IL1RAPL1

Summary

IL1RAPL1 (interleukin 1 receptor accessory protein like 1, HGNC:5996) is a protein-coding gene on chromosome Xp21.3-p21.2, encoding Interleukin-1 receptor accessory protein-like 1 (Q9NZN1). May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the interleukin 1 receptor family and is similar to the interleukin 1 accessory proteins. This protein has an N-terminal signal peptide, three extracellular immunoglobulin Ig-like domains, a transmembrane domain, an intracellular Toll/IL-1R domain, and a long C-terminal tail which interacts with multiple signalling molecules. This gene is located at a region on chromosome X that is associated with a non-syndromic form of X-linked intellectual disability. Deletions and mutations in this gene were found in patients with intellectual disability. This gene is expressed at a high level in post-natal brain structures involved in the hippocampal memory system, which suggests a specialized role in the physiological processes underlying memory and learning abilities, and plays a role in synapse formation and stabilization.

Source: NCBI Gene 11141 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 418 total — 24 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 19
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014271

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5996
Approved symbol	IL1RAPL1
Name	interleukin 1 receptor accessory protein like 1
Location	Xp21.3-p21.2
Locus type	gene with protein product
Status	Approved
Aliases	OPHN4, TIGIRR-2, IL1R8, IL1RAPL-1
Ensembl gene	ENSG00000169306
Ensembl biotype	protein_coding
OMIM	300206
Entrez	11141

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000378993

RefSeq mRNA: 1 — MANE Select: NM_014271 NM_014271

CCDS: CCDS14218

Canonical transcript exons

ENST00000378993 — 11 exons

Exon	Start	End
ENSE00001013357	29399155	29399308
ENSE00001013358	29396258	29396444
ENSE00001161119	29954522	29954692
ENSE00001161126	29941651	29941794
ENSE00001161138	29919949	29920094
ENSE00001161148	29917464	29917596
ENSE00001325615	29282938	29283217
ENSE00001330704	29668430	29668504
ENSE00001479458	29955102	29956718
ENSE00001479488	28789320	28789425
ENSE00001479491	28587446	28588047

Expression profiles

Bgee: expression breadth ubiquitous, 115 present calls, max score 96.02.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2817 / max 803.8024, expressed in 399 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195819	3.3180	324
195815	1.2479	187
195816	0.2275	88
209642	0.1878	91
195820	0.1395	67
195818	0.0886	49
195831	0.0460	18
195817	0.0265	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.02	gold quality
endothelial cell	CL:0000115	90.37	gold quality
corpus callosum	UBERON:0002336	89.59	gold quality
middle temporal gyrus	UBERON:0002771	88.43	gold quality
secondary oocyte	CL:0000655	86.56	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	85.92	gold quality
inferior olivary complex	UBERON:0002127	85.77	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.77	gold quality
entorhinal cortex	UBERON:0002728	83.23	gold quality
postcentral gyrus	UBERON:0002581	82.31	gold quality
parietal lobe	UBERON:0001872	81.56	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.22	gold quality
inferior vagus X ganglion	UBERON:0005363	80.73	gold quality
orbitofrontal cortex	UBERON:0004167	80.07	gold quality
medial globus pallidus	UBERON:0002477	79.91	gold quality
oocyte	CL:0000023	79.81	gold quality
superior frontal gyrus	UBERON:0002661	79.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.26	gold quality
globus pallidus	UBERON:0001875	78.47	gold quality
primary visual cortex	UBERON:0002436	78.05	gold quality
occipital lobe	UBERON:0002021	77.98	gold quality
CA1 field of hippocampus	UBERON:0003881	76.76	gold quality
ventral tegmental area	UBERON:0002691	76.30	gold quality
subthalamic nucleus	UBERON:0001906	75.67	gold quality
dorsal plus ventral thalamus	UBERON:0001897	75.32	gold quality
cranial nerve II	UBERON:0000941	74.98	gold quality
medulla oblongata	UBERON:0001896	74.68	gold quality
lateral nuclear group of thalamus	UBERON:0002736	72.82	gold quality
superior vestibular nucleus	UBERON:0007227	69.76	gold quality
sural nerve	UBERON:0015488	69.24	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	11885.06
E-HCAD-30	yes	10372.49
E-HCAD-35	yes	9967.92
E-HCAD-25	yes	6651.78
E-ANND-3	yes	4.38

Regulation

Is transcription factor: no

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 20)

• crystal structure at 2.3-A resolution of the TIR domain of IL-1RAPL (PMID:15123616)
• Nearly all patients with deletions involving DAX1, but not DMD, had mental retardation if IL1RAPL1 was deleted. If ILIRAPLI & DMD were intact, the patients with DAX1 deletions only rarely had normal development. (PMID:15300857)
• Report confirms the role of the IL1RAPL1 gene in causing nonspecific mental retardation in males. (PMID:16470793)
• DMD gene and its immediately distal neighbor, the 1.8 Mb IL1RAPL1 gene are abundantly expressed in normal brain but were dramatically underexpressed in every brain tumor cell line and xenograft. (PMID:18253029)
• Combined data suggested that IL1RAPL1 affected human cognitive ability to some extent, especially the memory and concentration capability. (PMID:18467032)
• The function of truncated IL1RAPL1 protein in an autistic female with Asperger syndrome is severely altered in hippocampal neurons, demonstrated by its effect on neurite outgrowth activity. (PMID:18801879)
• IL1RAPL1 plays an important role in the etiology of X-linked mental retardation. (PMID:19012350)
• Intragenic deletions in IL1RAPL1are relevant to the pathogenesis of X-linked mental retardation. (PMID:21271657)
• The IL1RAPL1 gene is of interest as a candidate gene for autism spectrum disorder as mutations or deletions in the gene have previously been reported in individuals from families with ASD. (PMID:21491612)
• The interaction of the IL1RAPL1 family of proteins with PTPdelta and RhoGAP2 reveals a pathophysiological mechanism of cognitive impairment associated with a novel type of trans-synaptic signaling. (PMID:21926414)
• Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis. (PMID:25305082)
• It was indicated that a defect in IL1RAPL1 that controls excitatory synapsis formation results in the excitation-inhibition balance affecting various cerebral functions. (PMID:25864829)
• Altered DNA methylation in IL1RAPL1 involves in the etiology of Bipolar disorder and Major Depressive disorder . (PMID:27440233)
• Our study expands the molecular repertoire of IL1RAPL1 mutations in intellectual disability and points out the need of more accurate clinical descriptions to better define the related phenotype (PMID:27470653)
• rs12007907 variant in IL1RAPL gene was negatively associated with asthma and IL-13 production in Latin American children. (PMID:28120837)
• IL-1R8 serves as a checkpoint for NK cell maturation and effector function; its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection in mice (PMID:29072292)
• Our study revealed that the expression of IL-1R8 significantly increased on in vitro-activated CD4+ T cells and was markedly higher on CD4+ T cells from allergic rhinitis patients than on cells from healthy controls. (PMID:29730558)
• The mutations and deletion of IL1RAPL1 gene are related to different phenotypes (even in the same family and in patients with the same mutation) including different severity of Intellectual Disability. (PMID:30548231)
• RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias. (PMID:36318984)
• IL-1R8 expression in DLBCL regulates NK cell recruitment and influences patient prognosis. (PMID:37907630)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	il1rapl1a	ENSDARG00000062045
danio_rerio	il1rapl1b	ENSDARG00000104853
mus_musculus	Il1rapl1	ENSMUSG00000052372
rattus_norvegicus	Il1rapl1	ENSRNOG00000029663

Paralogs (10): LAG3 (ENSG00000089692), IL1R2 (ENSG00000115590), IL1R1 (ENSG00000115594), IL1RL2 (ENSG00000115598), IL1RL1 (ENSG00000115602), IL18R1 (ENSG00000115604), IL18RAP (ENSG00000115607), SIGIRR (ENSG00000185187), IL1RAPL2 (ENSG00000189108), IL1RAP (ENSG00000196083)

Protein

Protein identifiers

Interleukin-1 receptor accessory protein-like 1 — Q9NZN1 (reviewed: Q9NZN1)

Alternative names: Oligophrenin-4, Three immunoglobulin domain-containing IL-1 receptor-related 2, X-linked interleukin-1 receptor accessory protein-like 1

All UniProt accessions (2): Q9NZN1, X5DNQ7

UniProt curated annotations — full annotation on UniProt →

Function. May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel. May activate the MAP kinase JNK. Plays a role in neurite outgrowth. During dendritic spine formation can bidirectionally induce pre- and post-synaptic differentiation of neurons by trans-synaptically binding to PTPRD.

Subunit / interactions. Homodimer. Interacts (calcium-independent) with NCS1. Interacts (via the first immunoglobilin domain) with PTPRD (via the second immunoglobilin domain); this interaction is PTPRD-splicing-dependent and induces pre- and post-synaptic differentiation of neurons and is required for IL1RAPL1-mediated synapse formation.

Subcellular location. Cell membrane. Cytoplasm. Cell projection. Axon. Dendrite.

Tissue specificity. Detected at low levels in heart, skeletal muscle, ovary, skin, amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra and thalamus. Detected at very low levels in tonsil, prostate, testis, small intestine, placenta, colon and fetal liver.

Disease relevance. Intellectual developmental disorder, X-linked 21 (XLID21) [MIM:300143] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic intellectual disability presents with associated physical, neurological and/or psychiatric manifestations. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.

Similarity. Belongs to the interleukin-1 receptor family.

Isoforms (1)

UniProt ID	Names	Canonical?
Q9NZN1-1	1	yes

RefSeq proteins (1): NP_055086* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000157	TIR_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015621	IL-1_rcpt_fam	Family
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR041416	IL-1RAcP-like_ig	Domain

Pfam: PF00047, PF01582, PF18452

Catalyzed reactions (Rhea), 1 shown:

• NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:16301)

UniProt features (77 total): strand 30, helix 15, glycosylation site 6, disulfide bond 5, sequence variant 4, domain 4, turn 3, region of interest 2, topological domain 2, signal peptide 1, chain 1, compositionally biased region 1, active site 1, site 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4M92	X-RAY DIFFRACTION	1.6
1T3G	X-RAY DIFFRACTION	2.3
5WY8	X-RAY DIFFRACTION	3.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZN1-F1	77.13	0.44

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 (2): 491; 34 (essential for interaction with ptprd)

Disulfide bonds (5): 31–126, 53–118, 143–185, 164–216, 267–334

Glycosylation sites (6): 63, 122, 138, 213, 264, 331

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-388844	Receptor-type tyrosine-protein phosphatases
R-HSA-9007892	Interleukin-38 signaling
R-HSA-112316	Neuronal System
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-446652	Interleukin-1 family signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 298 (showing top): GOBP_DENDRITE_DEVELOPMENT, CREL_01, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, PAX4_01, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, CMYB_01, TTTGTAG_MIR520D, AREB6_03, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_EXOCYTOSIS

GO Biological Process (12): cell surface receptor signaling pathway (GO:0007166), regulation of neuron projection development (GO:0010975), neuron differentiation (GO:0030182), negative regulation of exocytosis (GO:0045920), positive regulation of synapse assembly (GO:0051965), positive regulation of dendritic spine morphogenesis (GO:0061003), presynaptic membrane assembly (GO:0097105), regulation of postsynapse organization (GO:0099175), trans-synaptic signaling by trans-synaptic complex (GO:0099545), synaptic membrane adhesion (GO:0099560), regulation of presynapse assembly (GO:1905606), signal transduction (GO:0007165)

