VPS33A

Chr 12AR

VPS33A core subunit of CORVET and HOPS complexes

Also known as: MPSPS

NCBI Gene: 65082 ENSG00000139719 UniProt: Q96AX1 OMIM: 610034

The protein functions as a core component of the HOPS and CORVET endosomal tethering complexes that regulate vesicle trafficking to lysosomes, controlling endosome maturation and fusion of endosomes and autophagosomes with lysosomes. Mutations cause mucopolysaccharidosis-plus syndrome, inherited in an autosomal recessive pattern. The gene shows significant constraint against loss-of-function variants (LOEUF 0.44), reflecting its essential role in cellular trafficking pathways.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a tethering protein and a core subunit of the homotypic fusion and protein sorting (HOPS) complex. The HOPS complex and a second endosomal tethering complex called the class C core vacuole/endosome tethering (CORVET) complex, perform diverse functions in endocytosis including membrane tethering, RabGTPase interaction, activation and proofreading of synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) assembly to drive membrane fusion, and endosome-to-cytoskeleton attachment. The HOPS complex controls endosome maturation as well as endosome traffic to the lysosome. This complex is essential for vacuolar fusion and is required for adaptor protein complex 3-dependent transport from the golgi to the vacuole. The encoded protein belongs to the Sec1/Munc18 (SM) family of SNARE-mediated membrane fusion regulators. Naturally occurring mutations in this gene are associated with a novel mucopolysaccharidosis-like disease. [provided by RefSeq, Apr 2017]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.441 OMIM phenotype

Clinical Summary— VPS33A

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Gene-Disease Validity (ClinGen)

mucopolysaccharidosis-plus syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 145 VUS of 367 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.182

Z-score 4.01

OE 0.24 (0.14–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.64Z-score

OE missense 0.75 (0.68–0.83)

263 obs / 349.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.14–0.44)

0≤0.351.4

Missense OE?0.75 (0.68–0.83)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 8 / 32.8Missense obs/exp: 263 / 349.0Syn Z: -0.63

ClinVar Variant Classifications

367 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS145

Likely Benign160

Benign46

Conflicting2

Likely Pathogenic

145

VUS

160

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	5	131	8	1	145
Likely Benign	0	4	58	98	160
Benign	1	3	38	4	46
Conflicting	—				2
Total	6	139	104	103	354

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap VPS33A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →