Is VPS35 p.Arg226= (c.678C>T) pathogenic?

VPS35 p.Arg226= (c.678C>T) is classified Likely benign in VPS35 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-15). Ultra-rare (popmax 0.0285%, nfe); Associated with Parkinson disease 17.

What condition is associated with VPS35 p.Arg226= (c.678C>T)?

VPS35 p.Arg226= (c.678C>T) is associated with Parkinson disease 17 (ClinVar).

How common is VPS35 p.Arg226= (c.678C>T) in the general population?

VPS35 p.Arg226= (c.678C>T) is ultra-rare (popmax 0.0285%, 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.Arg226=

c.678C>T · rs376845827 · VCV319295

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, 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	Δ0.48	donor gain · deltas
Pangolin	Δ0.35	gain · loss 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.8	GERP 0.051, phastCons 1
Overall
CADD	17.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0285% European (non-Finnish) · 336/1,180,000 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.0221% 356/1,613,922 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0285%	3,512
Remaining individualsnot grpmax-eligible	0.0208%	4,806
African / African-American	0.00935%	10,699

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.Arg226=
Coding: c.678C>T
MANE Select: NM_018206
dbSNP: rs376845827
Type: single nucleotide variant
Location: chr16:46678985 (GRCh38)
Gene constraint: LOEUF 0.32 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.40 · 14 PDB
Residue 226: 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-arg226 (accessed [today's date]).

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