CRLF2

Summary

CRLF2 (cytokine receptor like factor 2, HGNC:14281) is a protein-coding gene on chromosome Xp22.3 and Yp11.3, encoding Cytokine receptor-like factor 2 (Q9HC73). Receptor for thymic stromal lymphopoietin (TSLP).

This gene encodes a member of the type I cytokine receptor family. The encoded protein is a receptor for thymic stromal lymphopoietin (TSLP). Together with the interleukin 7 receptor (IL7R), the encoded protein and TSLP activate STAT3, STAT5, and JAK2 pathways, which control processes such as cell proliferation and development of the hematopoietic system. Rearrangement of this gene with immunoglobulin heavy chain gene (IGH) on chromosome 14, or with P2Y purinoceptor 8 gene (P2RY8) on the same X or Y chromosomes is associated with B-progenitor acute lymphoblastic leukemia (ALL) and Down syndrome ALL. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 64109 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 21 total
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_022148

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14281
Approved symbol	CRLF2
Name	cytokine receptor like factor 2
Location	Xp22.3 and Yp11.3
Locus type	gene with protein product
Status	Approved
Aliases	CRL2, TSLPR
Ensembl gene	ENSG00000205755
Ensembl biotype	protein_coding
OMIM	300357, 400023
Entrez	64109

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 nonsense_mediated_decay

ENST00000381567, ENST00000400841, ENST00000467626

RefSeq mRNA: 2 — MANE Select: NM_022148 NM_001012288, NM_022148

CCDS: CCDS75944, CCDS75945

Canonical transcript exons

ENST00000400841 — 8 exons

Exon	Start	End
ENSE00001725348	1208806	1208908
ENSE00001752466	1198562	1198724
ENSE00003746279	1193218	1193302
ENSE00003755355	1196780	1196900
ENSE00003755862	1206433	1206599
ENSE00003755992	1212556	1212649
ENSE00003756004	1202402	1202535
ENSE00003758390	1190490	1191160

Expression profiles

Bgee: expression breadth broad, 67 present calls, max score 76.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9864 / max 751.1535, expressed in 44 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198240	0.6536	40
198241	0.2671	18
198238	0.0243	5
198237	0.0215	5
198239	0.0198	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.70	gold quality
vermiform appendix	UBERON:0001154	65.40	gold quality
gall bladder	UBERON:0002110	64.38	gold quality
palpebral conjunctiva	UBERON:0001812	62.21	silver quality
myocardium	UBERON:0002349	61.83	gold quality
tendon of biceps brachii	UBERON:0008188	61.69	gold quality
hair follicle	UBERON:0002073	61.06	gold quality
caecum	UBERON:0001153	59.93	gold quality
decidua	UBERON:0002450	56.55	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	54.99	gold quality
colonic epithelium	UBERON:0000397	53.68	silver quality
smooth muscle tissue	UBERON:0001135	51.22	gold quality
parietal pleura	UBERON:0002400	51.15	gold quality
visceral pleura	UBERON:0002401	50.74	gold quality
tibia	UBERON:0000979	50.59	gold quality
nasal cavity epithelium	UBERON:0005384	50.08	gold quality
vastus lateralis	UBERON:0001379	50.05	gold quality
quadriceps femoris	UBERON:0001377	49.83	gold quality
bone marrow cell	CL:0002092	49.35	gold quality
deltoid	UBERON:0001476	49.35	gold quality
rectum	UBERON:0001052	49.04	gold quality
bone marrow	UBERON:0002371	48.95	gold quality
right lung	UBERON:0002167	48.85	gold quality
lateral globus pallidus	UBERON:0002476	48.67	gold quality
urinary bladder	UBERON:0001255	48.60	gold quality
skin of hip	UBERON:0001554	48.31	silver quality
lower esophagus muscularis layer	UBERON:0035833	48.18	gold quality
upper lobe of left lung	UBERON:0008952	48.10	gold quality
lower esophagus	UBERON:0013473	48.03	gold quality
muscle tissue	UBERON:0002385	47.74	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	8.94
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting CRLF2, 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-4481	100.00	66.42	1669
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-4501	98.72	67.19	921
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-4769-3P	97.95	68.17	1002
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-193B-5P	97.91	65.88	837
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-6855-5P	97.51	66.03	830
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-8069	97.05	66.79	718
HSA-MIR-5579-5P	96.32	68.54	730
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-3170	95.84	64.32	721
HSA-MIR-184	94.24	64.40	152
HSA-MIR-5587-3P	82.90	60.79	138

Literature-anchored findings (GeneRIF, showing 40)

• The presence of TSLP receptors is unexpectedly demonstrated on activated human CD4-positive T cells. (PMID:17513717)
• A causal role of CRLF2 overexpression in lymphoid transformation. (PMID:19641190)
• report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor acute lymphoblastic leukemia that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. (PMID:19838194)
• Activating mutation in the TSLPR gene in B-cell precursor lymphoblastic leukemia; results indicate that TSLPR activation may occur independently of a JAK2R683 mutation and that TSLPR can also be the site of a point mutation (PMID:19907440)
• Results suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways. (PMID:19965641)
• Results implicate CRLF2 as an important factor in precursor B-cell acute lymphoblastic leukemia with diagnostic, prognostic, and therapeutic implications. (PMID:20018760)
• Induced homodimerization of receptor chimeras containing the transmembrane and cytoplasmic domains of both human and mouse TSLP receptors is not sufficient for driving cell proliferation. (PMID:20096461)
• Expression of TSLP receptor was upregulated on atopic DCs primed with H22-Fel d 1 through a pathway regulated by FcgammaRI-associated signaling components. (PMID:20109752)
• human TSLP receptor requires the function of JAK1 and JAK2 for STAT activation (PMID:20128689)
• Activation of CRLF2 expression, mutation of of JAK1 or JAK2, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis. (PMID:20139093)
• Our data indicate that epithelial cells express TSLPR and that TSLP induces bronchial epithelial cell proliferation and increases injury repair through IL-13 production. (PMID:20236697)
• Study reports an extremely high incidence of relapse (71% +/- 19%) in non-high-risk precursor B-cell acute lymphoblastic leukemia patients with P2RY8-CRLF2 rearrangement. (PMID:20378752)
• The hymic stromal lymphopoietin receptor is involved in the pathogenesis of allergic asthma through the activation of human airway smooth muscle cells by t hymic stromal lymphopoietin (PMID:20483734)
• The genotype and allele frequencies of the g.33G>C and g.19646A>G of the TSLPR gene were significantly associated in the atopic asthma patients rather than in the non-atopic asthma patients (PMID:20663412)
• increased CRLF2 expression associates with JAK2 mutation, a combination that transforms hematopoietic cells, suggesting that mutant JAK2 and CRLF2 may cooperate to contribute to B-progenitor acute lymphoblastic leukemia formation [review] (PMID:20807819)
• Studies indicate that of 19 total CRLF2 breakpoints, 7 are directly at CpGs and breakpoints are much closer to CpGs than expected by random chance. (PMID:20847213)
• Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97, 52 (6%) had CRLF2-d, but it was more prevalent among Down syndrome patients (54%). (PMID:21106984)
• Integrated genomic profiling has identified potential therapeutic targets in acute lymphoblastic leukemia, including aberrant cytokine receptor signaling mediated by rearrangements and mutation of CRLF2 (PMID:21169835)
• Data indicate that overexpression of CRLF2 was not observed in adult patients with Ph-positive or T-ALL but was limited to B-ALL patients with a normal diagnostic karyotype. (PMID:21457190)
• TSLPR expression was significantly higher in the inflammatory infiltrate and in the epithelial cells of chronic rhinosinusitis with or without nasal polyps (PMID:21978707)
• review highlights the current knowledge of the incidence, prognostic significance, and biology of CRLF2-overexpressing ALL and future directions for development of targeted therapies (PMID:22150304)
• This review sums up diverse mechanisms that mediate TSLP/TSLP receptor-signalling network in chronic airway diseases. (PMID:22168549)
• CRLF2 overexpression is associated with acute lymphoblastic leukemia. (PMID:22297722)
• High CRLF2 expression is associated with a very poor outcome in high-risk, but not standard-risk, acute lymphoblastic leukemia. (PMID:22368272)
• CRLF2 overexpression is associated with acute lymphoblastic leukemia. (PMID:22382891)
• Neither CRLF2 nor JAK2 were predictors for worse prognosis in children with Down’s syndrome and acute lymphoblastic leukemia. (PMID:22441210)
• Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. (PMID:22484421)
• CRLF2-deregulation and IGH locus translocations represent distinct subtypes of adolescent and adult acute lymphoblastic leukemia. (PMID:22851563)
• CRLF2-overexpressing B-cell acute lymphoblastic leukemias have a gain-of-function CRLF2 F232C mutation or activating mutations in JAK2. (PMID:22915648)
• P2RY8-CRLF2-positive clones do not have the necessary proliferative or selective advantage to evolve into a disease-relevant relapse clone. (PMID:23091296)
• Results show no clinical or laboratory difference between those with high and low crlf2 expression (PMID:23145900)
• IKZF1 deletions and CRLF2-high expression predicted poor outcomes in patients with HR-ALL but not in patients with SR-ALL in our Japanese cohort (PMID:23804397)
• Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases. (PMID:23974192)
• both IKZF1 deletions and IGH@-CRLF2 are associated with an increased risk of treatment failure in adult acute lymphoblastic leukemia (PMID:24018820)
• Data indicate that CD66c is frequently expressed in CRLF2-positive as well as hypodiploid cases. (PMID:24231528)
• The TSLPR in blood plateltes promotes platelet activation via activating the PI3K/AKT pathway. (PMID:24356513)
• we report noncysteine in-frame mutations in IL7R and CRLF2 located in a region of the transmembrane domain closer to the cytosolic domain in acute lymphoblastic leukemias (PMID:24787007)
• CRLF2 overexpression (OE) was detected in 30 (18%) of 167 patients, the P2RY8-CRLF2 fusion was identified in only 3 (1.8%) of 167 patients, all of which demonstrated CRLF2 OE. (PMID:24935070)
• Differences exist in the genetic profiles of Down syndrome-associated acute lymphoblastic leukemia patients in Japan and in Western countries, and that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients. (PMID:25044358)
• The levels of mRNA for TSLP and TSLPR were significantly elevated in parotid gland tissues from the KD group as compared to the control group. (PMID:25676453)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	ghrb	ENSDARG00000007671
danio_rerio	il11ra	ENSDARG00000026736
danio_rerio	lifrb	ENSDARG00000039863
danio_rerio	ghra	ENSDARG00000054771
danio_rerio	lifra	ENSDARG00000098857
danio_rerio	il6r	ENSDARG00000104474
mus_musculus	Crlf2	ENSMUSG00000033467
rattus_norvegicus	Crlf2	ENSRNOG00000049828

Paralogs (23): CRLF1 (ENSG00000006016), IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223)

Protein

Protein identifiers

Cytokine receptor-like factor 2 — Q9HC73 (reviewed: Q9HC73)

Alternative names: Cytokine receptor-like 2, IL-XR, Thymic stromal lymphopoietin protein receptor

All UniProt accessions (3): A0A0C4DH06, D0E2W4, Q9HC73

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for thymic stromal lymphopoietin (TSLP). Forms a functional complex with TSLP and IL7R which is capable of stimulating cell proliferation through activation of STAT3 and STAT5. Also activates JAK2. Implicated in the development of the hematopoietic system.

Subunit / interactions. Heterodimer of CRLF2 and IL7R.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Expressed in heart, skeletal muscle, kidney and adult and fetal liver. Primarily expressed in dendrites and monocytes. Weakly expressed in T-cells.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is important for association with JAKs.

Induction. Up-regulated in activated peripheral monocytes and THP-1 cells.

Miscellaneous. The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes.

Similarity. Belongs to the type I cytokine receptor family. Type 5 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HC73-1	1	yes
Q9HC73-2	2
Q9HC73-3	3

RefSeq proteins (2): NP_001012288, NP_071431* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR048648	CRLF2-like_D2	Domain
IPR053856	TSLPR_D1	Domain

Pfam: PF21605, PF22012

UniProt features (41 total): strand 14, glycosylation site 4, sequence conflict 4, splice variant 3, helix 3, disulfide bond 2, topological domain 2, short sequence motif 2, signal peptide 1, chain 1, turn 1, transmembrane region 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5J11	X-RAY DIFFRACTION	2.56
5J12	X-RAY DIFFRACTION	3.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HC73-F1	78.46	0.53

Functional residue map

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

Disulfide bonds (2): 71–84, 180–218

Glycosylation sites (4): 47, 55, 101, 169

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1266695	Interleukin-7 signaling

MSigDB gene sets: 133 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_MAST_CELL_ACTIVATION, GOBP_MYELOID_LEUKOCYTE_ACTIVATION, GOBP_REGULATION_OF_MAST_CELL_ACTIVATION, GOBP_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_MAST_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, KEGG_JAK_STAT_SIGNALING_PATHWAY, GOCC_SIDE_OF_MEMBRANE

GO Biological Process (6): positive regulation of cell population proliferation (GO:0008284), cytokine-mediated signaling pathway (GO:0019221), positive regulation of interleukin-5 production (GO:0032754), positive regulation of mast cell activation (GO:0033005), positive regulation of receptor signaling pathway via STAT (GO:1904894), cell surface receptor signaling pathway (GO:0007166)

GO Molecular Function (4): cytokine receptor activity (GO:0004896), coreceptor activity (GO:0015026), cytokine binding (GO:0019955), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
positive regulation of cytokine production	1
interleukin-5 production	1
regulation of interleukin-5 production	1
positive regulation of leukocyte activation	1
regulation of mast cell activation	1
mast cell activation	1
positive regulation of signal transduction	1
cell surface receptor signaling pathway via STAT	1
regulation of receptor signaling pathway via STAT	1
signal transduction	1
transmembrane signaling receptor activity	1
cytokine-mediated signaling pathway	1
cytokine binding	1
immune receptor activity	1
signaling receptor activity	1
protein binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
protein-containing complex	1

Protein interactions and networks

STRING

1071 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRLF2	TSLP	Q969D9	999
CRLF2	IL7R	P16871	997
CRLF2	P2RY8	Q86VZ1	953
CRLF2	IL33	O95760	946
CRLF2	JAK2	O60674	941
CRLF2	IL7	P13232	860
CRLF2	KLK11	Q9UBX7	840
CRLF2	EPOR	P19235	766
CRLF2	CCL17	Q92583	757
CRLF2	JAK1	P23458	739
CRLF2	STAT5B	P51692	723
CRLF2	STAT5A	P42229	718
CRLF2	IKZF1	Q13422	715
CRLF2	IL1RL1	Q01638	713
CRLF2	EBF1	Q9UH73	693
CRLF2	ETV6	P41212	693

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CRLF2	METTL15	psi-mi:“MI:0914”(association)	0.350
TEX13B	ARID1A	psi-mi:“MI:0914”(association)	0.350
AKT1	CRLF2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (57): ANTXR1 (Affinity Capture-MS), PIGB (Affinity Capture-MS), UGCG (Affinity Capture-MS), HS6ST1 (Affinity Capture-MS), ARL8B (Affinity Capture-MS), BMPR1A (Affinity Capture-MS), FGFR4 (Affinity Capture-MS), ST6GALNAC3 (Affinity Capture-MS), ZDHHC13 (Affinity Capture-MS), FUT8 (Affinity Capture-MS), RNF149 (Affinity Capture-MS), MAN2A2 (Affinity Capture-MS), TAMM41 (Affinity Capture-MS), METTL15 (Affinity Capture-MS), PRKDC (Affinity Capture-MS)

ESM2 similar proteins: K7NA32, K7NAJ3, O09030, O70458, O70535, P14753, P16310, P17181, P19235, P21183, P22272, P22273, P24055, P26955, P31785, P33896, P34902, P40190, P40223, P40321, P42701, P42702, P42703, P78552, Q00560, Q04790, Q07303, Q28589, Q5XNR9, Q60837, Q65Z14, Q6PHB0, Q6UXL0, Q764M8, Q7TNI4, Q80XF5, Q8K5B1, Q8MJS1, Q8NI17, Q95118

Diamond homologs: Q8CII9, Q8R4S8, Q9HC73, P19235, Q07303, Q2KL21, Q9MYZ9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TSLP	up-regulates	CRLF2	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — LUAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

855 predictions. Top by Δscore:

Variant	Effect	Δscore
X:1206597:AATC:A	acceptor_loss	1.0000
X:1206598:ATC:A	acceptor_loss	1.0000
X:1206599:TCTG:T	acceptor_loss	1.0000
X:1206600:C:A	acceptor_loss	1.0000
X:1206600:C:CC	acceptor_gain	1.0000
X:1206601:T:C	acceptor_loss	1.0000
X:1206625:A:T	acceptor_gain	1.0000
X:1208801:CTTA:C	donor_loss	1.0000
X:1208802:TTAC:T	donor_loss	1.0000
X:1208803:TACCT:T	donor_loss	1.0000
X:1208804:A:C	donor_loss	1.0000
X:1208906:CTG:C	acceptor_gain	1.0000
X:1208909:C:CC	acceptor_gain	1.0000
X:1206595:TGAAT:T	acceptor_gain	0.9900
X:1206607:T:C	acceptor_gain	0.9900
X:1206624:C:CT	acceptor_gain	0.9900
X:1208799:CACTT:C	donor_loss	0.9900
X:1208800:ACTTA:A	donor_loss	0.9900
X:1208804:A:AC	donor_gain	0.9900
X:1208805:C:CC	donor_gain	0.9900
X:1208904:TTCTG:T	acceptor_loss	0.9900
X:1208908:GC:G	acceptor_loss	0.9900
X:1208909:C:A	acceptor_loss	0.9900
X:1208910:T:A	acceptor_loss	0.9900
X:1208914:C:CT	acceptor_gain	0.9900
X:1212552:TTACC:T	donor_loss	0.9900
X:1212555:C:CT	donor_loss	0.9900
X:1212555:CCTG:C	donor_gain	0.9900
X:1202536:C:CC	acceptor_gain	0.9800
X:1206596:GAAT:G	acceptor_gain	0.9800

AlphaMissense

2433 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
Y:1208850:C:A	W46C	0.995
Y:1208850:C:G	W46C	0.995
Y:1206531:C:G	C84S	0.993
Y:1206532:A:T	C84S	0.993
Y:1208852:A:G	W46R	0.992
Y:1208852:A:T	W46R	0.992
Y:1191155:C:A	W286C	0.991
Y:1191155:C:G	W286C	0.991
Y:1191157:A:G	W286R	0.991
Y:1191157:A:T	W286R	0.991
Y:1198605:G:C	S201R	0.991
Y:1198605:G:T	S201R	0.991
Y:1198607:T:G	S201R	0.991
Y:1202531:T:A	K118N	0.990
Y:1202531:T:G	K118N	0.990
Y:1206570:C:G	C71S	0.990
Y:1206571:A:T	C71S	0.990
Y:1206532:A:G	C84R	0.988
Y:1202498:C:A	W129C	0.987
Y:1202498:C:G	W129C	0.987
Y:1198599:C:A	W203C	0.985
Y:1198599:C:G	W203C	0.985
Y:1198606:C:A	S201I	0.984
Y:1206571:A:G	C71R	0.982
Y:1193242:A:C	F276L	0.981
Y:1193242:A:T	F276L	0.981
Y:1193244:A:G	F276L	0.981
Y:1202405:C:A	W160C	0.981
Y:1202405:C:G	W160C	0.981
Y:1202529:G:T	P119H	0.980

dbSNP variants (sampled 300 via entrez): RS10449115 (X:1203340 G>A), RS10449116 (X:1203347 T>A,C,G), RS1057519743 (X:1196852 A>C), RS111161726 (X:1211435 A>G), RS111161727 (X:1211477 A>G,T), RS111162394 (X:1200319 G>A,T), RS111162396 (X:1201553 T>A,C,G), RS111162397 (X:1211545 A>G), RS111162398 (X:1211625 A>G), RS111162399 (X:1211705 A>G), RS111163209 (X:1196218 C>A,G,T), RS111221339 (X:1200195 A>C,G), RS111221368 (X:1196135 C>T), RS111241021 (X:1202858 A>G,T), RS111251329 (X:1209400 C>T)

Disease associations

OMIM: gene MIM:300357, MIM:400023 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — IL-2 receptor family

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression	1
butyraldehyde	increases expression	1
nickel chloride	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Allergens	increases expression	1
Arsenic	affects expression	1
Latex	increases expression	1
Nickel	increases expression	1
Perfume	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases expression, increases abundance	1

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2960	IHH-4	Cancer cell line	Male
CVCL_3219	TMH-1	Cancer cell line	Male
CVCL_A085	YCUB-5	Cancer cell line	Male
CVCL_B8E3	Abcam HCT 116 CRLF2 KO	Cancer cell line	Male
CVCL_B8UC	Abcam MCF-7 CRLF2 KO	Cancer cell line	Female
CVCL_B9GB	Abcam A-549 CRLF2 KO	Cancer cell line	Male
CVCL_W276	KOPN-49	Cancer cell line	Sex unspecified

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders