# NM_001035006.5(RPL17):c.176_178delinsA (p.Pro59fs)

https://sugi.bio/variant/rpl17-p-pro59fs

## Summary

**RPL17 p.Pro59fs (c.176_178delinsA)** is classified **Uncertain significance** in RPL17 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-28). Associated with Diamond-Blackfan anemia 22.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the RPL17 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Diamond-Blackfan anemia 22.

*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 dominant |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | RPL17 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Diamond-Blackfan anemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pure red cell aplasia — Very frequent (99-80%)
- Elevated red cell adenosine deaminase activity — Very frequent (99-80%)
- Abnormality of the head — Frequent (79-30%)
- Pallor — Frequent (79-30%)
- Lethargy — Frequent (79-30%)
- Growth delay — Frequent (79-30%)
- Small for gestational age — Frequent (79-30%)
- Reticulocytopenia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0028117/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RPL17](https://sugi.bio/atlas/gene/RPL17/) |
| Protein change (HGVS p.) | p.Pro59fs |
| Coding change (HGVS c.) | c.176_178delinsA |
| MANE Select transcript | [NM_001035006](https://www.ncbi.nlm.nih.gov/nuccore/NM_001035006) |
| Variant type | Indel |
| Location | chr18:49490831-49490833 (GRCh38) |
| ClinVar | [VCV4883991](https://www.ncbi.nlm.nih.gov/clinvar/variation/4883991/) |

**All HGVS expressions:** `NC_000018.10:g.49490831_49490833delinsT`, `NC_000018.9:g.47017201_47017203delinsT`, `NM_000985.5:c.176_178delinsA`, `NM_001035006.5:c.176_178delinsA`, `NM_001199340.2:c.176_178delinsA`, `NM_001199341.3:c.176_178delinsA`, `NM_001199342.3:c.176_178delinsA`, `NM_001199343.3:c.176_178delinsA`, `NM_001199344.3:c.176_178delinsA`, `NM_001199345.2:c.62_64delinsA`, `NM_001199355.1:c.176_178delinsA`, `NM_001199356.2:c.62_64delinsA`, `NM_001369555.1:c.191_193delinsA`, `NM_001369556.1:c.176_178delinsA`, `NM_001369557.1:c.176_178delinsA`, `NM_001369558.1:c.176_178delinsA`, `NM_001369560.1:c.146_148delinsA`, `NM_001369561.1:c.146_148delinsA`, `NM_001369562.1:c.62_64delinsA`, `NM_001369563.1:c.62_64delinsA`

## 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 10.917, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.184, pLI 0.99998), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 7**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**RPL17** population constraint: LOEUF 0.184, pLI 0.99998, missense-Z 2.1104. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.85, 81% of residues very-high.

**184 experimental structure(s)** (PDB): [4UG0](https://www.rcsb.org/structure/4UG0), [4V6X](https://www.rcsb.org/structure/4V6X), [5A8L](https://www.rcsb.org/structure/5A8L), [5AJ0](https://www.rcsb.org/structure/5AJ0), [5LKS](https://www.rcsb.org/structure/5LKS), [5T2C](https://www.rcsb.org/structure/5T2C) — incl. mutant structure 9GMO.

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

*Describes the biological roles of RPL17 (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:** RPL17's established molecular role includes RNA binding. In Reactome, RPL17 is annotated in disease pathway(s) including **Viral mRNA Translation**.

**Disease mechanism (Reactome):** RPL17 loss or alteration is curated in [Viral mRNA Translation](https://reactome.org/content/detail/R-HSA-192823).

### Pathways affected {#pathways}

RPL17 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Viral mRNA Translation](https://reactome.org/content/detail/R-HSA-192823) | curated |
| [Formation of a pool of free 40S subunits](https://reactome.org/content/detail/R-HSA-72689) | curated |
| [GTP hydrolysis and joining of the 60S ribosomal subunit](https://reactome.org/content/detail/R-HSA-72706) | curated |
| [L13a-mediated translational silencing of Ceruloplasmin expression](https://reactome.org/content/detail/R-HSA-156827) | curated |
| [Major pathway of rRNA processing in the nucleolus and cytosol](https://reactome.org/content/detail/R-HSA-6791226) | curated |
| [Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)](https://reactome.org/content/detail/R-HSA-975957) | curated |
| [Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)](https://reactome.org/content/detail/R-HSA-975956) | curated |
| [PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA](https://reactome.org/content/detail/R-HSA-9954714) | curated |
| [ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA](https://reactome.org/content/detail/R-HSA-9954716) | curated |
| [Eukaryotic Translation Termination](https://reactome.org/content/detail/R-HSA-72764) | electronic |
| [Peptide chain elongation](https://reactome.org/content/detail/R-HSA-156902) | electronic |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | electronic |
| [Response of EIF2AK4 (GCN2) to amino acid deficiency](https://reactome.org/content/detail/R-HSA-9633012) | electronic |
| [Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide](https://reactome.org/content/detail/R-HSA-9954709) | electronic |
| [SRP-dependent cotranslational protein targeting to membrane](https://reactome.org/content/detail/R-HSA-1799339) | electronic |
| [Selenocysteine synthesis](https://reactome.org/content/detail/R-HSA-2408557) | electronic |

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

**Molecular function:** RNA binding, structural constituent of ribosome.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-28 |

## Associated conditions {#conditions}

[Diamond-Blackfan anemia 22](https://sugi.bio/atlas/disease/diamond-blackfan-anemia-22/).

**Reported phenotype names (ClinVar):** Diamond-Blackfan anemia 22.

### 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 4883991). 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.*