VAC14

Chr 16AR

VAC14 component of PIKFYVE complex

Also known as: ArPIKfyve, TAX1BP2, TRX

NCBI Gene: 55697ENSG00000103043UniProt: Q08AM6

This gene encodes a scaffold protein that is a component of the PIKfyve protein kinase complex. This complex is responsible for the synthesis of phosphatidylinositol 3,5-bisphosphate, an important component of cellular membranes, from phosphatidylinositol 3-phosphate. Mice lacking a functional copy of this gene exhibit severe neurodegeneration. Mutations in the human gene have been identified in patients with a childhood onset progressive neurological disorder characterized by impaired movement, dystonia, and striatal abnormalities. [provided by RefSeq, May 2017]

Primary Disease Associations & Inheritance

Striatonigral degeneration, childhood-onsetMIM #617054
AR
0
Active trials
38
Pathogenic / LP
362
ClinVar variants
6
Pubs (1 yr)
2.2
Missense Z
0.42
LOEUF
Clinical Summary— VAC14
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 128 VUS of 362 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.42LOEUF
pLI 0.186
Z-score 4.29
OE 0.24 (0.14–0.42)
Moderately constrained

More LoF-intolerant than ~75% 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.
2.17Z-score
OE missense 0.72 (0.66–0.79)
335 obs / 467.2 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.0.24 (0.14–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.66–0.79)
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.1.09
0≤1.21.6
LoF obs/exp: 9 / 37.3Missense obs/exp: 335 / 467.2Syn Z: -0.97

ClinVar Variant Classifications

362 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic5
VUS128
Likely Benign169
Benign22
Conflicting5
33
Pathogenic
5
Likely Pathogenic
128
VUS
169
Likely Benign
22
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
3
25
0
33
Likely Pathogenic
0
1
4
0
5
VUS
0
109
19
0
128
Likely Benign
0
3
64
102
169
Benign
0
2
15
5
22
Conflicting
—5
Total5118127107362

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

View in ClinVar →

Protein Context — Lollipop Plot

VAC14 · protein map & ClinVar variants

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

Gene2Phenotype Curations

VAC14-related progressive neurological disorder and regression of developmental milestones

limited
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients