Is VPS35 p.Val457= (c.1371G>A) pathogenic?

VPS35 p.Val457= (c.1371G>A) is classified Likely benign in VPS35 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-05). Very rare (popmax 0.00203%, nfe); Associated with Parkinson disease 17.

What condition is associated with VPS35 p.Val457= (c.1371G>A)?

VPS35 p.Val457= (c.1371G>A) is associated with Parkinson disease 17 (ClinVar).

How common is VPS35 p.Val457= (c.1371G>A) in the general population?

VPS35 p.Val457= (c.1371G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

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

VPS35 p.Val457=

c.1371G>A · rs1009455831 · VCV1088814

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

Parkinson disease 17

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.68	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP 0.62, phastCons 1
Overall
CADD	19.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,932 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00192% 31/1,612,242 alleles · very rare exomes 29/1,460,086 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00963%	10,388
European (non-Finnish)grpmax	0.00203%	49,164
African / African-American	0.00134%	74,868

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: VPS35
Protein: p.Val457=
Coding: c.1371G>A
MANE Select: NM_018206
dbSNP: rs1009455831
Type: single nucleotide variant
Location: chr16:46671858 (GRCh38)
Gene constraint: LOEUF 0.32 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.40 · 14 PDB
Residue 457: the 'interaction with slc11a2' region; an α-helix

Full VPS35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Parkinson disease 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

VPS35 p.Asp620Asn Pathogenic ★★ same condition
VPS35 c.-19C>T Uncertain significance ★★ same condition
VPS35 c.*283C>A Uncertain significance ★★ same condition
VPS35 p.Arg138His Uncertain significance ★★ ⚠ same condition
VPS35 p.Arg284Gln Uncertain significance ★★ ⚠ same condition
VPS35 p.Arg493Cys Uncertain significance ★★ ⚠ same condition
VPS35 p.Asn37Ser Uncertain significance ★★ ⚠ same condition
VPS35 p.Asn381Ser 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/vps35-p-val457 (accessed [today's date]).

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