Is VPS35 p.Pro316Ser (c.946C>T) pathogenic?

VPS35 p.Pro316Ser (c.946C>T) is classified Uncertain significance in VPS35 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-13). AlphaMissense: likely benign (0.149); Ultra-rare (popmax 0.021%, nfe); Associated with Parkinson disease 17.

What condition is associated with VPS35 p.Pro316Ser (c.946C>T)?

VPS35 p.Pro316Ser (c.946C>T) is associated with Parkinson disease 17 (ClinVar).

How common is VPS35 p.Pro316Ser (c.946C>T) in the general population?

VPS35 p.Pro316Ser (c.946C>T) is ultra-rare (popmax 0.021%, 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.Pro316Ser (c.946C>T)?

AlphaMissense predicts likely benign (score 0.149) — an in-silico prediction, not a clinical call.

VPS35 p.Pro316Ser

c.946C>T · rs770029606 · VCV487671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Parkinson disease 17

Computational evidence

Protein change
AlphaMissense	0.149	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -8.26	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 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 14 kb · p 5.5e-12 · regional, not allelic
Overall
CADD	22.4	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 0.021% European (non-Finnish) · 248/1,178,874 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.0161% 260/1,610,730 alleles · ultra-rare exomes 244/1,460,002 · genomes 16/150,728 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.021%	4,754
Remaining individualsnot grpmax-eligible	0.0112%	8,910
Finnishnot grpmax-eligible	0.00631%	15,854
South Asian	0.0011%	90,704

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.Pro316Ser
Coding: c.946C>T
MANE Select: NM_018206
dbSNP: rs770029606
Type: single nucleotide variant
Location: chr16:46674629 (GRCh38)
Gene constraint: LOEUF 0.32 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.40 · 14 PDB
Residue 316: a UniProt-annotated variant site (found in a patient with parkinson disease)

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-pro316ser (accessed [today's date]).

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