AQP4
Chr 18ARaquaporin 4
Also known as: MIWC, MLC4, WCH4, hAQP4
This gene encodes aquaporin-4, a water-specific channel protein that maintains brain water homeostasis and facilitates glymphatic solute transport, including clearance of beta-amyloid peptides from brain interstitial fluid. Autosomal recessive mutations cause megalencephalic leukoencephalopathy with subcortical cysts 4, a remitting form of this white matter disorder. The gene shows minimal constraint against loss-of-function variants (pLI 0.002, LOEUF 0.99), consistent with recessive inheritance where heterozygous carriers are typically unaffected.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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
96 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 1 | 34 | 0 | 35 |
Likely Pathogenic | 0 | 1 | 1 | 0 | 2 |
VUS | 0 | 36 | 6 | 0 | 42 |
Likely Benign | 0 | 5 | 1 | 0 | 6 |
Benign | 0 | 1 | 0 | 4 | 5 |
Conflicting | — | 1 | |||
| Total | 0 | 44 | 42 | 4 | 91 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
AQP4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Precision Medicine in the Treatment of Epilepsy
RECRUITINGFrequency of FCGR3A Gene Polymorphisms in Patients With Neuromyelitis Optica Spectrum Disorders, Anti-oligodendrocyte Myelin Protein Antibody Disease, and Multiple Sclerosis.
RECRUITINGAquaporin-4 Single Nucleotide Polymorphisms in Patients With Idiopathic and Familial Parkinson's Disease
ACTIVE NOT RECRUITINGREACT MCI - Repeated Advanced Cognitive Training in Mild Cognitive Impairment
ACTIVE NOT RECRUITINGAnalysis of the Role of AIRE in Autoimmune Neurological Diseases Associated With Autoantibodies
RECRUITINGExternal Resources
Links to major genomics databases and tools