VPS41

Chr 7AR

VPS41 subunit of HOPS complex

Also known as: HVPS41, HVSP41, SCAR29, hVps41p

NCBI Gene: 27072 ENSG00000006715 OMIM: 605485

This protein functions as a component of the HOPS endosomal tethering complex, mediating vesicle fusion between late endosomes and lysosomes and facilitating autophagosome-lysosome fusion essential for cellular degradation pathways. Biallelic mutations cause spinocerebellar ataxia, autosomal recessive 29 through loss-of-function mechanisms that disrupt vesicle-mediated protein trafficking to lysosomal compartments.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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 ortholog of yeast Vps41 protein which is also conserved in Drosophila, tomato, and Arabidopsis. Expression studies in yeast and human indicate that this protein may be involved in the formation and fusion of transport vesicles from the Golgi. Several transcript variants encoding different isoforms have been described for this gene, however, the full-length nature of not all is known. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.841 OMIM phenotype

Clinical Summary— VPS41

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 118 VUS of 225 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.55

OE 0.64 (0.49–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.48Z-score

OE missense 0.80 (0.73–0.88)

358 obs / 446.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.49–0.84)

0≤0.351.4

Missense OE?0.80 (0.73–0.88)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 37 / 57.9Missense obs/exp: 358 / 446.1Syn Z: -0.39

This gene — mechanism propensity

0.6455th %ile

GOF

0.5464th %ile

LOF

0.2970th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

225 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic7

VUS118

Likely Benign11

Benign45

Pathogenic

Likely Pathogenic

118

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	5	2	0	0	7
VUS	4	112	2	0	118
Likely Benign	0	4	0	7	11
Benign	0	2	40	3	45
Total	11	122	42	10	185

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap VPS41 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →