ARHGEF15

Chr 17AD

Rho guanine nucleotide exchange factor 15

Also known as: ARGEF15, BSVD5, E5, Ephexin5, Vsm-RhoGEF

NCBI Gene: 22899 ENSG00000198844 UniProt: O94989 OMIM: 608504

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).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.671 OMIM phenotype

Clinical Summary— ARHGEF15

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 439 VUS of 721 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.000

Z-score 3.15

OE 0.44 (0.30–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.71Z-score

OE missense 0.91 (0.84–0.98)

475 obs / 520.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.30–0.67)

0≤0.351.4

Missense OE?0.91 (0.84–0.98)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 16 / 36.5Missense obs/exp: 475 / 520.9Syn Z: 1.04

This gene — mechanism propensity

0.6261th %ile

GOF

0.72top 25%

LOF

0.3647th %ile

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.

GOFprediction above median

DNprediction above median

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

721 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic1

VUS439

Likely Benign230

Benign32

Conflicting13

Pathogenic

Likely Pathogenic

439

VUS

230

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	3	0	3
Likely Pathogenic	0	1	0	0	1
VUS	25	389	23	2	439
Likely Benign	0	11	78	141	230
Benign	0	9	8	15	32
Conflicting	—				13
Total	25	410	112	158	718

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap ARHGEF15 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →