PLEKHG2
Chr 19ARpleckstrin homology and RhoGEF domain containing G2
Also known as: ARHGEF42, CLG, CTB-60E11.4, LDAMD
The protein functions as a guanine nucleotide exchange factor that activates CDC42 and RAC1 GTPases, regulating actin polymerization in cellular processes. Biallelic mutations cause autosomal recessive leukodystrophy with acquired microcephaly and variable dystonia. The gene is highly constrained against loss-of-function variants (LOEUF 0.611), consistent with severe clinical consequences when both copies are disrupted.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
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
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
PLEKHG2 · 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
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools