# NM_007259.5(VPS45):c.896del (p.Pro299fs)

https://sugi.bio/variant/vps45-p-pro299fs

## Summary

**VPS45 p.Pro299fs (c.896del)** is classified **Likely pathogenic** in VPS45 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). Very rare (popmax 0.00133%, afr); Associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the VPS45 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to congenital neutropenia-myelofibrosis-nephromegaly syndrome.

*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) | Infancy, Neonatal |
| Diagnostic panels | VPS45 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017585/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VPS45](https://sugi.bio/atlas/gene/VPS45/) |
| Protein change (HGVS p.) | p.Pro299fs |
| Coding change (HGVS c.) | c.896del |
| MANE Select transcript | [NM_007259](https://www.ncbi.nlm.nih.gov/nuccore/NM_007259) |
| Variant type | Deletion |
| Location | chr1:150081956-150081956 (GRCh38) |
| ClinVar | [VCV4815533](https://www.ncbi.nlm.nih.gov/clinvar/variation/4815533/) |

**All HGVS expressions:** `LRG_1170:g.19665del`, `LRG_1170t1:c.896del`, `NC_000001.10:g.150054039del`, `NC_000001.11:g.150081957del`, `NG_033910.1:g.19665del`, `NM_001279353.2:c.581del`, `NM_001279354.2:c.788del`, `NM_007259.5:c.896del`, `NM_007259.5:c.896delC`, `NR_103998.2:n.771del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.079, GERP 0.302, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.629, pLI 0.0075434. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 15**, 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.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/75,040 in the highest group · 1/1,613,418 alleles overall — very rare (popmax 0.00133%, afr).

*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}

**VPS45** population constraint: LOEUF 0.629, pLI 0.0075434, missense-Z 1.9567. *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 90.65, 78% of residues very-high.

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

*Describes the biological roles of VPS45 (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:** VPS45 participates in disease-associated pathways. In Reactome, VPS45 is annotated in disease pathway(s) including **SARS-CoV-2 modulates autophagy**.

**Disease mechanism (Reactome):** VPS45 loss or alteration is curated in [SARS-CoV-2 modulates autophagy](https://reactome.org/content/detail/R-HSA-9754560).

### Pathways affected {#pathways}

VPS45 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 modulates autophagy](https://reactome.org/content/detail/R-HSA-9754560) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [Intra-Golgi traffic](https://reactome.org/content/detail/R-HSA-6811438) | curated |

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-13.

**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 | 2025-04-13 |

## Associated conditions {#conditions}

[congenital neutropenia-myelofibrosis-nephromegaly syndrome](https://sugi.bio/atlas/disease/congenital-neutropenia-myelofibrosis-nephromegaly-syndrome/).

**Reported phenotype names (ClinVar):** Congenital neutropenia-myelofibrosis-nephromegaly syndrome, Severe congenital neutropenia 5, autosomal recessive.

## Similar variants {#similar}

Related VPS45 variant pages (same residue, condition, or type): [VPS45 p.Pro299=](/variant/vps45-p-pro299), [VPS45 p.Leu474fs](/variant/vps45-p-leu474fs), [VPS45 p.Met235fs](/variant/vps45-p-met235fs), [VPS45 p.Tyr91fs](/variant/vps45-p-tyr91fs), [VPS45 p.Pro299Ala](/variant/vps45-p-pro299ala), [VPS45 p.Pro488fs](/variant/vps45-p-pro488fs), [VPS45 c.1105-12_1105-9del](/variant/vps45-c-1105-minus-12-1105-minus-9del), [VPS45 c.1105-15del](/variant/vps45-c-1105-minus-15del).

### 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 4815533). 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.*