VPS13D

Chr 1AR

vacuolar protein sorting 13 homolog D

NCBI Gene: 55187ENSG00000048707UniProt: Q5THJ4

Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Functions in promoting mitochondrial clearance by mitochondrial autophagy (mitophagy), also possibly by positively regulating mitochondrial fission (PubMed:29307555, PubMed:29604224). Mitophagy plays an important role in regulating cell health and mitochondrial size and homeostasis

Primary Disease Associations & Inheritance

Spinocerebellar ataxia, autosomal recessive 4MIM #607317
AR
1885
ClinVar variants
19
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— VPS13D
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 268 VUS of 1885 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.33LOEUF
pLI 0.000
Z-score 9.80
OE 0.27 (0.21–0.33)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.50Z-score
OE missense 0.86 (0.82–0.89)
2029 obs / 2371.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.27 (0.21–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.82–0.89)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 55 / 207.3Missense obs/exp: 2029 / 2371.0Syn Z: 0.09

ClinVar Variant Classifications

1885 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic12
VUS268
Likely Benign140
Benign4
7
Pathogenic
12
Likely Pathogenic
268
VUS
140
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
6
0
7
Likely Pathogenic
5
2
5
0
12
VUS
0
260
7
1
268
Likely Benign
0
4
40
96
140
Benign
0
0
3
1
4
Total62666198431

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

View in ClinVar →

Protein Context — Lollipop Plot

VPS13D · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spinocerebellar ataxia, autosomal recessive 4

MIM #607317

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
VPS13D bridges the ER to mitochondria and peroxisomes via Miro.
Guillén-Samander A et al.·J Cell Biol
2021
VPS13D-related disorders: a severe case, review, and genotype-phenotype correlation.
Liu WL et al.·Neurocase
2025Review
Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders.
Sultan T et al.·Gene
2024
Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder.
Pauly MG et al.·Int J Mol Sci
2023Review
VPS13D-based disease: Expansion of the clinical phenotype in two brothers and mutation diversity in the Turkish population.
Öztop-Çakmak Ö et al.·Rev Neurol (Paris)
2022Case report
RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature.
Baker EK et al.·Mol Genet Genomics
2023Review
VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum-mitochondria interactions.
Du Y et al.·Mol Biol Cell
2021
Recent genetic advances in early-onset dystonia.
Steel D et al.·Curr Opin Neurol
2020Review
Clinical, genetic, and neuroimaging profiles of autosomal recessive spinocerebellar ataxia type 4 caused by novel VPS13D variants in Chinese.
Dong Y et al.·Am J Med Genet A
2024
VPS13D Gene Variant Is Associated with Altered IL-6 Production and Mortality in Septic Shock.
Nakada TA et al.·J Innate Immun
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools