OPHN1

Chr XXLR

oligophrenin 1

Also known as: ARHGAP41, MRX60, MRXSBL, OPN1

NCBI Gene: 4983ENSG00000079482UniProt: O60890

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]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Billuart typeMIM #300486
XLR
789
ClinVar variants
63
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— OPHN1
⚡
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
63 Pathogenic / Likely Pathogenic· 147 VUS of 789 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.51–0.66)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 1 / 29.5Missense obs/exp: 174 / 300.5Syn Z: 0.18

ClinVar Variant Classifications

789 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic22
VUS147
Likely Benign59
Benign27
Conflicting4
41
Pathogenic
22
Likely Pathogenic
147
VUS
59
Likely Benign
27
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
0
27
0
41
Likely Pathogenic
11
4
7
0
22
VUS
6
113
27
1
147
Likely Benign
0
2
25
32
59
Benign
0
4
18
5
27
Conflicting
—4
Total3112310438300

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

View in ClinVar →

Protein Context — Lollipop Plot

OPHN1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

OPHN1-related intellectual developmental disorder

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

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
OLIGOPHRENIN 1; OPHN1
MIM #300127 · *

Intellectual developmental disorder, X-linked syndromic, Billuart type

MIM #300486

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole exome sequencing analysis of 167 men with primary infertility.
Zhou H et al.·BMC Med Genomics
2024
X-linked mental deficiency.
des Portes V·Handb Clin Neurol
2013Review
The interaction of UBR4, LRP1, and OPHN1 in refractory epilepsy: Drosophila model to investigate the oligogenic effect on epilepsy.
Huang RN et al.·Neurobiol Dis
2025Functional
Nexus between genome-wide copy number variations and autism spectrum disorder in Northeast Han Chinese population.
Qiu S et al.·BMC Psychiatry
2023
Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia.
Moortgat S et al.·Eur J Med Genet
2018Review
Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders.
Schrauwen I et al.·Sci Rep
2024
Targeting the Lnc-OPHN1-5/androgen receptor/hnRNPA1 complex increases Enzalutamide sensitivity to better suppress prostate cancer progression.
Zhang M et al.·Cell Death Dis
2021
Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia.
Bergmann C et al.·Brain
2003Review
Genes responsible for nonspecific mental retardation.
Castellví-Bel S et al.·Mol Genet Metab
2001Review
Delineation of the clinical phenotype associated with OPHN1 mutations based on the clinical and neuropsychological evaluation of three families.
Chabrol B et al.·Am J Med Genet A
2005
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools