VPS16

Chr 20AD

VPS16 core subunit of CORVET and HOPS complexes

Also known as: DYT30, hVPS16

NCBI Gene: 64601 ENSG00000215305 UniProt: Q9H269 OMIM: 608550

The protein localizes to late endosome membranes and mediates vesicle trafficking in the endosome/lysosome pathway. Mutations cause dystonia 30, an autosomal dominant movement disorder. The pathogenic mechanism likely involves disrupted intracellular vesicle transport and lysosomal dysfunction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps16 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.821 OMIM phenotype

Clinical Summary— VPS16

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 204 VUS of 292 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — VPS16

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.62

OE 0.61 (0.46–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.82Z-score

OE missense 0.90 (0.83–0.97)

458 obs / 510.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.46–0.82)

0≤0.351.4

Missense OE?0.90 (0.83–0.97)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 32 / 52.5Missense obs/exp: 458 / 510.3Syn Z: 0.86

This gene — mechanism propensity

0.5772th %ile

GOF

0.4579th %ile

LOF

0.3454th %ile

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · 91% of P/LP variants are LoF

Literature Evidence

LOFLoss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32808683 ↗

ClinVar Variant Classifications

292 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic11

VUS204

Likely Benign20

Benign16

Conflicting4

Pathogenic

Likely Pathogenic

204

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	1	0	0	12
Likely Pathogenic	10	0	1	0	11
VUS	13	186	3	2	204
Likely Benign	0	4	2	14	20
Benign	0	1	11	4	16
Conflicting	—				4
Total	34	192	17	20	267

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

24 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap VPS16 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →