ARHGEF2

Chr 1AR

Rho/Rac guanine nucleotide exchange factor 2

Also known as: GEF, GEF-H1, GEFH1, LFP40, Lfc, NEDMHM, P40

NCBI Gene: 9181ENSG00000116584UniProt: Q92974OMIM: 607560

ARHGEF2 encodes a guanine nucleotide exchange factor that activates Rho-GTPases by promoting GDP-to-GTP exchange, playing critical roles in cell motility, neuronal development, and innate immune signaling. Autosomal recessive mutations cause neurodevelopmental disorder with midbrain and hindbrain malformations. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.156), indicating that complete loss of protein function is likely incompatible with normal development.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.161 OMIM phenotype
Clinical Summary— ARHGEF2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
17 unique Pathogenic / Likely Pathogenic· 116 VUS of 194 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.16LOEUF
pLI 1.000
Z-score 6.62
OE 0.07 (0.03–0.16)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
3.61Z-score
OE missense 0.60 (0.55–0.65)
378 obs / 633.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.07 (0.03–0.16)
0≤0.351.4
Missense OE0.60 (0.55–0.65)
0≤0.61.4
Synonymous OE0.93
0≤1.21.6
LoF obs/exp: 4 / 58.7Missense obs/exp: 378 / 633.3Syn Z: 0.84
DN
0.3395th %ile
GOF
0.5169th %ile
LOF
0.73top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.16

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

194 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic4
VUS116
Likely Benign20
Benign10
13
Pathogenic
4
Likely Pathogenic
116
VUS
20
Likely Benign
10
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
12
0
13
Likely Pathogenic
1
0
3
0
4
VUS
2
96
16
2
116
Likely Benign
0
2
3
15
20
Benign
0
1
6
3
10
Total4994020163

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

View in ClinVar →

Protein Context — Lollipop Plot

ARHGEF2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients