ARHGEF9

Chr XX-linked

Cdc42 guanine nucleotide exchange factor 9

Also known as: COLLYBISTIN, DEE8, EIEE8, HPEM-2, PEM-2, PEM2

NCBI Gene: 23229ENSG00000131089UniProt: O43307

The protein encoded by this gene is a Rho-like GTPase that switches between the active (GTP-bound) state and inactive (GDP-bound) state to regulate CDC42 and other genes. This brain-specific protein also acts as an adaptor protein for the recruitment of gephyrin and together these proteins facilitate receceptor recruitement in GABAnergic and glycinergic synapses. Defects in this gene are the cause of startle disease with epilepsy (STHEE), also known as hyperekplexia with epilepsy, as well as several other types of cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 8MIM #300607
X-linked
1
Active trials
58
Pathogenic / LP
341
ClinVar variants
4
Pubs (1 yr)
3.0
Missense Z
0.15
LOEUF· LoF intolerant
Clinical Summary— ARHGEF9
🧬
Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
58 Pathogenic / Likely Pathogenic· 147 VUS of 341 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — ARHGEF9
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.15LOEUF
pLI 0.999
Z-score 4.12
OE 0.00 (0.00–0.15)
Highly constrained

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

Missense Constraint
3.04Z-score
OE missense 0.41 (0.34–0.49)
86 obs / 210.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.15)
0≤0.351.4
Missense OE0.41 (0.34–0.49)
0≤0.61.4
Synonymous OE0.97
0≤1.21.6
LoF obs/exp: 0 / 19.8Missense obs/exp: 86 / 210.1Syn Z: 0.19
LOF
DN
0.3196th %ile
GOF
0.5268th %ile
LOF
0.71top 10%

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

LOFprediction above median · 28% of P/LP variants are LoF · LOEUF 0.15

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

341 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic19
VUS147
Likely Benign107
Benign17
Conflicting12
39
Pathogenic
19
Likely Pathogenic
147
VUS
107
Likely Benign
17
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
28
2
39
Likely Pathogenic
7
4
8
0
19
VUS
4
121
20
2
147
Likely Benign
1
5
45
56
107
Benign
0
0
15
2
17
Conflicting
—12
Total2113011662341

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

View in ClinVar →

ARHGEF9 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ARHGEF9-related developmental disorder

strong
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Literature
Landmark / reviewRecent case evidence
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