AFF2

Summary

AFF2 (ALF transcription elongation factor 2, HGNC:3776) is a protein-coding gene on chromosome Xq28, encoding AF4/FMR2 family member 2 (P51816). RNA-binding protein. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a putative transcriptional activator that is a member of the AF4\FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked cognitive disability. In addition, this gene contains 6-25 GCC repeats that are expanded to >200 repeats in the disease state. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 2334 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 599 total — 23 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002025

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3776
Approved symbol	AFF2
Name	ALF transcription elongation factor 2
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	FRAXE
Ensembl gene	ENSG00000155966
Ensembl biotype	protein_coding
OMIM	300806
Entrez	2334

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000286437, ENST00000342251, ENST00000370457, ENST00000370458, ENST00000370460, ENST00000671877, ENST00000673378

RefSeq mRNA: 6 — MANE Select: NM_002025 NM_001169122, NM_001169123, NM_001169124, NM_001169125, NM_001170628, NM_002025

CCDS: CCDS14684, CCDS55521, CCDS76040, CCDS78510

Canonical transcript exons

ENST00000370460 — 21 exons

Exon	Start	End
ENSE00001255965	148500617	148501144
ENSE00001294313	148843382	148843433
ENSE00001325472	148837647	148837733
ENSE00001452771	148991211	149000663
ENSE00003777344	148966790	148967079
ENSE00003778130	148885889	148885985
ENSE00003778576	148962715	148962937
ENSE00003780142	148973471	148973607
ENSE00003780167	148980738	148980790
ENSE00003780313	148661908	148662768
ENSE00003780400	148958337	148958458
ENSE00003780456	148955603	148956613
ENSE00003780611	148977933	148978004
ENSE00003780650	148953580	148953739
ENSE00003780986	148978362	148978455
ENSE00003781749	148651999	148652131
ENSE00003781838	148842966	148843002
ENSE00003782001	148987367	148987557
ENSE00003782072	148809876	148809920
ENSE00003783249	148967629	148967692
ENSE00003783831	148904221	148904258

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 89.85.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0407 / max 89.2489, expressed in 411 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197932	0.3876	191
197931	0.3372	134
197930	0.2466	105
197933	0.0693	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	89.85	gold quality
ganglionic eminence	UBERON:0004023	86.76	gold quality
calcaneal tendon	UBERON:0003701	82.97	gold quality
ventricular zone	UBERON:0003053	79.89	gold quality
bone marrow cell	CL:0002092	76.91	gold quality
adrenal tissue	UBERON:0018303	76.63	gold quality
Brodmann (1909) area 23	UBERON:0013554	76.31	gold quality
periodontal ligament	UBERON:0008266	76.03	silver quality
tendon	UBERON:0000043	75.15	gold quality
cerebellar cortex	UBERON:0002129	74.60	gold quality
cerebellum	UBERON:0002037	74.44	gold quality
cerebellar hemisphere	UBERON:0002245	74.44	gold quality
embryo	UBERON:0000922	73.25	gold quality
right lung	UBERON:0002167	72.87	gold quality
middle temporal gyrus	UBERON:0002771	72.84	silver quality
right hemisphere of cerebellum	UBERON:0014890	72.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	71.66	gold quality
tibialis anterior	UBERON:0001385	70.99	silver quality
primary visual cortex	UBERON:0002436	70.83	gold quality
endothelial cell	CL:0000115	70.59	gold quality
sural nerve	UBERON:0015488	70.12	gold quality
prefrontal cortex	UBERON:0000451	69.99	gold quality
adenohypophysis	UBERON:0002196	69.26	gold quality
cartilage tissue	UBERON:0002418	68.61	silver quality
pituitary gland	UBERON:0000007	68.58	gold quality
gall bladder	UBERON:0002110	68.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	67.96	gold quality
paraflocculus	UBERON:0005351	67.64	gold quality
cerebellar vermis	UBERON:0004720	67.57	silver quality
endometrium epithelium	UBERON:0004811	67.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, JUN

miRNA regulators (miRDB)

260 targeting AFF2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3173-3P	99.98	66.49	1217

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 15)

• FMR1 transcripts were detected in foreskin and male fetal lung fibroblasts, while FMR2 transcripts were not. However, both FMR1 and FMR2 were found to replicate late in S phase (approximately 6 h into the S phase of normal human fibroblasts). (PMID:17196195)
• CGG/GCC repeat polymorphism at the FMR1 and FMR2 loci observed in this study demonstrated a racial and ethnic variation among the populations in India. (PMID:21254876)
• overexpression of AFF2/3/4 interferes with the organization and/or biogenesis of nuclear speckles. (PMID:21330300)
• A report of novel deletions involving AFF2 provide evidence for a new mutational spectrum, microdeletions, that are responsible for Fragile X E in a small subset of patients. (PMID:22065534)
• 2.5% of males Autism spectrum disorder patients had missense mutations in AFF2 at highly conserved evolutionary sites. (PMID:22773736)
• FMR2 is an upstream regulator of FOS and JUN, and further link deregulation of the immediate early response genes to the pathology of ID- and FRAXE-associated ID in particular. (PMID:23562910)
• Partial AFF2 microduplication in a patient with auditory processing disorder, emotional impairment and macrosomia. (PMID:25256661)
• AFF2/FMR2 regulates the transcription and toxicity of expanded G4C2 repeats in human C9ORF72-ALS/FTD neurons. (PMID:31784536)
• Circ-AFF2/miR-650/CNP axis promotes proliferation, inflammatory response, migration, and invasion of rheumatoid arthritis synovial fibroblasts. (PMID:33653372)
• DEK-AFF2 Carcinoma of the Sinonasal Region and Skull Base: Detailed Clinicopathologic Characterization of a Distinctive Entity. (PMID:34049316)
• Simultaneous Screening of the FRAXA and FRAXE Loci for Rapid Detection of FMR1 CGG and/or AFF2 CCG Repeat Expansions by Triplet-Primed PCR. (PMID:34111553)
• Development and validation in 500 female samples of a TP-PCR assay to identify AFF2 GCC expansions. (PMID:34282157)
• Nuclear expression of AFF2 C-terminus is a sensitive and specific ancillary marker for DEK::AFF2 carcinoma of the sinonasal tract. (PMID:35701667)
• [AF4/FMR2 and IL-10 gene single nucleotide polymorphisms are correlated with disease susceptibility and immune infiltration in ankylosing spondylitis]. (PMID:37313815)
• ALKBH5/YTHDF2-mediated m6A modification of circAFF2 enhances radiosensitivity of colorectal cancer by inhibiting Cullin neddylation. (PMID:37381158)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aff2	ENSDARG00000052242
mus_musculus	Aff2	ENSMUSG00000031189
rattus_norvegicus	Aff2	ENSRNOG00000052572
drosophila_melanogaster	lilli	FBGN0041111

Paralogs (3): AFF4 (ENSG00000072364), AFF3 (ENSG00000144218), AFF1 (ENSG00000172493)

Protein

Protein identifiers

AF4/FMR2 family member 2 — P51816 (reviewed: P51816)

Alternative names: Protein FMR-2, Protein Ox19

All UniProt accessions (1): P51816

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein. Might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure.

Subcellular location. Nucleus speckle.

Tissue specificity. Brain (most abundant in hippocampus and amygdala), placenta and lung.

Disease relevance. Intellectual developmental disorder, X-linked 109 (XLID109) [MIM:309548] A form of mild to moderate intellectual disability associated with learning difficulties, communication deficits, attention problems, hyperactivity, and autistic behavior. It is associated with a fragile site on chromosome Xq28. Intellectual disability is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry. It is caused either by silencing of the AFF2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene. Loss of AFF2 expression is correlated with FRAXE CCG(N) expansion. Normal individuals have 6-35 copies of the repeat, whereas cytogenetically positive, developmentally delayed males have more than 200 copies and show methylation of the associated CPG island.

Similarity. Belongs to the AF4 family.

Isoforms (7)

UniProt ID	Names	Canonical?
P51816-1	1	yes
P51816-2	2
P51816-3	3
P51816-4	4
P51816-5	5
P51816-6	6
P51816-7	7

RefSeq proteins (6): NP_001162593, NP_001162594, NP_001162595, NP_001162596, NP_001164099, NP_002016* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007797	AF4/FMR2	Family
IPR043639	AF4_int	Conserved_site
IPR043640	AF4/FMR2_CHD	Domain

Pfam: PF05110, PF18875, PF18876

UniProt features (37 total): compositionally biased region 14, splice variant 8, region of interest 7, sequence conflict 4, modified residue 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51816-F1	49.27	0.15

Functional residue map

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

Post-translational modifications (2): 430, 517

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 247 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, TAATAAT_MIR126, GOBP_COGNITION, GOBP_BEHAVIOR, MORF_MSH3, MORF_BRCA1, MORF_ESR1, MORF_RAD51L3, PUJANA_CHEK2_PCC_NETWORK, CEBP_Q2, MARTINEZ_RB1_TARGETS_DN, ATF1_Q6, GOBP_NUCLEUS_ORGANIZATION, GOBP_RNA_SPLICING, GOBP_HEAD_DEVELOPMENT

GO Biological Process (8): mRNA processing (GO:0006397), brain development (GO:0007420), learning or memory (GO:0007611), RNA splicing (GO:0008380), regulation of gene expression (GO:0010468), negative regulation of gene expression (GO:0010629), nuclear speck organization (GO:0035063), regulation of RNA splicing (GO:0043484)

GO Molecular Function (2): G-quadruplex RNA binding (GO:0002151), RNA binding (GO:0003723)

GO Cellular Component (2): nuclear speck (GO:0016607), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
gene expression	2
regulation of gene expression	2
mRNA metabolic process	1
central nervous system development	1
animal organ development	1
head development	1
behavior	1
cognition	1
regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
nuclear body organization	1
RNA splicing	1
regulation of primary metabolic process	1
RNA binding	1
nucleic acid binding	1
nuclear ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1608 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFF2	TMEM185A	Q8NFB2	950
AFF2	FMR1	Q06787	946
AFF2	ELL	P55199	677
AFF2	MLLT1	Q03111	646
AFF2	MLLT3	P42568	638
AFF2	CBL	P22681	567
AFF2	AFF3	P51826	561
AFF2	FMR1NB	Q8N0W7	558
AFF2	CCNT1	O60563	552
AFF2	FHIT	P49789	538
AFF2	KMT2A	Q03164	512
AFF2	IDS	P22304	510
AFF2	SLITRK2	Q9H156	507
AFF2	GDI1	P31150	506
AFF2	IL1RAPL1	Q9NZN1	506

IntAct

8 interactions, top by confidence:

A	B	Type	Score
tat	AHCYL1	psi-mi:“MI:0914”(association)	0.560
AFF2	CRK	psi-mi:“MI:0915”(physical association)	0.400
GRB2	AFF2	psi-mi:“MI:0915”(physical association)	0.400
NCK1	AFF2	psi-mi:“MI:0915”(physical association)	0.400
AFF2	PLCG1	psi-mi:“MI:0915”(physical association)	0.400
AFF2	KPNA4	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (9): AFF2 (Affinity Capture-MS), AFF2 (Affinity Capture-MS), AFF2 (Synthetic Lethality), AFF2 (Proximity Label-MS), AFF2 (Proximity Label-MS), AFF2 (Protein-peptide), AFF2 (Protein-RNA), AFF2 (Affinity Capture-RNA), AFF2 (Affinity Capture-MS)

ESM2 similar proteins: A0A096MK47, A0JNH1, A6H5Y1, A6NCI8, A6NFA0, A6NGG8, B2RQL2, D3Z1D3, D3ZMK9, E9Q286, E9Q309, M0RD54, O14513, P51816, Q01613, Q03172, Q05860, Q2M2Z5, Q32LN6, Q3MHH3, Q3UXL4, Q3V0A6, Q569L8, Q571I4, Q5DTX6, Q5FW52, Q5HYW2, Q5R9I1, Q5VT06, Q5VWP3, Q60988, Q66HG9, Q68DA7, Q6P1W5, Q6P9P0, Q6PAC4, Q6PG16, Q711Q0, Q7TP36, Q7TSA6

Diamond homologs: B3MLB7, B3NAM7, B4JQ42, B4KFE1, B4LV24, B4MUE1, B4NXA8, O55112, P51816, P51826, P51827, Q29KG4, Q7YQM1, Q7YQM2, Q9ESC8, Q9UHB7, Q9VQI9, P51825, O88573

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
AFF2	“up-regulates activity”	“RNA Polymerase II”	binding
P-TEFb	“down-regulates quantity by destabilization”	AFF2	phosphorylation
AFF2	“up-regulates activity”	P-TEFb	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	11
Uncertain significance	298
Likely benign	77
Benign	11

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10526	NM_001169122.2(AFF2):c.-460GCC[6_25]	Pathogenic
1180513	GRCh37/hg19 Xq27.1-28(chrX:139484271-149442579)x1	Pathogenic
1526863	GRCh37/hg19 Xq27.3-28(chrX:146752853-150192253)	Pathogenic
1526865	GRCh37/hg19 Xq28(chrX:147516497-147652015)	Pathogenic
1526866	GRCh37/hg19 Xq28(chrX:147573612-147620560)	Pathogenic
153019	GRCh38/hg38 Xq27.2-28(chrX:142602008-149482800)x1	Pathogenic
1684653	Single allele	Pathogenic
1703601	GRCh37/hg19 Xq28(chrX:147458752-147628024)	Pathogenic
1807692	GRCh37/hg19 Xq27.1-28(chrX:139504564-149382013)x2	Pathogenic
1808671	GRCh37/hg19 Xq27.1-28(chrX:139493806-148855992)x1	Pathogenic
29983	NG_016313.2:g.(5527_156380)_(156514_166289)del	Pathogenic
3274528	NM_002025.4(AFF2):c.3618_3619insA (p.Gly1207fs)	Pathogenic
4082297	NM_002025.4(AFF2):c.3476+1G>A	Pathogenic
424137	NM_002025.4(AFF2):c.3575del (p.Asn1192fs)	Pathogenic
4279015	NM_002025.4:c.1350_1397+1491del	Pathogenic
442945	GRCh37/hg19 Xq21.1-28(chrX:78230501-155233731)x1	Pathogenic
521344	NM_002025.4(AFF2):c.76A>T (p.Lys26Ter)	Pathogenic
57038	GRCh38/hg38 Xq27.3-28(chrX:146896288-149621145)x1	Pathogenic
57991	GRCh38/hg38 Xq27.1-28(chrX:139230333-150628474)x1	Pathogenic
58006	GRCh38/hg38 Xq27.3-28(chrX:147151996-150364798)x1	Pathogenic
625213	NM_002025.4(AFF2):c.3229C>T (p.Gln1077Ter)	Pathogenic
625801	GRCh37/hg19 Xq28(chrX:147642893-147870805)	Pathogenic
975105	NM_002025.4(AFF2):c.3448G>T (p.Asp1150Tyr)	Pathogenic
1327917	NM_002025.4(AFF2):c.3481C>T (p.Arg1161Ter)	Likely pathogenic
1332788	NM_002025.4(AFF2):c.2885G>A (p.Cys962Tyr)	Likely pathogenic
1526867	GRCh37/hg19 Xq28(chrX:147573781-147628228)	Likely pathogenic
2664642	NM_002025.4(AFF2):c.3128C>T (p.Thr1043Met)	Likely pathogenic
2664656	NM_002025.4(AFF2):c.1262+1G>A	Likely pathogenic
3573463	NM_002025.4(AFF2):c.1699G>T (p.Glu567Ter)	Likely pathogenic
3598108	NM_002025.4(AFF2):c.232_233delinsG (p.Tyr78fs)	Likely pathogenic

SpliceAI

5294 predictions. Top by Δscore:

Variant	Effect	Δscore
X:148501142:GTG:G	donor_gain	1.0000
X:148501145:G:GG	donor_gain	1.0000
X:148523842:G:GT	donor_gain	1.0000
X:148523843:A:T	donor_gain	1.0000
X:148651992:A:AG	acceptor_gain	1.0000
X:148651993:T:G	acceptor_gain	1.0000
X:148651995:T:G	acceptor_gain	1.0000
X:148651997:A:AG	acceptor_gain	1.0000
X:148651998:G:GG	acceptor_gain	1.0000
X:148651998:GT:G	acceptor_gain	1.0000
X:148651998:GTC:G	acceptor_gain	1.0000
X:148651998:GTCA:G	acceptor_gain	1.0000
X:148651998:GTCAC:G	acceptor_gain	1.0000
X:148662764:GTGAA:G	donor_gain	1.0000
X:148662765:TGAA:T	donor_gain	1.0000
X:148662765:TGAAG:T	donor_loss	1.0000
X:148662766:GAA:G	donor_gain	1.0000
X:148662766:GAAG:G	donor_gain	1.0000
X:148662767:AAG:A	donor_loss	1.0000
X:148662769:G:GG	donor_gain	1.0000
X:148662769:G:T	donor_loss	1.0000
X:148662770:T:A	donor_loss	1.0000
X:148809871:TTCA:T	acceptor_loss	1.0000
X:148809872:TCAG:T	acceptor_loss	1.0000
X:148809875:GGT:G	acceptor_gain	1.0000
X:148809875:GGTA:G	acceptor_gain	1.0000
X:148809875:GGTAA:G	acceptor_gain	1.0000
X:148809917:GCGG:G	donor_gain	1.0000
X:148809919:GG:G	donor_gain	1.0000
X:148809920:GG:G	donor_gain	1.0000

AlphaMissense

8674 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:148955627:T:A	W528R	1.000
X:148955627:T:C	W528R	1.000
X:148955629:G:C	W528C	1.000
X:148955629:G:T	W528C	1.000
X:148955634:T:A	L530Q	1.000
X:148955634:T:C	L530P	1.000
X:148955642:T:A	W533R	1.000
X:148955642:T:C	W533R	1.000
X:148955644:G:C	W533C	1.000
X:148955644:G:T	W533C	1.000
X:148967660:G:C	A1079P	1.000
X:148967661:C:A	A1079D	1.000
X:148967665:G:C	K1080N	1.000
X:148967665:G:T	K1080N	1.000
X:148967670:T:C	L1082P	1.000
X:148967672:A:G	K1083E	1.000
X:148967674:G:C	K1083N	1.000
X:148967674:G:T	K1083N	1.000
X:148967681:G:C	A1086P	1.000
X:148967682:C:A	A1086D	1.000
X:148967684:G:C	D1087H	1.000
X:148967684:G:T	D1087Y	1.000
X:148967685:A:T	D1087V	1.000
X:148973490:C:A	A1096D	1.000
X:148973498:T:C	Y1099H	1.000
X:148973501:G:C	A1100P	1.000
X:148973502:C:A	A1100D	1.000
X:148973507:G:C	A1102P	1.000
X:148973508:C:A	A1102D	1.000
X:148973510:G:C	A1103P	1.000

dbSNP variants (sampled 300 via entrez): RS1000003792 (X:148758230 T>C), RS1000005695 (X:148879997 C>A), RS1000037632 (X:148701091 T>C), RS1000057387 (X:148942529 A>T), RS1000063840 (X:148541330 C>T), RS1000076305 (X:148602474 G>A), RS1000080666 (X:148952660 A>G), RS1000093853 (X:148639498 A>G), RS1000101301 (X:148712061 T>G), RS1000146183 (X:148639078 C>G), RS1000165950 (X:148532365 T>C), RS1000174355 (X:148888621 A>G), RS1000181935 (X:148708799 C>G,T), RS1000203726 (X:148649916 T>C), RS1000212471 (X:148780810 C>T)

Disease associations

OMIM: gene MIM:300806 | disease phenotypes: MIM:309548, MIM:309530, MIM:618950, MIM:160700

GenCC curated gene-disease

Disease	Classification	Inheritance
FRAXE intellectual disability	Definitive	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 (6): FRAXE intellectual disability (MONDO:0010659), non-syndromic X-linked intellectual disability (MONDO:0019181), intellectual disability (MONDO:0001071), Suleiman-El-Hattab syndrome (MONDO:0033532), myopia (MONDO:0001384), primary ovarian failure (MONDO:0005387)

Orphanet (4): FRAXE intellectual disability (Orphanet:100973), X-linked non-syndromic intellectual disability (Orphanet:777), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

26 total (27 of 26 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000426	Prominent nasal bridge
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001328	Specific learning disability
HP:0001419	X-linked recessive inheritance
HP:0001511	Intrauterine growth retardation
HP:0001609	Hoarse voice
HP:0002311	Incoordination
HP:0002312	Clumsiness
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0009904	Prominent ear helix
HP:0011341	Long upper lip
HP:0012172	Stereotypical body rocking
HP:0012471	Thick vermilion border
HP:0025116	Fetal distress
HP:0100023	Recurrent hand flapping
HP:0100710	Impulsivity
HP:0000545	Myopia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST90002379_201	Basophil count	2.000000e-38
GCST90002380_71	Basophil percentage of white cells	4.000000e-14
GCST90002380_72	Basophil percentage of white cells	1.000000e-28
GCST90002380_73	Basophil percentage of white cells	7.000000e-09
GCST90002393_126	Monocyte count	2.000000e-23
GCST90002393_127	Monocyte count	8.000000e-09
GCST90002394_219	Monocyte percentage of white cells	5.000000e-25
GCST90002394_220	Monocyte percentage of white cells	5.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009216	Myopia	C11.744.636
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724735 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.27	Kd	54	nM	MOLIBRESIB
7.22	IC50	60	nM	MOLIBRESIB
7.22	Kd	60	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2174618: Binding affinity to AFF2 (unknown origin) assessed as apparent dissociation constant	kd	0.0540	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	3
Valproic Acid	affects cotreatment, increases expression	2
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	increases methylation, affects cotreatment	1
terbufos	increases methylation	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Air Pollutants	affects expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Fonofos	increases methylation	1
Methapyrilene	decreases methylation	1
Ozone	affects expression, increases abundance	1
Parathion	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases abundance, decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5696848	Binding	Binding affinity to AFF2 (unknown origin) assessed as apparent dissociation constant	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

300 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
NCT00347204	PHASE4	COMPLETED	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00349843	PHASE4	COMPLETED	Investigation of Multi-Purpose Solution-Based Corneal Staining and Ocular Comfort
NCT00349882	PHASE4	COMPLETED	Effects of Contact Lens Care Regimens on the Corneal Epithelium
NCT00350246	PHASE4	COMPLETED	Long-term Effects of Laser Refractive Surgery
NCT00404105	PHASE4	COMPLETED	A Comparison of PRK and LASIK for Correction of Myopia
NCT00455455	PHASE4	COMPLETED	Corneal and Conjunctival Sensitivity and Staining Study
NCT00541177	PHASE4	UNKNOWN	Study of Myopia Prevention in Children With Low Concentration of Atropine
NCT00627302	PHASE4	COMPLETED	Efficacy of PEG-400 and Systane Artificial Tears (Alcon) on Quality of Vision
NCT00640341	PHASE4	COMPLETED	Comparative Performance of PureVision, Acuvue Oasys and O2Optix
NCT00770094	PHASE4	UNKNOWN	Multi Laser Platform Comparison Study for LASIK
NCT00821236	PHASE4	COMPLETED	Contralateral Comparison of Three Excimer Laser Systems in Performing LASIK
NCT00889941	PHASE4	COMPLETED	Effect of Preoperative Pupil Size on Quality of Vision After Wavefront-Guided LASIK
NCT00937105	PHASE4	COMPLETED	Daily Wear Corneal Infiltrative Event Study
NCT01173198	PHASE4	COMPLETED	An Evaluation of Outcomes Following Wavefront Optimized or Wavefront Guided Lasik Procedure in Low to Moderate Myopic Patients
NCT01250925	PHASE4	COMPLETED	Effect of Contact Lens Wear on Immune Cell Density and Morphology of the Ocular Surface
NCT01387360	PHASE4	COMPLETED	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01454843	PHASE4	COMPLETED	LASIK Using the Alcon Allegretto Wavefront-Guided Excimer Laser vs AMO Visx Wavefront-Guided Excimer Laser
NCT01693939	PHASE4	COMPLETED	Evaluation of the Post-LASIK Flap Thickness of the FS200 Femtosecond Laser Flap
NCT01706237	PHASE4	WITHDRAWN	Visual Outcomes And Contrast Sensitivity After Myopic Wavefront-Optimized Lasik With Nexisvision Shield Or Bandage Contact Lens
NCT01746589	PHASE4	COMPLETED	Visual Outcomes and Contrast Sensitivity After Myopic LASIK
NCT01977807	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT02186184	PHASE4	COMPLETED	Effect of Orthokeratology Versus Spectacles on Myopia Progression in Chinese Children: A Crossover Trial
NCT02544529	PHASE4	WITHDRAWN	Echothiophate Iodide for the Prevention of Progression of Myopia
NCT03001401	PHASE4	UNKNOWN	Comparison of Next Generation Laser Techniques of Myopia Correction: iDesign vs. SMILE
NCT03158142	PHASE4	COMPLETED	The Influence of Atropine on Choroidal Thickness
NCT03544827	PHASE4	COMPLETED	The Effects of Low Dose Atropine on Choroidal Thickness
NCT03881670	PHASE4	COMPLETED	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT03949101	PHASE4	UNKNOWN	Atropine for Children and Adolescent Myopia Progression Study
NCT04208750	PHASE4	COMPLETED	Clinical Investigation of the Vision-R800 Device.
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT05357326	PHASE4	UNKNOWN	Myopia Intervention in Children and Adolescents and Establishment of a Precise Intervention Model
NCT05448989	PHASE4	UNKNOWN	Efficacy and Safety of 1% Atropine 5+3 Regimen in Children and Adolescents Controlling Myopia
NCT05449015	PHASE4	UNKNOWN	Study on the Effect of Two Ways of Cycloplegia on Biological Parameters of Ciliary Muscle
NCT05733741	PHASE4	COMPLETED	Preservative-free Topical Anesthetics for Post-PRK Pain