GO Molecular Function (4): signaling receptor binding (GO:0005102), NAD+ nucleosidase activity, cyclic ADP-ribose generating (GO:0061809), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), postsynaptic membrane (GO:0045211), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Interleukin-1 family signaling	1
Immune System	1
Signaling by Interleukins	1
Cytokine Signaling in Immune system	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of synapse assembly	2
presynapse assembly	2
neuron projection	2
signal transduction	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
cell differentiation	1
generation of neurons	1
exocytosis	1
regulation of exocytosis	1
negative regulation of secretion by cell	1
synapse assembly	1
positive regulation of nervous system development	1
positive regulation of cell junction assembly	1
positive regulation of neuron projection development	1
positive regulation of dendrite morphogenesis	1
dendritic spine morphogenesis	1
positive regulation of dendritic spine development	1
regulation of dendritic spine morphogenesis	1
membrane assembly	1
presynaptic membrane organization	1
regulation of synapse organization	1
postsynapse organization	1
trans-synaptic signaling	1
synapse organization	1
cell-cell adhesion	1
regulation of presynapse organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein binding	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL1RAPL1	NCS1	P36610	978
IL1RAPL1	PTPRS	Q13332	874
IL1RAPL1	LRFN4	Q6PJG9	752
IL1RAPL1	PTPRD	P23468	751
IL1RAPL1	DLG4	P78352	719
IL1RAPL1	SLITRK3	O94933	715
IL1RAPL1	LRRC4B	Q9NT99	697
IL1RAPL1	SLITRK2	Q9H156	678
IL1RAPL1	PI4KB	P78405	676
IL1RAPL1	SLC16A2	P36021	646
IL1RAPL1	VSNL1	P28677	639
IL1RAPL1	PTPRF	P10586	636
IL1RAPL1	CADPS	Q9ULU8	636
IL1RAPL1	KCND1	Q9NSA2	634
IL1RAPL1	NTRK3	Q16288	627

IntAct

8 interactions, top by confidence:

A	B	Type	Score
IL1RAPL1	PTPRS	psi-mi:“MI:0915”(physical association)	0.540
IL1RAPL1	PTPRS	psi-mi:“MI:0407”(direct interaction)	0.540
IL1RAPL1	PILRB	psi-mi:“MI:0915”(physical association)	0.400
IL1RAPL1	PTPRD	psi-mi:“MI:0915”(physical association)	0.400
CFTR		psi-mi:“MI:0914”(association)	0.350

BioGRID (10): IL1RAPL1 (Two-hybrid), PTPRD (Affinity Capture-Western), ARHGAP22 (Two-hybrid), ARHGAP22 (Reconstituted Complex), IL1RAPL1 (Reconstituted Complex), NCS1 (Reconstituted Complex), NCS1 (Affinity Capture-Western), IL1RAPL1 (Proximity Label-MS), IL1RAPL1 (Affinity Capture-MS), IL1RAPL1 (Affinity Capture-MS)

ESM2 similar proteins: A0M8S8, A3KNS9, B5DFM7, B6ZK76, E9Q9F6, G5E8Q8, O54767, O55006, O73798, P06213, P0DP43, P15127, P15208, P20239, P59823, P59824, P60029, P84329, Q00PJ8, Q07081, Q07E01, Q07E37, Q07E48, Q25410, Q5EG71, Q5SY80, Q6DE92, Q6P7N7, Q6UW88, Q6UX71, Q6X782, Q6X784, Q6X786, Q7YQL9, Q86XM0, Q8BZT5, Q8IZF2, Q8N2E2, Q8SXT3, Q924X1

Diamond homologs: B6ZK76, B6ZK77, P08953, P59822, P59823, P59824, P60029, Q61730, Q63621, Q7YQL9, Q9ERS6, Q9NP60, Q9NPH3, Q9NZN1, P22366, Q13478, Q4V892, Q6IA17, Q6Y1S1, Q9JLZ8, A8QMS7, B2LT61, B2LT62, B2LT64, B2LT65, B3SRQ2, B3Y613, B3Y614, B3Y615, B3Y618, B5T267, C8BKC7, O60603, P27930, Q0GC71, Q0ZUL9, Q15399, Q2PZH4, Q2V897, Q599T9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IL1RAPL1	“up-regulates activity”	NCS1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	26
Uncertain significance	181
Likely benign	90
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11480	NM_014271.4(IL1RAPL1):c.1377C>A (p.Tyr459Ter)	Pathogenic
11482	NG_008292.2:g.(?707879)(1040749_?)del	Pathogenic
144544	GRCh38/hg38 Xp22.33-11.21(chrX:10701-58055053)x1	Pathogenic
1678121	NM_014271.4(IL1RAPL1):c.1239dup (p.Val414fs)	Pathogenic
235849	NM_014271.4(IL1RAPL1):c.894_903del (p.Trp299fs)	Pathogenic
2446468	GRCh37/hg19 Xp21.3-21.2(chrX:28983262-29783445)x1	Pathogenic
2497799	NM_014271.4(IL1RAPL1):c.555C>A (p.Cys185Ter)	Pathogenic
2685702	GRCh37/hg19 Xp21.3(chrX:28493281-29234189)x1	Pathogenic
280601	NM_014271.4(IL1RAPL1):c.703+1G>A	Pathogenic
29944	NG_008292.1:g.700375-?_1335033+?del	Pathogenic
3246718	NC_000023.10:g.(?29414355)(29417445_?)del	Pathogenic
4532187	NM_014271.4(IL1RAPL1):c.1027C>T (p.Arg343Ter)	Pathogenic
4622044	NM_014271.4(IL1RAPL1):c.660T>A (p.Tyr220Ter)	Pathogenic
4683019	GRCh37/hg19 Xp21.3(chrX:28780078-28893971)x0	Pathogenic
4683024	GRCh37/hg19 Xp21.3-21.2(chrX:29007766-29734333)x0	Pathogenic
564810	GRCh37/hg19 Xp21.3-21.2(chrX:29154202-29881444)x1	Pathogenic
564812	GRCh37/hg19 Xp21.2(chrX:29400224-29721917)x0	Pathogenic
58611	GRCh38/hg38 Xp21.3(chrX:28759823-29094411)x2	Pathogenic
58612	GRCh38/hg38 Xp21.2(chrX:29713271-29740951)x3	Pathogenic
59242	GRCh38/hg38 Xp21.3-21.2(chrX:29128906-29515069)x1	Pathogenic
59254	GRCh38/hg38 Xp21.3-21.2(chrX:29207382-29910715)x0	Pathogenic
620044	NM_014271.4(IL1RAPL1):c.1191_1201+6del	Pathogenic
620223	NM_014271.4(IL1RAPL1):c.1054C>T (p.Arg352Ter)	Pathogenic
813316	GRCh37/hg19 Xp21.2(chrX:29686547-29686621)	Pathogenic
1098368	NM_014271.4(IL1RAPL1):c.1046T>C (p.Leu349Pro)	Likely pathogenic
11481	NM_014271.4(IL1RAPL1):c.1460G>A (p.Trp487Ter)	Likely pathogenic
1174094	NM_014271.4(IL1RAPL1):c.1891_1897del (p.Asp631fs)	Likely pathogenic
1184891	NM_014271.4(IL1RAPL1):c.1372+1G>T	Likely pathogenic
1299178	NM_014271.4(IL1RAPL1):c.1354_1355del (p.Asp452fs)	Likely pathogenic
1320221	NM_014271.4(IL1RAPL1):c.1075del (p.Glu359fs)	Likely pathogenic

SpliceAI

4307 predictions. Top by Δscore:

Variant	Effect	Δscore
X:28718441:T:A	acceptor_gain	1.0000
X:28789306:A:AG	acceptor_gain	1.0000
X:28789307:A:G	acceptor_gain	1.0000
X:28789308:T:G	acceptor_gain	1.0000
X:28789312:T:A	acceptor_gain	1.0000
X:28789315:TTTA:T	acceptor_loss	1.0000
X:28789316:TTAG:T	acceptor_loss	1.0000
X:28789317:TAGG:T	acceptor_loss	1.0000
X:28789318:A:AG	acceptor_gain	1.0000
X:28789318:AG:A	acceptor_gain	1.0000
X:28789318:AGG:A	acceptor_gain	1.0000
X:28789319:G:A	acceptor_gain	1.0000
X:28789319:G:GG	acceptor_gain	1.0000
X:28789319:GGG:G	acceptor_gain	1.0000
X:28789319:GGGA:G	acceptor_gain	1.0000
X:28789319:GGGAA:G	acceptor_gain	1.0000
X:28789423:CCGG:C	donor_loss	1.0000
X:28789426:G:GG	donor_gain	1.0000
X:28604227:A:AG	acceptor_gain	0.9900
X:28604228:G:GG	acceptor_gain	0.9900
X:28718438:T:TA	acceptor_gain	0.9900
X:28718446:A:G	acceptor_gain	0.9900
X:28815282:G:GT	donor_gain	0.9900
X:28842983:C:T	donor_gain	0.9900
X:28876273:G:T	donor_gain	0.9900
X:28959099:G:GG	donor_gain	0.9900
X:28971224:A:G	donor_gain	0.9900
X:28604299:GT:G	donor_gain	0.9800
X:28619039:G:GT	donor_gain	0.9800
X:28718452:A:G	acceptor_gain	0.9800

AlphaMissense

4582 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:29282946:T:A	C31S	1.000
X:29282947:G:C	C31S	1.000
X:29283012:T:A	C53S	1.000
X:29283012:T:C	C53R	1.000
X:29283013:G:A	C53Y	1.000
X:29283013:G:C	C53S	1.000
X:29283014:T:G	C53W	1.000
X:29283081:T:A	W76R	1.000
X:29283081:T:C	W76R	1.000
X:29283083:G:C	W76C	1.000
X:29283083:G:T	W76C	1.000
X:29283207:T:C	C118R	1.000
X:29283208:G:A	C118Y	1.000
X:29283209:T:G	C118W	1.000
X:29668451:C:A	P242H	1.000
X:29917484:T:A	C267S	1.000
X:29917484:T:C	C267R	1.000
X:29917485:G:A	C267Y	1.000
X:29917485:G:C	C267S	1.000
X:29917486:C:G	C267W	1.000
X:29917532:T:A	W283R	1.000
X:29917532:T:C	W283R	1.000
X:29917533:G:C	W283S	1.000
X:29917534:G:C	W283C	1.000
X:29917534:G:T	W283C	1.000
X:29920037:T:A	C334S	1.000
X:29920037:T:C	C334R	1.000
X:29920038:G:A	C334Y	1.000
X:29920038:G:C	C334S	1.000
X:29920039:T:G	C334W	1.000

dbSNP variants (sampled 300 via entrez): RS1000001344 (X:29363200 A>G), RS1000006858 (X:28617158 A>G), RS1000008067 (X:28897554 A>G), RS1000010657 (X:29754162 G>A), RS1000011817 (X:29506705 T>C,G), RS1000012889 (X:29130121 A>G), RS1000012995 (X:29494414 A>G), RS1000015867 (X:28990302 A>G), RS1000016701 (X:29869726 T>C), RS1000018606 (X:29339761 G>C), RS1000026956 (X:29926812 G>A), RS1000028792 (X:29218382 C>T), RS1000029588 (X:29833231 A>G), RS1000030479 (X:28863364 C>T), RS1000037198 (X:28768478 T>C)

Disease associations

OMIM: gene MIM:300206 | disease phenotypes: MIM:300143, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 21	Definitive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Definitive	XL

Mondo (5): intellectual disability, X-linked 21 (MONDO:0010256), schizophrenia (MONDO:0005090), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (4): X-linked non-syndromic intellectual disability (Orphanet:777), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

19 total (20 of 19 shown, HPO-id order):

HPO	Term
HP:0000053	Macroorchidism
HP:0000194	Open mouth
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000486	Strabismus
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys
HP:0000678	Dental crowding
HP:0000717	Autism
HP:0000752	Hyperactivity
HP:0001250	Seizure
HP:0001382	Joint hypermobility
HP:0001419	X-linked recessive inheritance
HP:0001611	Hypernasal speech
HP:0002342	Moderate intellectual disability
HP:0003196	Short nose
HP:0009909	Uplifted earlobe
HP:0010804	Tented upper lip vermilion
HP:0100710	Impulsivity
HP:0100753	Schizophrenia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000789_3	Cardiovascular risk factors (age interaction)	1.000000e-07
GCST004785_27	Vitiligo	7.000000e-10
GCST004865_37	Itch intensity from mosquito bite adjusted by bite size	6.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008007	age at assessment
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
(+)-JQ1 compound	decreases expression, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
sotorasib	affects cotreatment, decreases expression	1
ethylbenzene	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation, increases methylation	1
benzo(e)pyrene	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
mirdametinib	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
trametinib	decreases expression, affects cotreatment	1
MT19c compound	increases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	decreases expression	1
Methapyrilene	increases methylation	1
Phthalic Acids	decreases methylation	1
Smoke	decreases expression	1
Toluene	affects cotreatment, decreases expression	1
Xylenes	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1WV	SHCDNi004-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety