ARHGEF9

Chr X

Cdc42 guanine nucleotide exchange factor 9

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

NCBI Gene: 23229 ENSG00000131089 UniProt: O43307

The protein acts as a guanine nucleotide exchange factor for CDC42 and facilitates recruitment of gephyrin at GABAergic and glycinergic synapses. Mutations cause developmental and epileptic encephalopathy 8 through an X-linked inheritance pattern, predominantly through loss-of-function mechanisms. The gene shows high constraint against loss-of-function variants, consistent with haploinsufficiency being pathogenic in this X-linked disorder.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.15

Clinical Summary— ARHGEF9

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

54 unique Pathogenic / Likely Pathogenic· 214 VUS of 548 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — ARHGEF9

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongARHGEF9-related developmental disorderLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

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 · 72% of P/LP variants are LoF · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

548 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31

Likely Pathogenic23

VUS214

Likely Benign173

Benign27

Conflicting21

Pathogenic

Likely Pathogenic

214

VUS

173

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	26	1	3	1	31
Likely Pathogenic	13	7	2	1	23
VUS	10	184	17	3	214
Likely Benign	1	9	73	90	173
Benign	0	2	21	4	27
Conflicting	—				21
Total	50	203	116	99	489

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 61) ClinVar copy-number / structural variants overlap ARHGEF9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →