VPS35

Chr 16AD

VPS35 retromer complex component

Also known as: MEM3, PARK17

NCBI Gene: 55737 ENSG00000069329 UniProt: Q96QK1 OMIM: 601501

The protein acts as a core component of the retromer complex, which mediates retrograde transport of proteins from endosomes to the trans-Golgi network and prevents their missorting into lysosomal degradation pathways. Mutations cause Parkinson disease 17, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants, indicating that proper protein dosage is critical for normal cellular function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Parkinson disease 17}MIM #614203

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Parkinson disease · AD · ClinGen 2021

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — VPS35

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.31LOEUF

pLI 0.969

Z-score 5.20

OE 0.17 (0.10–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.53Z-score

OE missense 0.52 (0.46–0.58)

220 obs / 424.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.31)

0≤0.351.4

Missense OE?0.52 (0.46–0.58)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 8 / 46.0Missense obs/exp: 220 / 424.9Syn Z: 0.26

Background carrier burden — how many people carry a rare variant somewhere in VPS35?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

607 rare PASS variants

Rare truncating (LoF)

1 in 1,700

43 rare PASS variants

Rare synonymous (reference)

1 in 180

292 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VPS35. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 170	1 in 5,500
South Asian	~43k	1 in 120	≈ 1 in 20,000
Remaining (unassigned)	~30k	1 in 110	1 in 4,900
European (Finnish)	~27k	1 in 650	≈ 1 in 12,000
Admixed American	~22k	1 in 120	1 in 430
African / African American	~21k	1 in 180	1 in 2,700
East Asian	~20k	1 in 130	1 in 1,900
Ashkenazi Jewish	~13k	1 in 620	≈ 1 in 5,900
Middle Eastern	~2,884	1 in 320	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 17 coding exons well covered in gnomAD exomes and genomes.? see exons ↓