Is VPS45 p.Asp409fs (c.1226_1227insATTCCTGAGGAACA) pathogenic?

VPS45 p.Asp409fs (c.12261227insATTCCTGAGGAACA) is classified Conflicting classifications of pathogenicity in VPS45 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-17). Very rare (popmax 0.00666%, amr); Associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome.

What condition is associated with VPS45 p.Asp409fs (c.1226_1227insATTCCTGAGGAACA)?

VPS45 p.Asp409fs (c.1226_1227insATTCCTGAGGAACA) is associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome (ClinVar).

How common is VPS45 p.Asp409fs (c.1226_1227insATTCCTGAGGAACA) in the general population?

VPS45 p.Asp409fs (c.1226_1227insATTCCTGAGGAACA) is very rare (popmax 0.00666%, amr) (gnomAD).

VPS45 p.Asp409fs

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

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

c.1226_1227insATTCCTGAGGAACA · rs781971789 · VCV2202548

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

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 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% Admixed American · 4/60,016 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00103% 15/1,461,808 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,004
African / African-American	0.00133%	75,022
European (non-Finnish)	0.000847%	117,999

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.Asp409fs
Coding: c.1226_1227insATTCCTGAGGAACA
MANE Select: NM_007259
dbSNP: rs781971789
Type: Insertion
Location: chr1:150092057 (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.Lys257fs Likely pathogenic ★ same condition
VPS45 p.Glu238Lys Likely pathogenic ★★ same condition
VPS45 p.Thr224Asn Pathogenic ★★ same condition
VPS45 c.687+5A>G Uncertain significance ★★ same condition
VPS45 p.Ala392Thr Uncertain significance ★★ ⚠ same condition
VPS45 p.Ala445Gly Uncertain significance ★★ ⚠ same condition
VPS45 p.Ala567Val Uncertain significance ★★ ⚠ same condition
VPS45 p.Arg148Gln Uncertain significance ★★ ⚠ 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-asp409fs (accessed [today's date]).

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