ARHGEF15
Chr 17ADRho guanine nucleotide exchange factor 15
Also known as: ARGEF15, BSVD5, E5, Ephexin5, Vsm-RhoGEF
This protein functions as a guanine nucleotide exchange factor that specifically activates RhoA, regulating actin cytoskeleton organization, vascular smooth muscle contractility, and excitatory synapse development. Mutations cause brain small vessel disease 5 with osteoporosis, affecting both the cerebrovascular system and bone metabolism. The condition follows autosomal dominant inheritance and the gene is highly constrained against loss-of-function variants (LOEUF 0.665).
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
451 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 | 0 | 15 | 0 | 15 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 9 | 214 | 19 | 1 | 243 |
Likely Benign | 0 | 6 | 66 | 97 | 169 |
Benign | 0 | 5 | 7 | 5 | 17 |
Conflicting | — | 4 | |||
| Total | 9 | 225 | 107 | 103 | 448 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
ARHGEF15 · 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