Is VPS45 p.Pro319= (c.957A>C) pathogenic?

VPS45 p.Pro319= (c.957A>C) is classified Likely benign in VPS45 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-29). Ultra-rare (popmax 0.01%, amr); Associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome.

What condition is associated with VPS45 p.Pro319= (c.957A>C)?

VPS45 p.Pro319= (c.957A>C) is associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome (ClinVar).

How common is VPS45 p.Pro319= (c.957A>C) in the general population?

VPS45 p.Pro319= (c.957A>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

VPS45 p.Pro319=

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

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

c.957A>C · rs587769473 · VCV1094730

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

congenital neutropenia-myelofibrosis-nephromegaly syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP -1, phastCons 0.86
Overall
CADD	9.204	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,744 alleles

Filtering AF 0.0043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000868% 14/1,613,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,957
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	0.000593%	168,533

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.Pro319=
Coding: c.957A>C
MANE Select: NM_007259
dbSNP: rs587769473
Type: single nucleotide variant
Location: chr1:150082736 (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.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
VPS45 p.Arg176Cys 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-pro319 (accessed [today's date]).

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