Is VPS45 p.Ala313= (c.939G>A) pathogenic?

VPS45 p.Ala313= (c.939G>A) is classified Likely benign in VPS45 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-01). Ultra-rare (popmax 0.0893%, eas); Associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome.

What condition is associated with VPS45 p.Ala313= (c.939G>A)?

VPS45 p.Ala313= (c.939G>A) is associated with congenital neutropenia-myelofibrosis-nephromegaly syndrome (ClinVar).

How common is VPS45 p.Ala313= (c.939G>A) in the general population?

VPS45 p.Ala313= (c.939G>A) is ultra-rare (popmax 0.0893%, eas) (gnomAD).

VPS45 p.Ala313=

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

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

c.939G>A · rs142461153 · VCV760620

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0893%, eas)

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 0.023	GERP -1.1, phastCons 0.78
Overall
CADD	13.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0893% East Asian · 40/44,782 alleles

Filtering AF 0.0674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0597%

Overall 0.00465% 75/1,611,352 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0893%	1,120
South Asian	0.00992%	10,078
Remaining individualsnot grpmax-eligible	0.00802%	12,476
European (non-Finnish)	0.00178%	56,124

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.Ala313=
Coding: c.939G>A
MANE Select: NM_007259
dbSNP: rs142461153
Type: single nucleotide variant
Location: chr1:150082718 (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.Ala313Val Uncertain significance ★ ⚠ same residue
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-ala313 (accessed [today's date]).

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