HECW2
Chr 2ADHECT, C2 and WW domain containing E3 ubiquitin protein ligase 2
Also known as: NDHSAL, NEDL2
The protein functions as an E3 ubiquitin ligase that regulates neural crest cell proliferation, migration and differentiation through GDNF/Ret signaling, and also stabilizes endothelial cell junctions via angiomotin-like 1 regulation. Loss-of-function mutations cause autosomal dominant neurodevelopmental disorder with hypotonia, seizures, and absent language. The protein is extremely intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
HECW2 · 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
External Resources
Links to major genomics databases and tools