1630-minus-1g-a), [PTCD3 c.1979+1G>A](/variant/ptcd3-c-1979-plus-1g-a), [PTCD3 c.805-2A>G](/variant/ptcd3-c-805-minus-2a-g), [PTCD3 p.Thr237fs](/variant/ptcd3-p-thr237fs), [PTCD3 p.Trp477Ter](/variant/ptcd3-p-trp477ter), [PTCD3 p.Asp676fs](/variant/ptcd3-p-asp676fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 982043). 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.*