VPS4A

Chr 16AD

vacuolar protein sorting 4 homolog A

Also known as: CIMDAG, SKD1, SKD1A, SKD2, VPS4, VPS4-1

NCBI Gene: 27183 ENSG00000132612 UniProt: Q9UN37 OMIM: 609982

The VPS4A protein is an ATPase that disassembles ESCRT-III complexes during endosomal protein trafficking and is essential for cellular processes including cytokinesis, chromosome segregation, and primary cilium organization. Mutations cause CIMDAG syndrome, which is inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants, indicating that functional copies are critical for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the AAA protein family (ATPases associated with diverse cellular activities), and is the homolog of the yeast Vps4 protein. In humans, two paralogs of the yeast protein have been identified. The former share a high degree of aa sequence similarity with each other, and also with yeast Vps4 and mouse Skd1 proteins. The mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be really an yeast Vps4 ortholog. Functional studies indicate that both human paralogs associate with the endosomal compartments, and are involved in intracellular protein trafficking, similar to Vps4 protein in yeast. The gene encoding this paralog has been mapped to chromosome 16; the gene for the other resides on chromosome 18. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.351 OMIM phenotype

Clinical Summary— VPS4A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 76 VUS of 112 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.945

Z-score 3.79

OE 0.13 (0.06–0.35)

Highly constrained

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

Missense Constraint?

2.68Z-score

OE missense 0.54 (0.47–0.62)

147 obs / 271.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.35)

0≤0.351.4

Missense OE?0.54 (0.47–0.62)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 3 / 22.4Missense obs/exp: 147 / 271.5Syn Z: -1.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveVPS4A-related CIMDAG Syndrome (monoallelic)DNAD

limitedVPS4A-related CIMDAG Syndrome (biallelic)OTHERAR

This gene — mechanism propensity

0.5476th %ile

GOF

0.4184th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.35

DN1 literature citation

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.

Literature Evidence

DNIn cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A.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 33186545 ↗

ClinVar Variant Classifications

112 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS76

Likely Benign14

Benign4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	3	0	0	3
VUS	7	63	5	1	76
Likely Benign	0	6	2	6	14
Benign	0	0	1	3	4
Total	7	76	8	10	101

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap VPS4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →