Is VPS35 p.Pro8Ser (c.22C>T) pathogenic?

VPS35 p.Pro8Ser (c.22C>T) is classified Uncertain significance in VPS35 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-03). AlphaMissense: likely benign (0.093); Very rare (popmax 8.48e-05%, nfe); Associated with Parkinson disease 17.

What condition is associated with VPS35 p.Pro8Ser (c.22C>T)?

VPS35 p.Pro8Ser (c.22C>T) is associated with Parkinson disease 17 (ClinVar).

How common is VPS35 p.Pro8Ser (c.22C>T) in the general population?

VPS35 p.Pro8Ser (c.22C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

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

What do computational predictors say about VPS35 p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

VPS35 p.Pro8Ser

c.22C>T · VCV3690250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Parkinson disease 17

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6.2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 7,702 bp · p 0.00035 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,750 alleles

Overall 6.2e-05% 1/1,613,406 alleles · very rare exomes 1/1,461,120 · genomes 0/152,286 · joint denominator

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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_018206
Type: single nucleotide variant
Location: chr16:46683588 (GRCh38)
Gene constraint: LOEUF 0.32 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.40 · 14 PDB

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-pro8ser (accessed [today's date]).

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