LEO1

Summary

LEO1 (LEO1 component of Paf1/RNA polymerase II complex, HGNC:30401) is a protein-coding gene on chromosome 15q21.2, encoding RNA polymerase-associated protein LEO1 (Q8WVC0). Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency.

LEO1, parafibromin (CDC73; MIM 607393), CTR9 (MIM 609366), and PAF1 (MIM 610506) form the PAF protein complex that associates with the RNA polymerase II subunit POLR2A (MIM 180660) and with a histone methyltransferase complex (Rozenblatt-Rosen et al., 2005 [PubMed 15632063]).

Source: NCBI Gene 123169 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 108 total — 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_138792

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30401
Approved symbol	LEO1
Name	LEO1 component of Paf1/RNA polymerase II complex
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166477
Ensembl biotype	protein_coding
OMIM	610507
Entrez	123169

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000299601, ENST00000315141, ENST00000558949, ENST00000924051, ENST00000924052, ENST00000971766

RefSeq mRNA: 6 — MANE Select: NM_138792 NM_001286430, NM_001323903, NM_001323904, NM_001426597, NM_001426598, NM_138792

CCDS: CCDS10146, CCDS66767

Canonical transcript exons

ENST00000299601 — 12 exons

Exon	Start	End
ENSE00001103213	51947292	51947389
ENSE00001103225	51949808	51949994
ENSE00001103317	51965749	51966504
ENSE00001103318	51962389	51962493
ENSE00001103329	51960639	51960733
ENSE00001103346	51959899	51960044
ENSE00001169697	51951844	51951979
ENSE00001169705	51953129	51953263
ENSE00001169716	51954481	51954575
ENSE00001169725	51958742	51958826
ENSE00001868211	51971688	51971778
ENSE00001939303	51938025	51938260

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 94.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.0544 / max 1937.7379, expressed in 1793 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149965	29.9833	1793
149966	0.0519	10
149967	0.0193	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	94.41	gold quality
cortical plate	UBERON:0005343	91.15	gold quality
ventricular zone	UBERON:0003053	89.60	gold quality
tendon	UBERON:0000043	89.37	gold quality
mucosa of transverse colon	UBERON:0004991	88.72	gold quality
ganglionic eminence	UBERON:0004023	88.71	gold quality
oocyte	CL:0000023	88.66	gold quality
rectum	UBERON:0001052	88.56	gold quality
islet of Langerhans	UBERON:0000006	88.21	gold quality
calcaneal tendon	UBERON:0003701	88.19	gold quality
medial globus pallidus	UBERON:0002477	87.98	gold quality
secondary oocyte	CL:0000655	87.29	gold quality
esophagus mucosa	UBERON:0002469	87.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.18	gold quality
gingival epithelium	UBERON:0001949	87.02	gold quality
stromal cell of endometrium	CL:0002255	86.36	gold quality
gingiva	UBERON:0001828	86.18	gold quality
skin of abdomen	UBERON:0001416	86.11	gold quality
minor salivary gland	UBERON:0001830	86.03	gold quality
mouth mucosa	UBERON:0003729	85.51	gold quality
cerebellar cortex	UBERON:0002129	85.28	gold quality
cerebellar hemisphere	UBERON:0002245	85.27	gold quality
gall bladder	UBERON:0002110	84.88	gold quality
endometrium	UBERON:0001295	84.82	gold quality
skin of leg	UBERON:0001511	84.81	gold quality
vermiform appendix	UBERON:0001154	84.77	gold quality
cerebellum	UBERON:0002037	84.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.59	gold quality
right adrenal gland	UBERON:0001233	84.52	gold quality
smooth muscle tissue	UBERON:0001135	84.50	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	11.69
E-MTAB-9801	yes	7.52
E-MTAB-6142	no	350.18
E-MTAB-6524	no	106.37
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting LEO1, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6750-3P	96.79	67.50	740

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• Screened glioblastomas and oligodendrogliomas for fusion genes by identifying aberrant 5’-3’ expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. (PMID:20196086)
• The results show that the Paf1/Leo1 heterodimer is necessary for its binding to histone H3, the histone octamer, and nucleosome in vitro. (PMID:24038468)
• PRL-3 and Leo1 levels were positively associated in AML patient samples. (PMID:24686170)
• Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to beta-catenin, promoting the nuclear accumulation of beta-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc (PMID:30305722)
• LEO1 is a partner for Cockayne syndrome protein B (CSB) in response to transcription-blocking DNA damage. (PMID:34096589)
• CDK12 and Integrator-PP2A complex modulates LEO1 phosphorylation for processive transcription elongation. (PMID:37205756)
• LEO1 Is Required for Efficient Entry into Quiescence, Control of H3K9 Methylation and Gene Expression in Human Fibroblasts. (PMID:38002344)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	leo1	ENSDARG00000055357
mus_musculus	Leo1	ENSMUSG00000042487
rattus_norvegicus	Leo1	ENSRNOG00000010116
drosophila_melanogaster	Atu	FBGN0019637
caenorhabditis_elegans		WBGENE00007110

Protein

Protein identifiers

RNA polymerase-associated protein LEO1 — Q8WVC0 (reviewed: Q8WVC0)

Alternative names: Replicative senescence down-regulated leo1-like protein

All UniProt accessions (1): Q8WVC0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and ‘Ser-2’- and ‘Ser-5’-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 ‘Lys-4’ (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of ‘Lys-120’ of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3’ end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Involved in polyadenylation of mRNA precursors. Connects PAF1C to Wnt signaling.

Subunit / interactions. Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8. The PAF1 complex interacts with PHF5A. Interacts with TCEA1, SUPT5H and CTNNB1. Interacts with SETD5. (Microbial infection) The PAF1 complex interacts with Zika virus French Polynesia 10087PF/2013 non-structural protein 5/NS5. The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription. (Microbial infection) The PAF1 complex interacts with Dengue virus DENV2 16681 non-structural protein 5/NS5. The PAF1 complex interacts with Dengue virus DENV4 Dominica/814669/1981 non-structural protein 5/NS5. The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in skeletal muscle and heart. Weakly expressed in placenta and liver.

Similarity. Belongs to the LEO1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WVC0-1	1	yes
Q8WVC0-2	2

RefSeq proteins (6): NP_001273359, NP_001310832, NP_001310833, NP_001413526, NP_001413527, NP_620147* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007149	Leo1	Family

Pfam: PF04004

UniProt features (61 total): modified residue 31, compositionally biased region 11, strand 10, region of interest 3, helix 3, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
9HVQ	ELECTRON MICROSCOPY	2
9MLC	ELECTRON MICROSCOPY	2.4
4M6T	X-RAY DIFFRACTION	2.5
7OOP	ELECTRON MICROSCOPY	2.9
9EGX	ELECTRON MICROSCOPY	2.9
9EGY	ELECTRON MICROSCOPY	2.9
9EGZ	ELECTRON MICROSCOPY	2.9
7OPC	ELECTRON MICROSCOPY	3
7OPD	ELECTRON MICROSCOPY	3
7UNC	ELECTRON MICROSCOPY	3
7UND	ELECTRON MICROSCOPY	3
6GMH	ELECTRON MICROSCOPY	3.1
6TED	ELECTRON MICROSCOPY	3.1
9EH2	ELECTRON MICROSCOPY	3.1
8A3Y	ELECTRON MICROSCOPY	3.3
9EH0	ELECTRON MICROSCOPY	3.6
9RTT	ELECTRON MICROSCOPY	4.01
9S3G	ELECTRON MICROSCOPY	6.4
9S0U	ELECTRON MICROSCOPY	6.72
9RZE	ELECTRON MICROSCOPY	8.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WVC0-F1	54.94	0.06

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 (31): 2, 10, 14, 66, 151, 154, 162, 171, 179, 188, 197, 205, 212, 220, 229, 238, 246, 254, 277, 279 …

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-75955	RNA Polymerase II Transcription Elongation
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses
R-HSA-9943411	CHD1 and CHD2 subfamily
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8852135	Protein ubiquitination

MSigDB gene sets: 121 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_CELL_FATE_COMMITMENT_INVOLVED_IN_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_MRNA_3_END_PROCESSING, GOBP_GASTRULATION, GOBP_ENDODERM_DEVELOPMENT, GOBP_MAINTENANCE_OF_CELL_NUMBER, GOCC_RNA_POLYMERASE_COMPLEX, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_MYELOID_CELL_DIFFERENTIATION, GOBP_ENDODERM_FORMATION, GOBP_EMBRYO_DEVELOPMENT

GO Biological Process (8): endodermal cell fate commitment (GO:0001711), transcription elongation by RNA polymerase II (GO:0006368), Wnt signaling pathway (GO:0016055), stem cell population maintenance (GO:0019827), mRNA 3’-end processing (GO:0031124), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), negative regulation of myeloid cell differentiation (GO:0045638), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (2): RNA polymerase II C-terminal domain phosphoserine binding (GO:1990269), protein binding (GO:0005515)

GO Cellular Component (5): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), centrosome (GO:0005813), Cdc73/Paf1 complex (GO:0016593)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
RNA Polymerase II Transcription	2
RNA Polymerase II Transcription Elongation	1
TCF dependent signaling in response to WNT	1
Protein ubiquitination	1
Dengue Virus-Host Interactions	1
CHD chromatin remodelers	1
Signal Transduction	1
Signaling by WNT	1
Metabolism of proteins	1
Gene expression (Transcription)	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
cellular anatomical structure	2
endodermal cell differentiation	1
cell fate commitment involved in formation of primary germ layer	1
DNA-templated transcription elongation	1
cell surface receptor signaling pathway	1
multicellular organismal process	1
maintenance of cell number	1
mRNA processing	1
RNA 3’-end processing	1
transcription elongation by RNA polymerase II	1
positive regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
positive regulation of transcription by RNA polymerase II	1
myeloid cell differentiation	1
negative regulation of cell differentiation	1
regulation of myeloid cell differentiation	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
phosphoserine residue binding	1
RNA polymerase II C-terminal domain binding	1
binding	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
transcription elongation factor complex	1
RNA polymerase II, holoenzyme	1

Protein interactions and networks

STRING

2762 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEO1	CDC73	Q6P1J9	999
LEO1	CTR9	Q6PD62	999
LEO1	RTF1	Q92541	999
LEO1	SKIC8	Q9GZS3	997
LEO1	POLR2A	P24928	832
LEO1	PAF1	Q8N7H5	787
LEO1	PHF6	Q8IWS0	731
LEO1	SUPT5H	O00267	717
LEO1	TCEA1	P23193	715
LEO1	TCEA2	Q15560	715
LEO1	TCEA3	O75764	713
LEO1	SUPT4H1	P63272	693
LEO1	SUPT16H	Q9Y5B9	667
LEO1	SUPT6H	Q7KZ85	648
LEO1	RNF20	Q5VTR2	619

IntAct

146 interactions, top by confidence:

A	B	Type	Score
PAF1	CDC73	psi-mi:“MI:0914”(association)	0.960
PAF1	LEO1	psi-mi:“MI:0915”(physical association)	0.950
LEO1	PAF1	psi-mi:“MI:0915”(physical association)	0.950
CDC73	CTR9	psi-mi:“MI:0914”(association)	0.940
CTR9	CDC73	psi-mi:“MI:0914”(association)	0.940
CDC73	CTR9	psi-mi:“MI:0915”(physical association)	0.940

BioGRID (391): LEO1 (Two-hybrid), LEO1 (Affinity Capture-MS), LEO1 (Affinity Capture-MS), LEO1 (Affinity Capture-Western), LEO1 (Affinity Capture-Western), LEO1 (Affinity Capture-MS), CDC73 (Co-fractionation), CHD2 (Co-fractionation), CTR9 (Co-fractionation), LEO1 (Co-fractionation), PAF1 (Co-fractionation), RTF1 (Co-fractionation), SSRP1 (Co-fractionation), SUPT16H (Co-fractionation), SUPT4H1 (Co-fractionation)

ESM2 similar proteins: A1CQS5, A1D3N8, A2QPM6, A3LXX5, A4QYF9, A5DLG8, A5E145, A6SMQ7, A6ZQX9, A7ER98, A7TR90, A8N7N4, B0D1Q8, F4IP06, O14210, O17917, P0CO38, P0CO39, P38439, P40019, Q05021, Q05913, Q0C807, Q0V3E0, Q10239, Q17431, Q1E4L8, Q2GNS7, Q2UBH8, Q4I327, Q4I650, Q4INZ9, Q4WJ31, Q4WRE2, Q59RN6, Q5B2V2, Q641X2, Q6C784, Q6C9G2, Q6CF40

Diamond homologs: P38439, Q17431, Q52KV5, Q54MB8, Q5R4D6, Q5XJE5, Q641X2, Q6NYV9, Q8WVC0, Q94546, Q9P6R2, Q9FNQ0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LEO1	“form complex”	PAF1C	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 110 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
Pausing and recovery of Tat-mediated HIV elongation	8	37.3×	2e-09
Tat-mediated HIV elongation arrest and recovery	8	37.3×	2e-09
HIV elongation arrest and recovery	8	35.0×	3e-09
Pausing and recovery of HIV elongation	8	35.0×	3e-09
Formation of RNA Pol II elongation complex	13	31.9×	2e-14
RNA Polymerase II Transcription Elongation	13	31.9×	2e-14
Abortive elongation of HIV-1 transcript in the absence of Tat	5	31.4×	9e-06
MicroRNA (miRNA) biogenesis	5	28.9×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
transcription elongation by RNA polymerase II	10	43.9×	1e-11
stem cell population maintenance	5	20.9×	6e-04
Wnt signaling pathway	9	8.9×	2e-04
mRNA splicing, via spliceosome	8	7.2×	2e-03
protein stabilization	9	6.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	88
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2690954	NM_138792.4(LEO1):c.607C>T (p.Gln203Ter)	Likely pathogenic

SpliceAI

2099 predictions. Top by Δscore:

Variant	Effect	Δscore
15:51947286:TCTTA:T	donor_loss	1.0000
15:51947287:CTTAC:C	donor_loss	1.0000
15:51947288:TTAC:T	donor_loss	1.0000
15:51947289:TACCT:T	donor_loss	1.0000
15:51947290:A:AC	donor_gain	1.0000
15:51947290:ACC:A	donor_loss	1.0000
15:51947291:C:CC	donor_gain	1.0000
15:51947291:CCT:C	donor_gain	1.0000
15:51947385:TTCCT:T	acceptor_gain	1.0000
15:51947386:TCCT:T	acceptor_gain	1.0000
15:51947387:CCTC:C	acceptor_gain	1.0000
15:51947388:CT:C	acceptor_gain	1.0000
15:51947390:C:CC	acceptor_gain	1.0000
15:51947390:CTGA:C	acceptor_loss	1.0000
15:51949803:CTCA:C	donor_loss	1.0000
15:51949804:TCA:T	donor_loss	1.0000
15:51949805:CAC:C	donor_loss	1.0000
15:51949806:A:AC	donor_gain	1.0000
15:51949806:ACC:A	donor_loss	1.0000
15:51949807:C:CC	donor_gain	1.0000
15:51949807:CCT:C	donor_gain	1.0000
15:51949991:CTTT:C	acceptor_gain	1.0000
15:51949992:TTT:T	acceptor_gain	1.0000
15:51949993:TT:T	acceptor_gain	1.0000
15:51949993:TTC:T	acceptor_loss	1.0000
15:51949994:TCTG:T	acceptor_loss	1.0000
15:51949995:C:CC	acceptor_gain	1.0000
15:51949995:C:CG	acceptor_loss	1.0000
15:51949996:T:A	acceptor_loss	1.0000
15:51953124:GTTA:G	donor_loss	1.0000

AlphaMissense

4494 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:51949833:T:A	K591N	1.000
15:51949833:T:G	K591N	1.000
15:51949837:A:C	I590S	1.000
15:51949837:A:G	I590T	1.000
15:51949837:A:T	I590N	1.000
15:51949846:A:G	L587S	1.000
15:51949848:G:C	S586R	1.000
15:51949848:G:T	S586R	1.000
15:51949850:T:G	S586R	1.000
15:51949942:C:G	R555P	1.000
15:51949945:C:G	R554P	1.000
15:51949955:A:G	S551P	1.000
15:51949959:C:A	R549S	1.000
15:51949959:C:G	R549S	1.000
15:51949963:C:G	R548P	1.000
15:51949964:G:T	R548S	1.000
15:51949970:A:G	S546P	1.000
15:51949973:C:G	A545P	1.000
15:51949974:C:A	R544S	1.000
15:51949974:C:G	R544S	1.000
15:51949978:A:G	L543S	1.000
15:51949981:C:G	R542P	1.000
15:51951860:C:G	R532P	1.000
15:51951861:G:T	R532S	1.000
15:51951872:G:T	P528H	1.000
15:51951893:A:G	L521S	1.000
15:51951896:A:C	I520S	1.000
15:51951896:A:G	I520T	1.000
15:51951896:A:T	I520N	1.000
15:51951898:T:A	R519S	1.000

dbSNP variants (sampled 300 via entrez): RS1000045780 (15:51966784 G>A,T), RS1000060306 (15:51967174 T>A,C), RS1000288774 (15:51943527 C>G), RS1000494044 (15:51953548 A>G), RS1000568213 (15:51958493 C>T), RS1000595696 (15:51942340 T>TC), RS1000599404 (15:51958231 G>A), RS1000662181 (15:51943779 A>G,T), RS1000858512 (15:51938578 T>G), RS1000869732 (15:51945282 C>A,T), RS1000983904 (15:51944975 A>G), RS1001103902 (15:51948333 C>G,T), RS1001135027 (15:51948072 G>C), RS1001179538 (15:51965276 T>A), RS1001240690 (15:51944901 A>G)

Disease associations

OMIM: gene MIM:610507 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Moderate	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (2): complex neurodevelopmental disorder (MONDO:0100038), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90020053_13	Frailty index	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009885	frailty measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724636 (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
7.16	Kd	69	nM	MOLIBRESIB
7.16	IC50	70	nM	MOLIBRESIB
7.03	Kd	94	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	2174625: Binding affinity to LEO1 (unknown origin) assessed as apparent dissociation constant	kd	0.0690	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
titanium dioxide	increases methylation	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Caffeine	decreases phosphorylation	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Potassium Dichromate	increases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Tunicamycin	decreases expression	1
Valproic Acid	affects expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Thapsigargin	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
CHEMBL5696855	Binding	Binding affinity to LEO1 (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)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism