FBL

Summary

FBL (fibrillarin rRNA 2’-O-methyltransferase, HGNC:3599) is a protein-coding gene on chromosome 19q13.2, encoding rRNA 2’-O-methyltransferase fibrillarin (P22087). S-adenosyl-L-methionine-dependent methyltransferase that has the ability to methylate both RNAs and proteins. It is a common-essential gene (DepMap: required in 98.8% of cancer cell lines).

This gene product is a component of a nucleolar small nuclear ribonucleoprotein (snRNP) particle thought to participate in the first step in processing preribosomal RNA. It is associated with the U3, U8, and U13 small nuclear RNAs and is located in the dense fibrillar component (DFC) of the nucleolus. The encoded protein contains an N-terminal repetitive domain that is rich in glycine and arginine residues, like fibrillarins in other species. Its central region resembles an RNA-binding domain and contains an RNP consensus sequence. Antisera from approximately 8% of humans with the autoimmune disease scleroderma recognize fibrillarin.

Source: NCBI Gene 2091 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 56 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3599
Approved symbol	FBL
Name	fibrillarin rRNA 2’-O-methyltransferase
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	RNU3IP1, FLRN, FIB, Nop1
Ensembl gene	ENSG00000105202
Ensembl biotype	protein_coding
OMIM	134795
Entrez	2091

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 25 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000221801, ENST00000593503, ENST00000594309, ENST00000594443, ENST00000595545, ENST00000597224, ENST00000597634, ENST00000598417, ENST00000599134, ENST00000599159, ENST00000601274, ENST00000902419, ENST00000902420, ENST00000902421, ENST00000902422, ENST00000916308, ENST00000916309, ENST00000916310, ENST00000916311, ENST00000916312, ENST00000916313, ENST00000916314, ENST00000916315, ENST00000916316, ENST00000916317, ENST00000916318, ENST00000963401, ENST00000963402

RefSeq mRNA: 1 — MANE Select: NM_001436 NM_001436

CCDS: CCDS12545

Canonical transcript exons

ENST00000221801 — 9 exons

Exon	Start	End
ENSE00001140301	39846291	39846379
ENSE00003077582	39834458	39834562
ENSE00003463881	39834668	39834813
ENSE00003485812	39837711	39837843
ENSE00003489871	39840617	39840787
ENSE00003549570	39840233	39840327
ENSE00003678871	39840414	39840515
ENSE00003785673	39836556	39836668
ENSE00003791038	39839035	39839205

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 146.3353 / max 977.3706, expressed in 1827 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180919	141.3759	1827
180918	1.5711	768
180915	1.3505	740
180917	1.3317	726
180916	0.6815	377
180912	0.0246	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	99.42	gold quality
left ovary	UBERON:0002119	99.27	gold quality
ovary	UBERON:0000992	99.23	gold quality
cortical plate	UBERON:0005343	99.15	gold quality
right ovary	UBERON:0002118	99.13	gold quality
skin of abdomen	UBERON:0001416	99.09	gold quality
zone of skin	UBERON:0000014	99.06	gold quality
skin of leg	UBERON:0001511	99.06	gold quality
endocervix	UBERON:0000458	99.02	gold quality
ventricular zone	UBERON:0003053	98.99	gold quality
ectocervix	UBERON:0012249	98.94	gold quality
fallopian tube	UBERON:0003889	98.93	gold quality
monocyte	CL:0000576	98.91	gold quality
leukocyte	CL:0000738	98.88	gold quality
lymph node	UBERON:0000029	98.87	gold quality
body of uterus	UBERON:0009853	98.85	gold quality
body of pancreas	UBERON:0001150	98.80	gold quality
lower esophagus mucosa	UBERON:0035834	98.80	gold quality
esophagus mucosa	UBERON:0002469	98.75	gold quality
rectum	UBERON:0001052	98.74	gold quality
vagina	UBERON:0000996	98.70	gold quality
left testis	UBERON:0004533	98.68	gold quality
pancreas	UBERON:0001264	98.67	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.67	gold quality
uterine cervix	UBERON:0000002	98.66	gold quality
islet of Langerhans	UBERON:0000006	98.66	gold quality
left uterine tube	UBERON:0001303	98.66	gold quality
mucosa of transverse colon	UBERON:0004991	98.63	gold quality
granulocyte	CL:0000094	98.57	gold quality
right testis	UBERON:0004534	98.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.69
E-MTAB-9067	yes	10.37

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 17)

• Increased levels of exogenous BRAG2 in nucleoli result in redistribution of FBL to the nucleolar periphery. (PMID:17461797)
• Our data suggest that fibrillarin would play a critical role in the maintenance of nuclear shape and cellular growth. (PMID:17603021)
• Evidence that BIG1 and nucleolin, but not fibrillarin, can be present with p62 at the nuclear envelope confirms the presence of BIG1 and nucleolin in dynamic molecular complexes that change in composition while moving through nuclei (PMID:18292223)
• Data demonstrate that fibrillarin and Nop56 directly interact in vivo, and that this interaction is indispensable for the association of both proteins with the box C/D snoRNPs. (PMID:19331828)
• p32 is a new rRNA maturation factor involved in the remodeling from pre-90S particles to pre-40S and pre-60S particles that requires the exchange of FBL for Nop52. (PMID:21536856)
• NS1 protein of the human H3N2 virus interacts primarily via the C-terminal NLS2/NoLS and to a minor extent via the N-terminal NLS1 with the main nucleolar proteins, nucleolin, B23 and fibrillarin. (PMID:22909121)
• FBL overexpression contributes to tumorigenesis and is associated with poor survival in patients with breast cancer. (PMID:24029231)
• Nucleolar Methyltransferase Fibrillarin: Evolution of Structure and Functions. (PMID:27682166)
• Fibrillarin acts as a central node in a regulatory network engaged in imparting immunity against bacterial pathogens. (PMID:30190478)
• SIRT7-dependent deacetylation impacts nucleolar activity by an FBL-driven circuitry that mediates cell-cycle-dependent fluctuation of ribosomal DNA transcription. (PMID:30540930)
• This is the first report on the clinical aspect of ribosome biogenesis in pediatric BCP-ALL [B-cell precursor acute lymphoblastic leukemia ], and it shows that overexpression of CMYC and C/D box nucleoproteins FBL and NOP56 is an antecedent event in patients who subsequently relapse. (PMID:32011831)
• Fibrillarin Ribonuclease Activity is Dependent on the GAR Domain and Modulated by Phospholipids. (PMID:32384686)
• Phase transition of fibrillarin LC domain regulates localization and protein interaction of fibrillarin. (PMID:33522570)
• A PRC2-independent function for EZH2 in regulating rRNA 2’-O methylation and IRES-dependent translation. (PMID:33795875)
• Current research on viral proteins that interact with fibrillarin. (PMID:36928641)
• FBL promotes cancer cell resistance to DNA damage and BRCA1 transcription via YBX1. (PMID:37489617)
• Fibrillarin reprograms glucose metabolism by driving the enhancer-mediated transcription of PFKFB4 in liver cancer. (PMID:39182558)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbl	ENSDARG00000053912
mus_musculus	Fbl	ENSMUSG00000046865
rattus_norvegicus	Fbl	ENSRNOG00000019229
drosophila_melanogaster	Fib	FBGN0003062
drosophila_melanogaster	CG10909	FBGN0038090
caenorhabditis_elegans		WBGENE00001423

Paralogs (1): FBLL1 (ENSG00000188573)

Protein

Protein identifiers

rRNA 2’-O-methyltransferase fibrillarin — P22087 (reviewed: P22087)

Alternative names: 34 kDa nucleolar scleroderma antigen, Histone-glutamine methyltransferase, U6 snRNA 2’-O-methyltransferase fibrillarin

All UniProt accessions (9): P22087, M0QXC9, M0QXL5, M0R0P1, M0R1H0, M0R299, M0R2B0, M0R2Q4, M0R2U2

UniProt curated annotations — full annotation on UniProt →

Function. S-adenosyl-L-methionine-dependent methyltransferase that has the ability to methylate both RNAs and proteins. Involved in pre-rRNA processing by catalyzing the site-specific 2’-hydroxyl methylation of ribose moieties in pre-ribosomal RNA. Site specificity is provided by a guide RNA that base pairs with the substrate. Methylation occurs at a characteristic distance from the sequence involved in base pairing with the guide RNA. Probably catalyzes 2’-O-methylation of U6 snRNAs in box C/D RNP complexes. U6 snRNA 2’-O-methylation is required for mRNA splicing fidelity. Also acts as a protein methyltransferase by mediating methylation of ‘Gln-105’ of histone H2A (H2AQ104me), a modification that impairs binding of the FACT complex and is specifically present at 35S ribosomal DNA locus. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.

Subunit / interactions. Component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles that contain SNU13, FBL, NOP5 and NOP56, plus a guide RNA. It is associated with the U3, U8, U13, X and Y small nuclear RNAs. Component of several ribosomal and nucleolar protein complexes. Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3. Interacts with PRMT5 and UTP20. Interacts with DDX5 and C1QBP. Interacts with NOL11. Interacts with PIH1D1. Interacts with RRP1B. Interacts with NOLC1. Interacts with SDE2. Interacts with NOP2 and NOP56.

Subcellular location. Nucleus. Nucleolus. Nucleoplasm.

Post-translational modifications. Ubiquitinated. Ubiquitination leads to proteasomal degradation. Deubiquitinated by USP36. By homology to other fibrillarins, some or all of the N-terminal domain arginines are modified to asymmetric dimethylarginine (DMA). Acetylated by CREBBP/CBP, preventing methylation of ‘Gln-105’ of histone H2A (H2AQ104me), without affecting rRNA methylation. Deacetylation by SIRT7 restores methylation of ‘Gln-105’ of histone H2A (H2AQ104me).

Similarity. Belongs to the methyltransferase superfamily. Fibrillarin family.

RefSeq proteins (1): NP_001427* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000692	Fibrillarin	Family
IPR020813	Fibrillarin_CS	Conserved_site
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF01269

Catalyzed reactions (Rhea), 3 shown:

• a ribonucleotide in rRNA + S-adenosyl-L-methionine = a 2’-O-methylribonucleotide in rRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:48628)
• L-glutaminyl-[histone H2A] + S-adenosyl-L-methionine = N(5)-methyl-L-glutaminyl-[histone H2A] + S-adenosyl-L-homocysteine + H(+) (RHEA:50904)
• a ribonucleotide in U6 snRNA + S-adenosyl-L-methionine = a 2’-O-methylribonucleotide in U6 snRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:63088)

UniProt features (57 total): strand 14, modified residue 12, helix 8, cross-link 6, mutagenesis site 6, binding site 4, region of interest 2, turn 2, chain 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7SE7	X-RAY DIFFRACTION	1.75
7SE8	X-RAY DIFFRACTION	1.75
7SE9	X-RAY DIFFRACTION	1.75
7SEB	X-RAY DIFFRACTION	1.81
2IPX	X-RAY DIFFRACTION	1.82
7SEC	X-RAY DIFFRACTION	1.9
7SED	X-RAY DIFFRACTION	1.9
7SEA	X-RAY DIFFRACTION	1.91
7SE6	X-RAY DIFFRACTION	1.99
7MQA	ELECTRON MICROSCOPY	2.7
7MQ8	ELECTRON MICROSCOPY	3.6
7MQ9	ELECTRON MICROSCOPY	3.87

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22087-F1	79.11	0.61

Functional residue map

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

Ligand- & substrate-binding residues (4): 172–173; 191–192; 216–217; 236–239

Post-translational modifications (18): 21, 24, 27, 102, 116, 121, 124, 126, 205, 206, 84, 102, 109, 131, 143, 158, 8, 15

Mutagenesis-validated functional residues (6):

Position	Phenotype
102	mimics acetylation; impaired ability to methylate histone h2a; when associated with q-121 and 205-q-q-206.
102	decreased acetylation; restores ability to methylate histone h2a; when associated with r-121 and 205-r-r-206.
121	mimics acetylation; impaired ability to methylate histone h2a; when associated with q-102 and 205-q-q-206.
121	decreased acetylation; restores ability to methylate histone h2a; when associated with r-102 and 205-r-r-206.
205–206	mimics acetylation; impaired ability to methylate histone h2a; when associated with q-102 and q-121.
205–206	decreased acetylation; restores ability to methylate histone h2a; when associated with r-102 and r-121.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6790901	rRNA modification in the nucleus and cytosol
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol

MSigDB gene sets: 255 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_RIBOSOME_BIOGENESIS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, HORIUCHI_WTAP_TARGETS_DN, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_MATURATION_OF_SSU_RRNA, GOBP_SNO_S_RNA_METABOLIC_PROCESS, MORF_UBE2I, HSIAO_HOUSEKEEPING_GENES, GOBP_OSTEOBLAST_DIFFERENTIATION, USF_C, GOBP_RNA_METHYLATION, GOBP_MRNA_MODIFICATION, PUJANA_CHEK2_PCC_NETWORK, MUELLER_PLURINET

GO Biological Process (9): box C/D sno(s)RNA 3’-end processing (GO:0000494), osteoblast differentiation (GO:0001649), rRNA processing (GO:0006364), rRNA methylation (GO:0031167), ribosomal small subunit biogenesis (GO:0042274), snoRNA localization (GO:0048254), chromatin remodeling (GO:0006338), sno(s)RNA metabolic process (GO:0016074), methylation (GO:0032259)

GO Molecular Function (9): TFIID-class transcription factor complex binding (GO:0001094), RNA binding (GO:0003723), rRNA methyltransferase activity (GO:0008649), ATPase binding (GO:0051117), U6 snRNA 2’-O-ribose methyltransferase activity (GO:0180021), histone H2AQ104 methyltransferase activity (GO:1990259), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (11): fibrillar center (GO:0001650), granular component (GO:0001652), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), Cajal body (GO:0015030), membrane (GO:0016020), box C/D methylation guide snoRNP complex (GO:0031428), small-subunit processome (GO:0032040), extracellular exosome (GO:0070062), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
rRNA processing in the nucleus and cytosol	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
nucleolus	3
ribosome biogenesis	2
nuclear lumen	2
sno(s)RNA 3’-end processing	1
box C/D sno(s)RNA processing	1
ossification	1
cell differentiation	1
RNA processing	1
rRNA metabolic process	1
rRNA modification	1
RNA methylation	1
ribonucleoprotein complex biogenesis	1
RNA localization	1
chromatin organization	1
RNA metabolic process	1
metabolic process	1
RNA polymerase II general transcription initiation factor binding	1
nucleic acid binding	1
RNA methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
catalytic activity, acting on a rRNA	1
enzyme binding	1
small RNA 2’-O-ribose methyltransferase activity	1
protein-glutamine N-methyltransferase activity	1
histone H2A methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
nuclear ribonucleoprotein granule	1
box C/D RNP complex	1
preribosome	1
t-UTP complex	1
nuclear protein-containing complex	1
extracellular vesicle	1
protein-containing complex	1

Protein interactions and networks

STRING

4374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBL	NOP56	O00567	999
FBL	NOP58	Q9Y2X3	999
FBL	SNU13	P55769	997
FBL	NUCLEOLIN	P19338	990
FBL	DKC1	O60832	973
FBL	NOLC1	Q14978	955
FBL	NHP2	Q9NX24	953
FBL	RRP9	O43818	939
FBL	COIL	P38432	935
FBL	NOP10	Q9NPE3	920
FBL	UBTF	P17480	908
FBL	RRP1	P56182	895
FBL	GAR1	Q9NY12	883
FBL	NPM1	P06748	862
FBL	SMN1	Q16637	850

IntAct

240 interactions, top by confidence:

A	B	Type	Score
NOP58	FBL	psi-mi:“MI:0914”(association)	0.800
FBL	NOP56	psi-mi:“MI:0914”(association)	0.800
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DDX21	DKC1	psi-mi:“MI:0914”(association)	0.640
NEUROG3	GXYLT2	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
RRP1B	FBL	psi-mi:“MI:0915”(physical association)	0.600
FBL	NOL11	psi-mi:“MI:0915”(physical association)	0.560
FBL	ZNF792	psi-mi:“MI:0915”(physical association)	0.560
FBL	DDX5	psi-mi:“MI:0915”(physical association)	0.540
DDX5	FBL	psi-mi:“MI:0915”(physical association)	0.540
FBL	DDX5	psi-mi:“MI:0403”(colocalization)	0.540
DLD	PDHB	psi-mi:“MI:0914”(association)	0.530
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
FBL	ZNF316	psi-mi:“MI:0914”(association)	0.530
ARFGEF1	NCL	psi-mi:“MI:0914”(association)	0.500
FBL	COPS5	psi-mi:“MI:0403”(colocalization)	0.490
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (1082): FBL (Affinity Capture-RNA), FBL (Affinity Capture-RNA), FBL (Affinity Capture-RNA), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS), FBL (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5AG16, A4QEZ2, A6NHQ2, A9Q1D5, B1VGC2, B8BDQ4, C3PH19, C8VBH4, F4IF36, O83861, P13567, P15646, P22087, P22232, P22509, P34498, P35549, P35550, P35551, P35901, Q0AK69, Q22053, Q24957, Q27200, Q55CW0, Q5PAJ5, Q68FL4, Q6BQ34, Q6FN88, Q6H442, Q756P0, Q767L0, Q7S9B6, Q7URR0, Q7XTS3, Q80WS3, Q829X3, Q8FPA7, Q8I1F4, Q8SR42

Diamond homologs: A0B6X7, A1RRJ7, A3CSX5, A3DNY7, A3MV65, A4FYN1, A4WKL2, A6NHQ2, A6UV22, A6VJQ1, A9A6C8, B0R515, B1YAJ6, B6YXH6, B9LMQ1, C3MPR8, C3MYR2, C3N5E4, C3NDZ8, C3NHQ5, C4KH10, C5A403, C6A2L3, O27283, O28192, O57811, P0CW08, P0CW09, P15646, P22087, P22232, P22509, P35549, P35550, P35551, P35552, P35553, P58032, Q18H64, Q22053

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
USP36	“up-regulates quantity by stabilization”	FBL	deubiquitination
FBL	“form complex”	“U3 snoRNP”	binding
SIRT7	“up-regulates activity”	FBL	deacetylation
CREBBP	“down-regulates activity”	FBL	acetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 177 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Oncogenic MAPK signaling	5	10.7×	7e-03
SUMOylation of transcription cofactors	5	10.5×	7e-03
Activation of NF-kappaB in B cells	6	10.2×	3e-03
Formation of the ternary complex, and subsequently, the 43S complex	5	9.3×	9e-03
SARS-CoV-1-host interactions	6	9.1×	5e-03
Cellular Senescence	6	7.1×	9e-03
MAPK family signaling cascades	7	6.2×	7e-03
Major pathway of rRNA processing in the nucleolus and cytosol	10	5.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mRNA stabilization	5	12.5×	7e-03
translational initiation	5	12.2×	7e-03
rRNA processing	9	8.7×	1e-03
mRNA splicing, via spliceosome	9	5.6×	7e-03
translation	8	5.6×	9e-03
RNA splicing	9	5.4×	7e-03
positive regulation of apoptotic process	11	4.2×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	37
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1330177	GRCh37/hg19 19p13.11-q13.2(chr19:19546923-41313229)x3	Pathogenic

SpliceAI

1361 predictions. Top by Δscore:

Variant	Effect	Δscore
19:39834814:CTAA:C	acceptor_loss	1.0000
19:39836551:CGCAC:C	donor_loss	1.0000
19:39836552:GCAC:G	donor_loss	1.0000
19:39836554:A:AT	donor_loss	1.0000
19:39836555:C:CA	donor_loss	1.0000
19:39836573:AGTGT:A	donor_gain	1.0000
19:39836577:T:TA	donor_gain	1.0000
19:39836580:T:TA	donor_gain	1.0000
19:39836664:CATTG:C	acceptor_gain	1.0000
19:39836665:ATTG:A	acceptor_gain	1.0000
19:39836666:T:TC	acceptor_gain	1.0000
19:39836666:TTG:T	acceptor_loss	1.0000
19:39836667:TG:T	acceptor_gain	1.0000
19:39836669:C:CC	acceptor_gain	1.0000
19:39837746:T:TA	donor_gain	1.0000
19:39837839:CCATC:C	acceptor_gain	1.0000
19:39837840:CATC:C	acceptor_gain	1.0000
19:39837840:CATCC:C	acceptor_gain	1.0000
19:39837842:TC:T	acceptor_gain	1.0000
19:39837843:CC:C	acceptor_gain	1.0000
19:39837844:C:A	acceptor_loss	1.0000
19:39837844:C:CC	acceptor_gain	1.0000
19:39837844:C:T	acceptor_gain	1.0000
19:39837849:A:AC	acceptor_gain	1.0000
19:39839029:A:AC	donor_gain	1.0000
19:39839030:C:CC	donor_gain	1.0000
19:39839030:CT:C	donor_gain	1.0000
19:39839030:CTCA:C	donor_gain	1.0000
19:39839033:ACCGG:A	donor_loss	1.0000
19:39839101:AGC:A	donor_gain	1.0000

AlphaMissense

2045 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:39834677:C:T	G311E	1.000
19:39834678:C:G	G311R	1.000
19:39834678:C:T	G311R	1.000
19:39834683:A:T	V309D	1.000
19:39834689:G:T	A307D	1.000
19:39834690:C:G	A307P	1.000
19:39834691:A:C	H306Q	1.000
19:39834691:A:T	H306Q	1.000
19:39834692:T:C	H306R	1.000
19:39834692:T:G	H306P	1.000
19:39834693:G:A	H306Y	1.000
19:39834693:G:C	H306D	1.000
19:39834693:G:T	H306N	1.000
19:39834713:A:G	L299P	1.000
19:39834713:A:T	L299H	1.000
19:39834772:A:C	F279L	1.000
19:39834772:A:T	F279L	1.000
19:39834773:A:G	F279S	1.000
19:39834774:A:G	F279L	1.000
19:39834776:A:T	V278E	1.000
19:39834803:A:T	I269N	1.000
19:39834805:G:C	C268W	1.000
19:39834806:C:T	C268Y	1.000
19:39834807:A:G	C268R	1.000
19:39834812:G:T	A266D	1.000
19:39836556:C:A	K265N	1.000
19:39836556:C:G	K265N	1.000
19:39836557:T:A	K265M	1.000
19:39836558:T:C	K265E	1.000
19:39836558:T:G	K265Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000489231 (19:39841354 C>G,T), RS1000504195 (19:39840093 G>A,T), RS1000861057 (19:39836354 C>A,G), RS1001032503 (19:39842555 T>G), RS1001128074 (19:39836068 T>A,C), RS1001487333 (19:39841563 G>A), RS1001539491 (19:39841917 AAAC>A), RS1001614124 (19:39847240 T>C,G), RS1001658857 (19:39835224 A>T), RS1001774834 (19:39841386 G>A), RS1001799950 (19:39835539 AAAAT>A), RS1002221630 (19:39837022 A>G), RS1002403138 (19:39836946 G>A), RS1002489986 (19:39842938 C>A), RS1002540865 (19:39843275 A>T)

Disease associations

OMIM: gene MIM:134795 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): specific learning disability (MONDO:0016225)

Orphanet (1): Specific learning disability (Orphanet:211047)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000067559	Specific Learning Disorder	C10.597.606.150.550.700; C23.888.592.604.150.550.700; F03.625.374.188.700; F03.625.562.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066942 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.67	Kd	21.38	nM	CHEMBL5653589
7.67	ED50	21.38	nM	CHEMBL5653589
5.26	Kd	5444	nM	CHEMBL3752910
5.26	ED50	5444	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148377: Binding affinity to human FBL incubated for 45 mins by Kinobead based pull down assay	kd	0.0214	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148377: Binding affinity to human FBL incubated for 45 mins by Kinobead based pull down assay	kd	5.4443	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	4
bisphenol A	decreases expression	3
Arsenic	affects cotreatment, increases abundance, increases expression	2
Rotenone	increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	affects localization, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
biochanin A	increases expression	1
2,4,6-tribromophenol	decreases expression	1
deoxynivalenol	increases expression	1
lead acetate	affects localization	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
decabromobiphenyl ether	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
hydroxyhydroquinone	decreases expression	1
beta-lapachone	increases expression	1
arsenite	increases reaction, affects binding	1
tetrabromobisphenol A	increases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
didecyldimethylammonium	decreases expression	1
tetrachloroplatinate	affects localization	1
chromium hexavalent ion	decreases expression, increases abundance	1
K 7174	decreases expression	1
fenpyroximate	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
pyrimidifen	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651419	Binding	Binding affinity to human FBL incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03261076	Not specified	UNKNOWN	Reading Remediation and Outcomes in Detention
NCT04122820	Not specified	UNKNOWN	Ambulatory Screening for Specific Learning Disabilities (SLD) and Developmental Coordination Disorder (DCD).
NCT04783987	Not specified	UNKNOWN	Single and Dual Task Gait Parameters in Children With Specific Learning Difficulties
NCT05319197	Not specified	COMPLETED	HAND FUNCTIONS OF CHILDREN WITH A SPECIFIC LEARNING DISORDER
NCT05780853	Not specified	RECRUITING	A Game-based Neurodevelopmental Assessment for Young Children
NCT05787483	Not specified	COMPLETED	Biopsychosocial Outcomes of Mindfulness-based Instruction
NCT05872737	Not specified	RECRUITING	FAB Programme for Parents of Children With NDD
NCT05902143	Not specified	UNKNOWN	Fine Motor Function in Children With Specific Learning Disorders
NCT05923645	Not specified	UNKNOWN	Efficacy of rTMS as an Adjunct to AI Enabled Remedial Intervention in Children With Dyslexia
NCT05998083	Not specified	COMPLETED	The Effectiveness of Purposeful Exercises in Children Diagnosed With Special Learning Disabilities
NCT06086951	Not specified	RECRUITING	Pai.ACT - An Artificial Intelligence Driven Chatbot Assisted ACT
NCT06112483	Not specified	UNKNOWN	SWELE Program: An Unstructured Outdoor Play With Mindfulness-based Interventions to Promote Mental Health Among Students With Special Education Needs
NCT06262646	Not specified	COMPLETED	Video-conferencing FACT for Young Children With Special Needs
NCT06713863	Not specified	RECRUITING	Intervention Effectiveness Study of BEtter AT LEarning (BEATLE)- Digital Neuropsychological Rehabilitation Program
NCT06878690	Not specified	COMPLETED	Sleep Disorders in Specific Learning Disabilities
NCT07054164	Not specified	COMPLETED	Effect of Dual-Task Aerobic Exercise on Children With Specific Learning Disorder
NCT07240142	Not specified	COMPLETED	Neurotransmitter Levels in Children With Specific Learning Disorder
NCT07376902	Not specified	COMPLETED	White Noise in SLD and ADHD
NCT07488650	Not specified	NOT_YET_RECRUITING	Children With Specific Learning Disabilities and Exercise
NCT07611942	Not specified	NOT_YET_RECRUITING	Plaque Removal Efficiency in Children With Specific Learning Disabilities
NCT07611981	Not specified	NOT_YET_RECRUITING	Dental Caries and Oral Hygiene Status in Children With Specific Learning Disabilities