Is VPS45 p.Pro299fs (c.896del) pathogenic?

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.

What condition is associated with VPS45 p.Pro299fs (c.896del)?

VPS45 p.Pro299fs (c.896del) is associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome (ClinVar).

How common is VPS45 p.Pro299fs (c.896del) in the general population?

VPS45 p.Pro299fs (c.896del) is very rare (popmax 0.00133%, afr) (gnomAD).

VPS45 p.Pro299fs

Q: How is Congenital neutropenia-myelofibrosis-nephromegaly syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.896del · VCV4815533

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

congenital neutropenia-myelofibrosis-nephromegaly syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP 0.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,040 alleles

Overall 6.2e-05% 1/1,613,418 alleles · very rare exomes 1/1,461,084 · genomes 0/152,334 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VPS45
Protein: p.Pro299fs
Coding: c.896del
MANE Select: NM_007259
Type: Deletion
Location: chr1:150081956 (GRCh38)
Gene constraint: LOEUF 0.629 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.65

Full VPS45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital neutropenia-myelofibrosis-nephromegaly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital neutropenia-myelofibrosis-nephromegaly syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VPS45 p.Pro299= Benign/Likely benign ★★ same residue
VPS45 p.Leu474fs Likely pathogenic ★ same condition
VPS45 p.Met235fs Likely pathogenic ★ same condition
VPS45 p.Tyr91fs Likely pathogenic ★ same condition
VPS45 p.Pro299Ala Uncertain significance ★ ⚠ same residue
VPS45 p.Pro488fs Uncertain significance ★ same condition
VPS45 c.1105-12_1105-9del Likely benign ★ same condition
VPS45 c.1105-15del Likely benign ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vps45-p-pro299fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown