OPHN1

Chr XXLR

oligophrenin 1

Also known as: ARHGAP41, MRX60, MRXSBL, OPN1

NCBI Gene: 4983 ENSG00000079482 UniProt: O60890 OMIM: 300127

This gene encodes a Rho-GTPase-activating protein that stimulates GTP hydrolysis of Rho family members and is critical for dendritic spine stabilization, synaptic function, and synaptic vesicle endocytosis. Mutations cause X-linked intellectual developmental disorder with cerebellar hypoplasia and distinctive facial dysmorphism (Billuart type). The gene shows extreme constraint against loss-of-function variants and follows X-linked recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a Rho-GTPase-activating protein that promotes GTP hydrolysis of Rho subfamily members. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Mutations in this gene are responsible for OPHN1-related X-linked cognitive disability with cerebellar hypoplasia and distinctive facial dysmorhphism. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.161 OMIM phenotype

Clinical Summary— OPHN1

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Gene-Disease Validity (ClinGen)

X-linked intellectual disability-cerebellar hypoplasia syndrome · 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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Clinical Trials

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 4.86

OE 0.03 (0.01–0.16)

Highly constrained

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

Missense Constraint?

2.59Z-score

OE missense 0.58 (0.51–0.66)

174 obs / 300.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.16)

0≤0.351.4

Missense OE?0.58 (0.51–0.66)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 29.5Missense obs/exp: 174 / 300.5Syn Z: 0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveOPHN1-related intellectual developmental disorderLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.4091th %ile

GOF

0.5071th %ile

LOF

0.70top 10%

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

LOFprediction above median · LOEUF 0.16 · 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.