ARHGEF9

Chr XX-linked

Cdc42 guanine nucleotide exchange factor 9

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

NCBI Gene: 23229ENSG00000131089UniProt: O43307OMIM: 300429

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]

GeneReviewsOMIMResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 8MIM #300607
X-linked

Clinical highlights

Gene-disease validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitivesufficient evidence for diagnostic panels
Interpreting a novel variant
Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.
1
Active trials
5
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.15
LOEUF· LoF intol.
LOF
Mechanism· G2P
📖
GeneReview available — ARHGEF9
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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 OE?0.00 (0.00–0.15)
0≤0.351.4
Missense OE?0.41 (0.34–0.49)
0≤0.61.4
Synonymous OE?0.97
0≤1.21.6
LoF obs/exp: 0 / 19.8Missense obs/exp: 86 / 210.1Syn Z: 0.19

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

ARHGEF9 · protein map & ClinVar variants

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

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