OPHN1

Summary

OPHN1 (oligophrenin 1, HGNC:8148) is a protein-coding gene on chromosome Xq12, encoding Oligophrenin-1 (O60890). Stimulates GTP hydrolysis of members of the Rho family. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 4983 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked intellectual disability-cerebellar hypoplasia syndrome (Definitive, ClinGen)
• GWAS associations: 9
• Clinical variants (ClinVar): 651 total — 52 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 62
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002547

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8148
Approved symbol	OPHN1
Name	oligophrenin 1
Location	Xq12
Locus type	gene with protein product
Status	Approved
Aliases	OPN1, ARHGAP41
Ensembl gene	ENSG00000079482
Ensembl biotype	protein_coding
OMIM	300127
Entrez	4983

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 11 protein_coding, 7 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000355520, ENST00000467444, ENST00000484842, ENST00000486068, ENST00000491714, ENST00000679394, ENST00000679748, ENST00000679822, ENST00000679914, ENST00000680262, ENST00000680417, ENST00000680503, ENST00000680592, ENST00000680595, ENST00000680612, ENST00000680804, ENST00000680976, ENST00000681349, ENST00000681408, ENST00000681520, ENST00000905069, ENST00000917825, ENST00000949826

RefSeq mRNA: 1 — MANE Select: NM_002547 NM_002547

CCDS: CCDS14388

Canonical transcript exons

ENST00000355520 — 25 exons

Exon	Start	End
ENSE00000672082	68234487	68234588
ENSE00000672083	68213862	68213972
ENSE00000672084	68212108	68212212
ENSE00000672092	68119248	68119332
ENSE00000672097	68113181	68113239
ENSE00000869176	68192919	68192993
ENSE00000897983	68052540	68052590
ENSE00000897987	68053645	68053810
ENSE00001040953	68048416	68048457
ENSE00001267780	68210153	68210282
ENSE00001267980	68274738	68274809
ENSE00001267983	68283056	68283117
ENSE00001464214	68042344	68047163
ENSE00001464287	68432867	68433024
ENSE00001735411	68433168	68433495
ENSE00003480658	68096870	68097029
ENSE00003485727	68073152	68073299
ENSE00003512592	68206573	68206673
ENSE00003534125	68193890	68193952
ENSE00003547747	68111854	68111959
ENSE00003556310	68063854	68064177
ENSE00003643953	68201619	68201710
ENSE00003660547	68197186	68197264
ENSE00003682383	68194465	68194498
ENSE00003688903	68299001	68299096

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 91.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1809 / max 287.0723, expressed in 1550 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199517	4.0469	1222
199519	1.4852	825
199518	1.0300	509
199516	0.4574	231
199512	0.1221	49
199514	0.0294	9
199513	0.0099	4

Top tissues by expression

147 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	91.18	gold quality
calcaneal tendon	UBERON:0003701	88.75	gold quality
sural nerve	UBERON:0015488	88.14	gold quality
ventricular zone	UBERON:0003053	87.28	gold quality
ganglionic eminence	UBERON:0004023	84.74	gold quality
amygdala	UBERON:0001876	83.53	gold quality
temporal lobe	UBERON:0001871	83.02	gold quality
nucleus accumbens	UBERON:0001882	82.97	gold quality
cortical plate	UBERON:0005343	82.97	gold quality
caudate nucleus	UBERON:0001873	81.79	gold quality
putamen	UBERON:0001874	80.74	gold quality
anterior cingulate cortex	UBERON:0009835	79.41	gold quality
colonic epithelium	UBERON:0000397	79.15	gold quality
right frontal lobe	UBERON:0002810	79.15	gold quality
uterine cervix	UBERON:0000002	79.07	gold quality
Ammon’s horn	UBERON:0001954	78.73	gold quality
endocervix	UBERON:0000458	78.32	gold quality
superior frontal gyrus	UBERON:0002661	78.19	gold quality
brain	UBERON:0000955	78.15	gold quality
tibial nerve	UBERON:0001323	78.15	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.14	gold quality
cerebral cortex	UBERON:0000956	78.06	gold quality
substantia nigra	UBERON:0002038	77.91	gold quality
central nervous system	UBERON:0001017	77.90	gold quality
hypothalamus	UBERON:0001898	77.87	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.79	gold quality
prefrontal cortex	UBERON:0000451	77.49	gold quality
primary visual cortex	UBERON:0002436	77.33	gold quality
stromal cell of endometrium	CL:0002255	77.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.15	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-106540	yes	1164.95
E-MTAB-5061	yes	695.64
E-HCAD-35	yes	69.77
E-CURD-119	yes	43.84
E-HCAD-25	yes	24.82
E-GEOD-84465	yes	23.26
E-ANND-3	yes	15.89
E-CURD-112	yes	3.47
E-GEOD-124858	no	790.41
E-MTAB-6379	no	489.57
E-GEOD-70580	no	266.13
E-GEOD-81547	no	5.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

174 targeting OPHN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-12119	99.87	68.35	1653

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• The OPHN1 gene plays a role during the development of the human cerebellum. (PMID:12807966)
• Found in glial cells forming myelin sheaths in the vagus nerve, sciatic nerve and dorsal roots of guinea-pig, rat and human, in chromaffin cells of the adrenal medulla, and in chromaffin cells associated with sympathetic ganglia. (PMID:15026118)
• Oligophrenin 1 mutations were found in 12% (2/17) of individuals with mental retardatin and known cerebellar anomalies and in 1% (2/196) of the X-linked mental retardation group. (PMID:16221952)
• Disruption of the OPHN1 gene on Xq12 is associated with mental retardation and tall stature (PMID:17845870)
• oligophrenin 1 gene (OPHN1) is an Rho-GTPase-activating protein involved in the regulation of the G-protein cycle required for dendritic spine morphogenesis (PMID:18261018)
• Data suggest that OPHN1 defect may be an important contributory factor to XLMR. (PMID:20528889)
• This mutation determines the production of a mutant oligophrenin 1 protein with 16 extra amino acids inserted in-frame in the N-terminal BAR (Bin1/amphiphysin/Rvs167) domain. (oligophrenin 1 protein ) (PMID:21796728)
• Several genes expressed at exceptionally high levels were identified associated with early oocyte development, TMEFF2, the Rho-GTPase-activating protein oligophrenin 1 (OPHN1) and the mitochondrial-encoded ATPase6 (ATP6). (PMID:22238370)
• In response to GPVI stimulation, OPHN1 becomes phosphorylated at Tyr370 and plays a role in the formation of filopodia during platelet spreading on collagen. (PMID:23619296)
• This is the first description of an in-frame deletion within the BAR domain of OPHN1 and could provide new insights into the role of this domain in relation to brain and cognitive development or function. (PMID:24105372)
• Our results demonstrate that multiple post-transcriptional events occur on OPHN1, a gene playing an important role in brain function and development. (PMID:24637888)
• results suggest that oligophrenin-1 is involved in tumor progression in prostate cancer (PMID:25170626)
• Here, we report that chronic treatment in adult mouse with Fasudil, is able to counteract vertical and horizontal hyperactivities, restores recognition memory and limits the brain ventricular dilatation observed in Ophn1(-)(/y) However, deficits in working and spatial memories are partially or not rescued by the treatment (PMID:27146843)
• A neuronal stem cell-based model for the treatment of OPHN1 syndrome and other neurological disorders due to ROCK dysfunction. (PMID:27160703)
• we reported on the first male patient carrying an OPHN1 mutation with IQ score within the normal limits. This observation expands the phenotypic spectrum of OPHN1 mutations. (PMID:27390894)
• Furthermore, we found that olfactory behaviour was perturbed in OPHN1 ko mice. Chronic treatment with a Rho kinase inhibitor rescued most of the defects of the newly generated neurons. Altogether, our data indicated that OPHN1 plays a key role in regulating the number, morphology and function of adult-born inhibitory interneurons and contributed to identify potential therapeutic targets. (PMID:27742778)
• Novel unconventional variants expand the allelic spectrum of OPHN1 gene. (PMID:33638601)
• Androgen deprivationinduced OPHN1 amplification promotes castrationresistant prostate cancer. (PMID:34738630)
• Effect of the OPHN1 novel variant c.1025+1 G>A on RNA splicing: insights from a minigene assay. (PMID:38956616)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ophn1	ENSDARG00000035420
mus_musculus	Ophn1	ENSMUSG00000031214
rattus_norvegicus	Ophn1	ENSRNOG00000026573
drosophila_melanogaster	Graf	FBGN0030685
caenorhabditis_elegans		WBGENE00020209

Paralogs (3): ARHGAP10 (ENSG00000071205), ARHGAP26 (ENSG00000145819), ARHGAP42 (ENSG00000165895)

Protein

Protein identifiers

Oligophrenin-1 — O60890 (reviewed: O60890)

All UniProt accessions (7): O60890, A0A7P0T8V5, A0A7P0T9G2, A0A7P0T9W4, A0A7P0TBB6, A0A7P0TBH4, A0A7P0Z4E9

UniProt curated annotations — full annotation on UniProt →

Function. Stimulates GTP hydrolysis of members of the Rho family. Its action on RHOA activity and signaling is implicated in growth and stabilization of dendritic spines, and therefore in synaptic function. Critical for the stabilization of AMPA receptors at postsynaptic sites. Critical for the regulation of synaptic vesicle endocytosis at presynaptic terminals. Required for the localization of NR1D1 to dendrites, can suppress its repressor activity and protect it from proteasomal degradation.

Subunit / interactions. Interacts with HOMER1. Interacts with AMPA receptor complexes. Interacts with SH3GL2 (endophilin-A1). Interacts (via C-terminus) with NR1D1.

Subcellular location. Postsynapse. Presynapse. Cell projection. Axon. Dendritic spine. Dendrite. Cytoplasm.

Tissue specificity. Expressed in brain.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Billuart type (MRXSBL) [MIM:300486] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSBL patients manifest intellectual disability associated with cerebellar hypoplasia and distinctive facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
O60890-1	1	yes
O60890-2	2

RefSeq proteins (1): NP_002538* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001849	PH_domain	Domain
IPR004148	BAR_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR047225	PH_GRAF	Domain
IPR047234	GRAF_fam	Family
IPR047267	OPHN1_BAR	Domain

Pfam: PF00169, PF00620, PF16746

UniProt features (17 total): sequence variant 5, region of interest 4, domain 2, splice variant 2, compositionally biased region 2, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60890-F1	74.86	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 409 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle

MSigDB gene sets: 379 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, BIOCARTA_RHO_PATHWAY, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_ESTABLISHMENT_OF_EPITHELIAL_CELL_POLARITY, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (21): substrate-dependent cell migration, cell extension (GO:0006930), signal transduction (GO:0007165), nervous system development (GO:0007399), axon guidance (GO:0007411), cerebellar granule cell differentiation (GO:0021707), cerebral cortex neuron differentiation (GO:0021895), actin cytoskeleton organization (GO:0030036), regulation of endocytosis (GO:0030100), neuron differentiation (GO:0030182), neuron projection development (GO:0031175), cell junction assembly (GO:0034329), regulation of Rho protein signal transduction (GO:0035023), establishment of epithelial cell apical/basal polarity (GO:0045198), synaptic vesicle endocytosis (GO:0048488), cell morphogenesis involved in neuron differentiation (GO:0048667), regulation of synaptic transmission, glutamatergic (GO:0051966), maintenance of postsynaptic specialization structure (GO:0098880), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), regulation of synaptic vesicle endocytosis (GO:1900242), negative regulation of proteasomal protein catabolic process (GO:1901799), endocytosis (GO:0006897)

GO Molecular Function (5): actin binding (GO:0003779), GTPase activator activity (GO:0005096), phospholipid binding (GO:0005543), ionotropic glutamate receptor binding (GO:0035255), protein binding (GO:0005515)

GO Cellular Component (11): cytoplasm (GO:0005737), actin cytoskeleton (GO:0015629), terminal bouton (GO:0043195), dendritic spine (GO:0043197), glutamatergic synapse (GO:0098978), axon (GO:0030424), dendrite (GO:0030425), cell projection (GO:0042995), synapse (GO:0045202), presynapse (GO:0098793), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	10

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
synapse	3
neuron development	2
neuron projection	2
substrate-dependent cell migration	1
plasma membrane bounded cell projection assembly	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
axonogenesis	1
neuron projection guidance	1
cell differentiation in hindbrain	1
cerebellar granular layer formation	1
central nervous system neuron differentiation	1
glutamatergic neuron differentiation	1
forebrain neuron differentiation	1
cytoskeleton organization	1
actin filament-based process	1
endocytosis	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
cell differentiation	1
generation of neurons	1
plasma membrane bounded cell projection organization	1
cellular component assembly	1
cell junction organization	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
polarized epithelial cell differentiation	1
establishment of apical/basal cell polarity	1
establishment or maintenance of epithelial cell apical/basal polarity	1
establishment of epithelial cell polarity	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
cell morphogenesis	1
neuron differentiation	1
synaptic transmission, glutamatergic	1

Protein interactions and networks

STRING

1208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OPHN1	ARHGEF6	Q15052	843
OPHN1	PJA1	Q8NG27	828
OPHN1	RPS6KA6	Q9UK32	788
OPHN1	EFNB1	P98172	748
OPHN1	HOMER1	Q86YM7	740
OPHN1	YIPF6	Q96EC8	705
OPHN1	ARHGEF7	Q14155	668
OPHN1	FGD1	P98174	655
OPHN1	BIN1	O00499	651
OPHN1	ARHGEF9	O43307	638
OPHN1	OPN5	Q6U736	624
OPHN1	OPN3	Q9H1Y3	622
OPHN1	SH3GLB2	Q9NR46	622
OPHN1	SH3GLB1	Q9Y371	601
OPHN1	SH3GL2	Q99962	583

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ARHGAP26	ARHGAP10	psi-mi:“MI:0914”(association)	0.510
ARHGAP26	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
MAD2L1	MED19	psi-mi:“MI:0914”(association)	0.350
UBR4	METTL15	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): OPHN1 (Affinity Capture-RNA), OPHN1 (Affinity Capture-MS), OPHN1 (Affinity Capture-RNA), OPHN1 (Positive Genetic), OPHN1 (Affinity Capture-RNA), RHOA (Biochemical Activity), RAC1 (Biochemical Activity), CDC42 (Biochemical Activity), OPHN1 (Affinity Capture-MS), OPHN1 (Affinity Capture-MS), OPHN1 (Affinity Capture-MS), OPHN1 (Proximity Label-MS), OPHN1 (Proximity Label-MS), OPHN1 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JTR4, A1A4S6, A2AWA9, A4FUD6, A4II46, A6H6A9, A6QNS3, A6QQZ7, O60890, P09851, P0CAX5, P20936, P23727, P26450, P27986, P50904, Q08DP6, Q12979, Q5R372, Q5R5M3, Q5R685, Q5R6F2, Q5R8I6, Q5RCC1, Q5RCW6, Q5SSL4, Q5T2T1, Q5U2Y3, Q5ZJ17, Q5ZLX4, Q5ZMW5, Q62696, Q63787, Q6Y5D8, Q6ZQ82, Q7YQL5, Q7YQL6, Q8AVG0, Q8BPU7, Q8K0F1

Diamond homologs: A0A0G2JTR4, A1A4S6, A2AB59, A2RUV4, A4IF90, A4II46, A6NI28, A6QNS3, A7YY57, A8WRJ2, B2RQE8, B5DFQ4, D3ZFJ3, F1LQX4, F1LXF1, O14559, O60890, O74360, O94466, P0CAX5, P11274, P15882, P30337, P34288, P46941, P52757, P55194, P81128, P83509, P97393, Q03070, Q08DP6, Q12979, Q13017, Q13459, Q15311, Q17QN0, Q17R89, Q20498, Q52LW3

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
OPHN1	“up-regulates activity”	RHOA	“gtpase-activating protein”
OPHN1	“up-regulates activity”	CDC42	“gtpase-activating protein”
OPHN1	“up-regulates activity”	RAC1	“gtpase-activating protein”
OPHN1	up-regulates	F-actin_assembly
NR1D1	“up-regulates activity”	OPHN1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

651 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	42
Uncertain significance	238
Likely benign	108
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11577	NM_002547.3(OPHN1):c.1579del (p.Ile527fs)	Pathogenic
11578	NM_002547.3(OPHN1):c.745_752dup (p.Lys251fs)	Pathogenic
11579	NM_002547.3(OPHN1):c.184C>T (p.Gln62Ter)	Pathogenic
11580	NG_008960.1:g.337629_355297del	Pathogenic
11581	NM_002547.3(OPHN1):c.644_645del (p.Val215fs)	Pathogenic
1164011	NM_002547.3(OPHN1):c.170T>A (p.Val57Asp)	Pathogenic
1164012	NM_002547.3(OPHN1):c.2159-1G>C	Pathogenic
1251919	NC_000023.11:g.68119248_68212212dup	Pathogenic
1323384	NM_002547.3(OPHN1):c.384+1G>A	Pathogenic
1326119	NM_002547.3(OPHN1):c.702+1G>A	Pathogenic
1326263	Single allele	Pathogenic
1459294	NM_002547.3(OPHN1):c.1711dup (p.Ser571fs)	Pathogenic
146620	GRCh38/hg38 Xq12(chrX:68060610-68353960)x2	Pathogenic
1526810	GRCh37/hg19 Xq12(chrX:67497166-67594258)	Pathogenic
159477	NM_002547.3(OPHN1):c.496C>T (p.Gln166Ter)	Pathogenic
1685999	NM_002547.3(OPHN1):c.597+2T>C	Pathogenic
1701065	NM_002547.3(OPHN1):c.1045C>T (p.Gln349Ter)	Pathogenic
1701603	NM_002547.3(OPHN1):c.1173del (p.Lys392fs)	Pathogenic
2006098	NM_002547.3(OPHN1):c.312+1del	Pathogenic
2424481	NC_000023.10:g.(?67494560)(67518958_?)del	Pathogenic
2700439	NM_002547.3(OPHN1):c.899dup (p.Met300fs)	Pathogenic
2825863	NM_002547.3(OPHN1):c.1010_1011del (p.Ile337fs)	Pathogenic
290595	NM_002547.3(OPHN1):c.772del (p.Gln258fs)	Pathogenic
2920720	NM_002547.2(OPHN1):c.313_326del	Pathogenic
2984577	NM_002547.3(OPHN1):c.1224C>A (p.Tyr408Ter)	Pathogenic
29934	NG_008960.1:g.224486-?_245539+?del	Pathogenic
3062529	GRCh37/hg19 Xq12(chrX:67404716-67443299)	Pathogenic
3062562	GRCh37/hg19 Xq12(chrX:67404716-67468068)	Pathogenic
3204354	NM_002547.3(OPHN1):c.2110_2111del (p.Phe704fs)	Pathogenic
3340962	NM_002547.3(OPHN1):c.1789C>T (p.Arg597Ter)	Pathogenic

SpliceAI

5750 predictions. Top by Δscore:

Variant	Effect	Δscore
X:68048458:C:CC	acceptor_gain	1.0000
X:68073148:TGAC:T	donor_loss	1.0000
X:68073149:GA:G	donor_loss	1.0000
X:68073151:C:CT	donor_loss	1.0000
X:68076965:CAGAA:C	donor_gain	1.0000
X:68096865:CATA:C	donor_loss	1.0000
X:68096866:ATACC:A	donor_loss	1.0000
X:68096867:TACC:T	donor_loss	1.0000
X:68096868:ACCT:A	donor_loss	1.0000
X:68097025:ACACA:A	acceptor_gain	1.0000
X:68097026:CACA:C	acceptor_gain	1.0000
X:68097026:CACAC:C	acceptor_gain	1.0000
X:68097027:ACA:A	acceptor_gain	1.0000
X:68097028:CA:C	acceptor_gain	1.0000
X:68097028:CAC:C	acceptor_gain	1.0000
X:68097030:C:CC	acceptor_gain	1.0000
X:68097034:C:CT	acceptor_gain	1.0000
X:68111848:ACTT:A	donor_loss	1.0000
X:68111849:CTT:C	donor_loss	1.0000
X:68111850:TT:T	donor_loss	1.0000
X:68111851:TA:T	donor_loss	1.0000
X:68111852:A:AC	donor_gain	1.0000
X:68111852:ACT:A	donor_loss	1.0000
X:68111853:C:CG	donor_gain	1.0000
X:68111853:CTTGA:C	donor_gain	1.0000
X:68111855:TG:T	donor_gain	1.0000
X:68111958:CT:C	acceptor_gain	1.0000
X:68111960:C:CC	acceptor_gain	1.0000
X:68111972:A:T	acceptor_gain	1.0000
X:68113180:C:CT	donor_gain	1.0000

AlphaMissense

5345 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:68096912:G:C	F548L	1.000
X:68096912:G:T	F548L	1.000
X:68096914:A:G	F548L	1.000
X:68096961:A:G	L532P	1.000
X:68192969:C:G	R409P	1.000
X:68192970:G:T	R409S	1.000
X:68197215:A:G	W359R	1.000
X:68197215:A:T	W359R	1.000
X:68201645:G:C	F333L	1.000
X:68201645:G:T	F333L	1.000
X:68201647:A:G	F333L	1.000
X:68206656:A:G	W284R	1.000
X:68206656:A:T	W284R	1.000
X:68212127:A:G	L228P	1.000
X:68212190:A:G	L207P	1.000
X:68212199:A:G	L204P	1.000
X:68274763:C:G	R120P	1.000
X:68274766:A:G	F119S	1.000
X:68274787:A:G	L112P	1.000
X:68283087:A:G	L94P	1.000
X:68299060:A:G	L64P	1.000
X:68299072:A:G	F60S	1.000
X:68432884:A:G	L46P	1.000
X:68432893:C:T	G43D	1.000
X:68432956:A:G	L22P	1.000
X:68096917:T:C	K547E	0.999
X:68096970:C:T	G529E	0.999
X:68096971:C:A	G529W	0.999
X:68096971:C:G	G529R	0.999
X:68096971:C:T	G529R	0.999

dbSNP variants (sampled 300 via entrez): RS1000028047 (X:68248154 C>A), RS1000029094 (X:68319923 T>C), RS1000082292 (X:68106745 T>C), RS1000082592 (X:68433470 C>T), RS1000087548 (X:68173965 A>G), RS1000097427 (X:68219488 C>T), RS1000110190 (X:68088405 G>A), RS1000111232 (X:68347737 T>G), RS1000124393 (X:68399531 G>A), RS1000163888 (X:68348170 A>C), RS1000164268 (X:68144411 A>G), RS1000169874 (X:68223647 C>A), RS1000176308 (X:68137470 T>C), RS1000199604 (X:68231003 T>G), RS1000201805 (X:68423059 T>A)

Disease associations

OMIM: gene MIM:300127 | disease phenotypes: MIM:300486, MIM:308350, MIM:213000

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked intellectual disability-cerebellar hypoplasia syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked intellectual disability-cerebellar hypoplasia syndrome	Definitive	XL

Mondo (8): X-linked intellectual disability-cerebellar hypoplasia syndrome (MONDO:0010337), congenital nervous system disorder (MONDO:0002320), genetic developmental and epileptic encephalopathy (MONDO:0100062), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), pathologic nystagmus (MONDO:0004843), oligohydramnios (MONDO:0005881), isolated cerebellar hypoplasia/agenesis (MONDO:0008939)

Orphanet (5): X-linked intellectual disability-cerebellar hypoplasia syndrome (Orphanet:137831), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000219	Thin upper lip vermilion
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000336	Prominent supraorbital ridges
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000601	Hypotelorism
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000742	Self-mutilation
HP:0000744	Low frustration tolerance
HP:0000752	Hyperactivity
HP:0000817	Reduced eye contact
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001320	Cerebellar vermis hypoplasia

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003979_8	Excessive daytime sleepiness	4.000000e-08
GCST006661_104	Male-pattern baldness	1.000000e-18
GCST006661_219	Male-pattern baldness	5.000000e-178
GCST006661_233	Male-pattern baldness	5.000000e-61
GCST006661_249	Male-pattern baldness	4.000000e-24
GCST006661_257	Male-pattern baldness	4.000000e-22
GCST006661_276	Male-pattern baldness	2.000000e-38
GCST006661_309	Male-pattern baldness	2.000000e-10
GCST007020_404	Male-pattern baldness	4.000000e-178

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007875	excessive daytime sleepiness measurement
EFO:0007825	balding measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D016104	Oligohydramnios	C12.050.703.560
C562568	Cerebellar Hypoplasia (supp.)
C537456	Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
potassium chromate(VI)	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	2
Aflatoxin B1	affects methylation, decreases expression	2
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	increases methylation	1
diallyl trisulfide	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
chromium hexavalent ion	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Irinotecan	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Antimycin A	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances