FRG1

Summary

FRG1 (FSHD region gene 1, HGNC:3954) is a protein-coding gene on chromosome 4q35.2, encoding Protein FRG1 (Q14331). Binds to mRNA in a sequence-independent manner.

This gene maps to a location 100 kb centromeric of the repeat units on chromosome 4q35 which are deleted in facioscapulohumeral muscular dystrophy (FSHD). It is evolutionarily conserved and has related sequences on multiple human chromosomes but DNA sequence analysis did not reveal any homology to known genes. In vivo studies demonstrate the encoded protein is localized to the nucleolus.

Source: NCBI Gene 2483 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 106 total — 5 pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004477

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3954
Approved symbol	FRG1
Name	FSHD region gene 1
Location	4q35.2
Locus type	gene with protein product
Status	Approved
Aliases	FSG1, FRG1A
Ensembl gene	ENSG00000109536
Ensembl biotype	protein_coding
OMIM	601278
Entrez	2483

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000226798, ENST00000505327, ENST00000507103, ENST00000514482, ENST00000524583, ENST00000531991, ENST00000533157, ENST00000711580, ENST00000711581, ENST00000896233, ENST00000896234, ENST00000940554, ENST00000940555, ENST00000965223

RefSeq mRNA: 1 — MANE Select: NM_004477 NM_004477

CCDS: CCDS34121

Canonical transcript exons

ENST00000226798 — 9 exons

Exon	Start	End
ENSE00002435152	189960748	189960839
ENSE00003463981	189955037	189955151
ENSE00003534566	189943202	189943272
ENSE00003576006	189953068	189953125
ENSE00003577067	189952162	189952287
ENSE00003694079	189961822	189961932
ENSE00003785530	189957398	189957502
ENSE00004016057	189963093	189963192
ENSE00004016059	189940872	189941071

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 97.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.2183 / max 975.0310, expressed in 1816 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50973	39.8940	1816
50974	0.3243	146
50972	0.0001	0

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.32	gold quality
ganglionic eminence	UBERON:0004023	96.16	gold quality
embryo	UBERON:0000922	96.15	gold quality
monocyte	CL:0000576	95.61	gold quality
leukocyte	CL:0000738	95.49	gold quality
lymph node	UBERON:0000029	95.20	gold quality
ventricular zone	UBERON:0003053	95.15	gold quality
placenta	UBERON:0001987	94.96	gold quality
descending thoracic aorta	UBERON:0002345	94.86	gold quality
smooth muscle tissue	UBERON:0001135	94.84	gold quality
tibial artery	UBERON:0007610	94.82	gold quality
popliteal artery	UBERON:0002250	94.81	gold quality
mucosa of stomach	UBERON:0001199	94.79	gold quality
cortical plate	UBERON:0005343	94.65	gold quality
tibial nerve	UBERON:0001323	94.60	gold quality
endometrium	UBERON:0001295	94.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.41	gold quality
thoracic mammary gland	UBERON:0005200	94.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.30	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.27	gold quality
body of uterus	UBERON:0009853	94.24	gold quality
left coronary artery	UBERON:0001626	94.22	gold quality
left ovary	UBERON:0002119	94.12	gold quality
ovary	UBERON:0000992	94.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.11	gold quality
corpus callosum	UBERON:0002336	94.10	gold quality
lower esophagus	UBERON:0013473	94.10	gold quality
uterus	UBERON:0000995	94.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.07	gold quality
bone marrow	UBERON:0002371	93.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.19

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 18)

• FRG1 transgenic mice develop a muscular dystrophy with features characteristic of the human disease; by contrast, FRG2 and ANT1 transgenic mice seem normal (PMID:16341202)
• differently from normal myoblasts, the 4qA/B marker interacted directly with the promoters of the FRG1 and ANT1 genes in Facio-Scapulo-Humeral Dystrophy cells (PMID:18852887)
• Data show that frg1 is expressed in and essential for the development of the tadpole musculature, and suggest that maintenance of normal FRG1 levels is critical for proper muscle development in frogs and humans. (PMID:19097195)
• study compared chromatin structure & tridimensional interaction of the D4Z4 array and FRG1 gene promoter, and FRG1 expression, in control and FSHD cells (PMID:19607661)
• in muscle FRG1 is a developmentally regulated sarcomeric protein suggesting FRG1 may perform a muscle-specific function (PMID:20970242)
• depressed myoblast proliferation may contribute to the pathology of mice overexpressing FRG1 and may play a part in facioscapulohumeral muscular dystrophy (PMID:21603621)
• new insights into the gene deregulation characterizing both FSHD-1 and FSHD-2, in which miRNAs may play a role (PMID:21695143)
• These data provide the first biochemical activities (actin binding and RNA binding) for human FRG1 and the characterization of the endogenous human FRG1, together indicating that FRG1 is involved in multiple aspects of RNA biogenesis. (PMID:21699900)
• This study suggests a novel role of FRG1 as epigenetic regulator of muscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis. (PMID:23720823)
• Study showed that the variability in clinical severity of facioscapulohumeral muscular dystrophy in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. (PMID:25256356)
• Our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to Facioscapulohumeral muscular dystrophy. (PMID:25326393)
• Penetrance of FSHD1 is low for largest alleles in the range of 9-10 RUs, and lower in women than men. (PMID:25603992)
• FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype (PMID:25695429)
• Immunohistochemistry analysis showed reduced FRG1 levels in tumors which were supported by in silico analysis data. These findings suggest that reduction in FRG1 expression in gastric, colon and oral cavity tumor might have a role in tumor progression, by regulating cell migration and invasiveness. To elucidate a better understanding of molecular signaling involving FRG1 in angiogenesis regulation, further study is requir (PMID:28947680)
• Mutations in FRG1 and KMT2C were found to be associated with a younger age especially after correcting for tobacco smoking and sex in Chinese patients with lung adenocarcinoma. (PMID:30821106)
• FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation. (PMID:30975102)
• Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model. (PMID:34795329)
• Unveiling FRG1’s DNA repair role in breast cancer. (PMID:39169067)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	frg1	ENSDARG00000056504
mus_musculus	Frg1	ENSMUSG00000031590
rattus_norvegicus	Frg1-ps1	ENSRNOG00000000964
rattus_norvegicus	Frg1	ENSRNOG00000009846
drosophila_melanogaster	FRG1	FBGN0036964
caenorhabditis_elegans		WBGENE00014177

Paralogs (1): (ENSG00000273748)

Protein

Protein identifiers

Protein FRG1 — Q14331 (reviewed: Q14331)

Alternative names: FSHD region gene 1 protein

All UniProt accessions (6): Q14331, A0AAA9YHY9, E9PI42, E9PLY7, E9PRR7, J3KSQ7

UniProt curated annotations — full annotation on UniProt →

Function. Binds to mRNA in a sequence-independent manner. May play a role in regulation of pre-mRNA splicing or in the assembly of rRNA into ribosomal subunits. May be involved in mRNA transport. May be involved in epigenetic regulation of muscle differentiation through regulation of activity of the histone-lysine N-methyltransferase KMT5B.

Subunit / interactions. Homodimer and homotetramer in solution. Identified in the spliceosome C complex. Interacts with KMT5B (via C-terminus). Interacts (via N-terminus) with KPNA2 and NXF1/TAP. Interacts with F-actin with a stoichiometry of 2:1. Interacts with GARIN3, SMN1 and PABPN1.

Subcellular location. Nucleus. Cajal body. Nucleolus. Cytoplasm. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed in adult muscle, lymphocytes, fetal brain, muscle, and placenta. Also expressed in the smooth muscle of arteries and veins, the sweat glands and the epidermis.

Disease relevance. Facioscapulohumeral muscular dystrophy 1 (FSHD1) [MIM:158900] A degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. The gene represented in this entry may be involved in disease pathogenesis. Overexpression of human FRG1 in mice leads to development of facioscapulohumeral muscular dystrophy (FSHD1)-like symptoms such as kyphosis, progressive muscle dystrophy and skeletal muscle atrophy. It also causes aberrant pre-mRNA splicing of TNNT3 and MTMR1, affects the localization and activity of KMT5B, and leads to increased levels of EID3, resulting in inhibited muscle differentiation. These results suggest that FSHD1 results from inappropriate overexpression of FRG1 which leads to abnormal alternative splicing of specific pre-mRNAs.

Similarity. Belongs to the FRG1 family.

RefSeq proteins (1): NP_004468* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008999	Actin-crosslinking	Homologous_superfamily
IPR010414	FRG1	Family

Pfam: PF06229

UniProt features (7 total): short sequence motif 2, helix 2, chain 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6ZYM	ELECTRON MICROSCOPY	3.4
8I0W	ELECTRON MICROSCOPY	3.4
7A5P	ELECTRON MICROSCOPY	5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14331-F1	75.15	0.23

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 244 (showing top): GOBP_RIBOSOME_BIOGENESIS, PUJANA_CHEK2_PCC_NETWORK, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, chr4q35, GOBP_RNA_SPLICING, GOMF_ACTIN_BINDING, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, MORF_MT4, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, GCM_ACTG1, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_DN, GOCC_I_BAND, GOCC_U2_TYPE_SPLICEOSOMAL_COMPLEX

GO Biological Process (6): mRNA splicing, via spliceosome (GO:0000398), rRNA processing (GO:0006364), muscle organ development (GO:0007517), mRNA processing (GO:0006397), RNA splicing (GO:0008380), ribosome biogenesis (GO:0042254)

GO Molecular Function (4): RNA binding (GO:0003723), actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (8): nucleolus (GO:0005730), Cajal body (GO:0015030), Z disc (GO:0030018), striated muscle dense body (GO:0055120), catalytic step 2 spliceosome (GO:0071013), nucleus (GO:0005634), spliceosomal complex (GO:0005681), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	3
cellular anatomical structure	3
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
animal organ development	1
muscle structure development	1
mRNA metabolic process	1
ribonucleoprotein complex biogenesis	1
nucleic acid binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
nuclear ribonucleoprotein granule	1
I band	1
contractile muscle fiber	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
intracellular membrane-bounded organelle	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRG1	FRG2	Q64ET8	987
FRG1	DUX4L2	P0CJ85	928
FRG1	MTMR1	Q13613	781
FRG1	TNNT3	P45378	763
FRG1	NUCLEOLIN	P19338	622
FRG1	FAM149A	A5PLN7	581
FRG1	YY1	P25490	580
FRG1	KLKB1	P03952	576
FRG1	RBMXL1	Q96E39	553
FRG1	TRIML1	Q8N9V2	547
FRG1	TRIML2	Q8N7C3	513
FRG1	SLC25A4	P12235	510
FRG1	SNRPF	P62306	510
FRG1	MYOD1	P15172	503
FRG1	LSM6	P62312	499

IntAct

48 interactions, top by confidence:

A	B	Type	Score
SART3	PRPF4	psi-mi:“MI:0914”(association)	0.730
FRG1	KRT40	psi-mi:“MI:0915”(physical association)	0.560
FRG1	EXOSC8	psi-mi:“MI:0915”(physical association)	0.560
LZTS2	FRG1	psi-mi:“MI:0915”(physical association)	0.560
KRT40	FRG1	psi-mi:“MI:0915”(physical association)	0.560
EXOSC8	FRG1	psi-mi:“MI:0915”(physical association)	0.560
FRG1	LZTS2	psi-mi:“MI:0915”(physical association)	0.560
FRG1	GNMT	psi-mi:“MI:0915”(physical association)	0.560
FRG1	CWC22	psi-mi:“MI:0915”(physical association)	0.510
CWC22	FRG1	psi-mi:“MI:0915”(physical association)	0.510
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
FRG1	CFAP418	psi-mi:“MI:0915”(physical association)	0.370
RBPMS	FRG1	psi-mi:“MI:0915”(physical association)	0.370
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
CFTR	POTEF	psi-mi:“MI:0914”(association)	0.350
LIN28A	MEX3A	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
SF3B1	RBM10	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): EXOSC8 (Two-hybrid), LZTS2 (Two-hybrid), KRT40 (Two-hybrid), UBE2O (Affinity Capture-MS), FRG1 (Proximity Label-MS), FRG1 (Proximity Label-MS), FRG1 (Two-hybrid), FRG1 (Affinity Capture-MS), FRG1 (Affinity Capture-MS), FRG1 (Affinity Capture-MS), FRG1 (Affinity Capture-MS), FRG1 (Affinity Capture-MS), FRG1 (Affinity Capture-MS), FRG1 (Affinity Capture-MS), FRG1 (Proximity Label-MS)

ESM2 similar proteins: A0JMQ0, A2VE39, A2VEI2, B3MIF1, D2HRF1, O18282, O60870, O70400, O73747, P09874, P11103, P18493, P26446, P27008, P31669, P52944, P97376, Q02892, Q0VA16, Q14331, Q17Q06, Q1JQD4, Q1MTD3, Q24498, Q28Z41, Q498D9, Q5R981, Q5RHR0, Q5U2Z5, Q68EV5, Q6FRV0, Q6GLS8, Q6GPP0, Q6GQ76, Q74ZK6, Q803R5, Q8CCP0, Q8K224, Q8K339, Q8N1G2

Diamond homologs: O18282, O73747, P97376, Q14331, Q6GLS8, Q9VWA8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FRG1	“down-regulates activity”	KMT5B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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
mRNA Splicing - Minor Pathway	5	32.0×	5e-05
mRNA Splicing - Major Pathway	11	17.2×	6e-09
mRNA Splicing	5	15.7×	7e-04
CHD1 and CHD2 subfamily	5	15.5×	7e-04
mRNA Polyadenylation	6	15.1×	2e-04
Dengue Virus-Host Interactions	11	14.4×	2e-08
Processing of Capped Intron-Containing Pre-mRNA	6	14.1×	2e-04
Metabolism of RNA	7	8.3×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
mRNA splicing, via spliceosome	9	17.9×	7e-07
RNA splicing	6	11.5×	2e-03
mRNA processing	6	10.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	56
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
146880	GRCh38/hg38 4q35.2(chr4:189792437-190018234)x1	Pathogenic
153176	GRCh38/hg38 4q35.2(chr4:189588653-190036318)	Pathogenic
1696825	NM_004477.3(FRG1):c.322G>A (p.Ala108Thr)	Pathogenic
242851	GRCh37/hg19 4q35.2(chr4:188498590-190915650)x1	Pathogenic
635958	Single allele	Pathogenic

SpliceAI

1188 predictions. Top by Δscore:

Variant	Effect	Δscore
4:189941069:GAG:G	donor_gain	1.0000
4:189941071:GGTG:G	donor_loss	1.0000
4:189941072:G:GA	donor_loss	1.0000
4:189953063:A:AG	acceptor_gain	1.0000
4:189953066:A:AG	acceptor_gain	1.0000
4:189953067:G:GA	acceptor_gain	1.0000
4:189955028:A:AG	acceptor_gain	1.0000
4:189955028:AAT:A	acceptor_gain	1.0000
4:189955029:A:G	acceptor_gain	1.0000
4:189955030:T:G	acceptor_gain	1.0000
4:189955030:T:TA	acceptor_gain	1.0000
4:189955032:TACAG:T	acceptor_loss	1.0000
4:189955034:C:G	acceptor_gain	1.0000
4:189955035:A:AG	acceptor_gain	1.0000
4:189955036:G:GT	acceptor_gain	1.0000
4:189955036:GA:G	acceptor_gain	1.0000
4:189955036:GAA:G	acceptor_gain	1.0000
4:189955036:GAAT:G	acceptor_gain	1.0000
4:189955036:GAATC:G	acceptor_gain	1.0000
4:189955147:AAAAT:A	donor_gain	1.0000
4:189955148:AAAT:A	donor_gain	1.0000
4:189955149:AAT:A	donor_gain	1.0000
4:189955150:AT:A	donor_gain	1.0000
4:189955150:ATG:A	donor_loss	1.0000
4:189955151:TGT:T	donor_loss	1.0000
4:189955152:G:GG	donor_gain	1.0000
4:189955152:GTAA:G	donor_loss	1.0000
4:189955153:T:A	donor_loss	1.0000
4:189957393:CTTA:C	acceptor_loss	1.0000
4:189957394:TTA:T	acceptor_loss	1.0000

AlphaMissense

1715 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:189955131:T:A	W138R	1.000
4:189955131:T:C	W138R	1.000
4:189961829:T:C	F213L	1.000
4:189961831:T:A	F213L	1.000
4:189961831:T:G	F213L	1.000
4:189963095:G:C	R248T	1.000
4:189963096:A:C	R248S	1.000
4:189963096:A:T	R248S	1.000
4:189955049:G:C	K110N	0.999
4:189955049:G:T	K110N	0.999
4:189955093:T:A	V125D	0.999
4:189955098:G:A	G127R	0.999
4:189955098:G:C	G127R	0.999
4:189955098:G:T	G127W	0.999
4:189955099:G:A	G127E	0.999
4:189955110:G:C	A131P	0.999
4:189955117:G:A	G133E	0.999
4:189961838:T:C	F216L	0.999
4:189961840:C:A	F216L	0.999
4:189961840:C:G	F216L	0.999
4:189961923:T:C	L244P	0.999
4:189961926:T:C	L245P	0.999
4:189963108:A:C	K252N	0.999
4:189963108:A:T	K252N	0.999
4:189963112:G:C	D254H	0.999
4:189963113:A:T	D254V	0.999
4:189963114:C:A	D254E	0.999
4:189963114:C:G	D254E	0.999
4:189963116:G:C	R255T	0.999
4:189963117:A:C	R255S	0.999

dbSNP variants (sampled 300 via entrez): RS1000090727 (4:189951773 T>C,G), RS10001956 (4:189945400 C>A,T), RS1000366802 (4:189940790 C>G,T), RS1000419021 (4:189940941 G>A,C,T), RS10007357 (4:189958292 C>T), RS1000852990 (4:189950837 A>G), RS1000905356 (4:189951124 T>C), RS1001322127 (4:189944599 G>A,T), RS10018452 (4:189943798 A>T), RS1001928762 (4:189943267 T>A,C,G), RS1002039866 (4:189956185 T>C), RS1002454598 (4:189956383 TTAGA>T), RS1002455832 (4:189962502 G>A), RS1002556728 (4:189962706 A>G), RS1002642771 (4:189953921 T>A)

Disease associations

OMIM: gene MIM:601278 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): neurodevelopmental disorder (MONDO:0700092), CIC-rearranged sarcoma (MONDO:0956989)

Orphanet (0):

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000298	Mask-like facies
HP:0000407	Sensorineural hearing impairment
HP:0000491	Keratitis
HP:0000509	Conjunctivitis
HP:0000541	Retinal detachment
HP:0000544	External ophthalmoplegia
HP:0000572	Visual loss
HP:0000767	Pectus excavatum
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001288	Gait disturbance
HP:0001538	Protuberant abdomen
HP:0002015	Dysphagia
HP:0002091	Restrictive ventilatory defect
HP:0002093	Respiratory insufficiency
HP:0002359	Frequent falls
HP:0002650	Scoliosis
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003307	Hyperlordosis
HP:0003323	Progressive muscle weakness
HP:0003325	Limb-girdle muscle weakness
HP:0003376	Steppage gait
HP:0003458	EMG: myopathic abnormalities
HP:0003547	Shoulder girdle muscle weakness
HP:0003677	Slowly progressive
HP:0003691	Scapular winging
HP:0003724	Shoulder girdle muscle atrophy
HP:0004673	Decreased facial expression

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002126_22	Periodontitis (CDC/AAP)	7.000000e-07
GCST004796_3	Brain volume in infants (cerebrospinal fluid)	6.000000e-07
GCST006463_9	Urinary albumin excretion (no hypertensive medication)	3.000000e-21
GCST006586_14	Urinary albumin excretion	1.000000e-33

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004285	albuminuria

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): CHEMBL5724682 (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

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

pChembl	Type	Value	Unit	Molecule
5.17	IC50	6720	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 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	2178863: Inhibition of FRG1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	6.7200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, increases reaction	1
zinc chromate	increases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
Temozolomide	decreases expression	1
Air Pollutants	increases abundance, affects expression	1
Copper	affects binding, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Disulfiram	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Urethane	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Gold Compounds	decreases expression	1
Volatile Organic Compounds	affects expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697593	Binding	Inhibition of FRG1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

205 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
NCT02389244	PHASE2	ACTIVE_NOT_RECRUITING	A Phase II Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas
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
NCT06414434	PHASE1	ACTIVE_NOT_RECRUITING	BTX-A51 in Patients With Liposarcoma or CIC-rearranged Sarcoma
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