FGD1

Summary

FGD1 (FYVE, RhoGEF and PH domain containing 1, HGNC:3663) is a protein-coding gene on chromosome Xp11.22, encoding FYVE, RhoGEF and PH domain-containing protein 1 (P98174). Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that contains Dbl (DH) and pleckstrin (PH) homology domains and is similar to the Rho family of small GTP-binding proteins. The encoded protein specifically binds to the Rho family GTPase Cdc42Hs and can stimulate the GDP-GTP exchange of the isoprenylated form of Cdc42Hs. It also stimulates the mitogen activated protein kinase cascade leading to c-Jun kinase SAPK/JNK1 activation. Defects in this gene are the cause of the faciogenital dysplasia in Aarskog-Scott syndrome and a syndromatic form of X-linked cognitive disability.

Source: NCBI Gene 2245 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Aarskog-Scott syndrome, X-linked (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 590 total — 52 pathogenic, 33 likely-pathogenic
• Phenotypes (HPO): 94
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004463

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3663
Approved symbol	FGD1
Name	FYVE, RhoGEF and PH domain containing 1
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Aliases	ZFYVE3
Ensembl gene	ENSG00000102302
Ensembl biotype	protein_coding
OMIM	300546
Entrez	2245

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000375135, ENST00000934019, ENST00000934020, ENST00000934021, ENST00000934022

RefSeq mRNA: 1 — MANE Select: NM_004463 NM_004463

CCDS: CCDS14359

Canonical transcript exons

ENST00000375135 — 18 exons

Exon	Start	End
ENSE00000671580	54447311	54447454
ENSE00000671581	54448806	54448967
ENSE00000671582	54449143	54449268
ENSE00000671583	54449659	54449760
ENSE00000671584	54450271	54450301
ENSE00000671585	54455448	54455527
ENSE00000671588	54456220	54456366
ENSE00000671590	54456509	54456567
ENSE00000671592	54465451	54465589
ENSE00000671594	54465696	54465852
ENSE00000671596	54467784	54467932
ENSE00000671598	54468787	54468876
ENSE00000671599	54470016	54470457
ENSE00000671600	54470583	54470760
ENSE00000671601	54471314	54471487
ENSE00001228999	54455692	54455784
ENSE00001465866	54445454	54446414
ENSE00001465909	54495126	54496234

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 86.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.5063 / max 109.6849, expressed in 1398 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199393	3.0172	1176
199394	2.5090	1093
199396	2.5067	1066
199395	1.1223	699
199392	0.3510	168

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	86.74	gold quality
stromal cell of endometrium	CL:0002255	83.84	gold quality
ganglionic eminence	UBERON:0004023	81.73	gold quality
ventricular zone	UBERON:0003053	81.55	gold quality
embryo	UBERON:0000922	80.47	gold quality
cartilage tissue	UBERON:0002418	78.66	gold quality
postcentral gyrus	UBERON:0002581	76.59	silver quality
entorhinal cortex	UBERON:0002728	74.90	silver quality
parietal lobe	UBERON:0001872	74.51	silver quality
prefrontal cortex	UBERON:0000451	74.20	gold quality
superior frontal gyrus	UBERON:0002661	73.47	gold quality
right ovary	UBERON:0002118	73.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.62	gold quality
body of uterus	UBERON:0009853	72.37	gold quality
right coronary artery	UBERON:0001625	72.09	gold quality
pancreatic ductal cell	CL:0002079	72.05	silver quality
frontal cortex	UBERON:0001870	72.05	gold quality
ectocervix	UBERON:0012249	71.96	gold quality
popliteal artery	UBERON:0002250	71.82	gold quality
tibial artery	UBERON:0007610	71.80	gold quality
left ovary	UBERON:0002119	71.67	gold quality
neocortex	UBERON:0001950	71.53	gold quality
cervix squamous epithelium	UBERON:0006922	71.39	gold quality
aorta	UBERON:0000947	71.38	gold quality
apex of heart	UBERON:0002098	71.35	gold quality
descending thoracic aorta	UBERON:0002345	71.11	gold quality
right adrenal gland cortex	UBERON:0035827	71.11	gold quality
endocervix	UBERON:0000458	70.98	gold quality
right adrenal gland	UBERON:0001233	70.97	gold quality
thoracic aorta	UBERON:0001515	70.93	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-36552	no	28.79
E-ANND-3	no	1.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting FGD1, 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-8485	100.00	77.57	4731
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5010-3P	99.83	70.60	2357

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 29)

• non-syndromal X-linked mental retardation were found to have a novel missense mutation in FGD1 (PMID:11940089)
• alleles include one with an extra exon in intron 8 and one with an extra exon in intron 7, both with premature termination (PMID:15327482)
• a novel target of the SCF(FWD1/beta-TrCP) ubiquitin ligase (PMID:15743413)
• Neurobehavioral disorders are described in two unrelated boys with Aarskog-Scott syndrome affected by novel FGD1 mutations. (PMID:16688726)
• Brain cortex malformations such as PMG could be initiated by mutations in the evolutionary conserved RhoGEF domain of FGD1, by perturbing the signaling via Rho GTPases (PMID:17847065)
• First case of the faciogenital dysplasia 1 (FGD1) gene in a patient with Aarskog-Scott syndrome. (PMID:19110080)
• Findings suggest a central role for Fgd1 in the focal degradation of the ECM in vitro and, for the first time, show a connection between Fgd1 and cancer progression, proposing that it might function during tumorigenesis. (PMID:19141649)
• FGD1 is preferentially associated with the trans-Golgi network (TGN), suggesting its involvement in export of proteins from the Golgi. (PMID:19261807)
• analysis of nine novel mutations of the FGD1 gene in Aarskog-Scott syndrome (PMID:20082460)
• Mutations in the FGD1 gene is not associated with Aarskog syndrome. (PMID:20607856)
• This study showed that the proline-rich doman of FGD1 is critical for persistent cell migration; FGD1 also augments EGF-stimulated c-Jun NH(2)-terminal kinase (JNK) activation. (PMID:21212517)
• These results demonstrate an important role for FGD1/Cdc42 signaling in human mesenchymal stem cells osteogenesis. (PMID:21356349)
• This is the first report of inheritance by germline mosaicism for the FGD1 gene (PMID:21739585)
• Authors discuss the hypothesis that FGD1 might be an important regulator of events controlling extracellular matrix remodelling and possibly cell invasion in physiological and pathological settings. (PMID:22854039)
• The faciogenital dysplasia 1 (FGD1)gene encodes for a protein involved in skeletal and neuronal development. (PMID:22876573)
• branch point variant in FGD1 identified by exome sequencing in Aarskog-Scott syndrome (PMID:23169394)
• A novel mutation in exon 6 (G1341A substituting tryptophan with a stop codon at amino acid position 447) may have influenced the clinical phenotype of these 5 patients with Aarskog-Scott syndrome. (PMID:23211637)
• Mutational analyses revealed a novel mutation (c.308-2G), hemizygous in the boy and heterozygous in the mother with Aarskog syndrome. (PMID:23443263)
• No significant association was observed between IDD and allele or genotype frequencies, or the haplotype of the 5 SNPs of the FGD1 gene in the Chinese population. (PMID:24446295)
• Results identify a novel mutation of FDG1 in a family with Aarskog syndrome and underscore the phenotypical variability of this condition. (PMID:24770546)
• Sequencing analyses in numerous types of cancer have found missense mutations in the FGD1 gene in metastatic tumors. (PMID:27199457)
• Splice site mutation of FGD1 gene is associated with Aarskog-Scott syndrome patient with a large anterior fontanel. (PMID:27544718)
• A novel variant in FGD1 (a novel hemizygous mutation in FGD1 c.53del (p.Pro18Argfs*106) for which the mother is heterozygous) was found in an Emirati family with two brothers suffering from Aarskog-Scott syndrome. The variant is predicted to be a null mutation, and this is the first report of its kind from the United Arab Emirates. (PMID:28103835)
• FGD1 promotes tumor progression and regulates tumor immune response in osteosarcoma via inhibiting PTEN activity. (PMID:32194840)
• Xp11.22 duplications in four unrelated Chinese families: delineating the genotype-phenotype relationship for HSD17B10 and FGD1. (PMID:32381089)
• Intersection of TKS5 and FGD1/CDC42 signaling cascades directs the formation of invadopodia. (PMID:32673397)
• A novel truncating variant in the FGD1 gene associated with Aarskog-Scott syndrome in a family previously diagnosed with Tel Hashomer camptodactyly. (PMID:34145742)
• Silencing FYVE, RhoGEF, and PH domain containing 1 (FGD1) suppresses melanoma progression by inhibiting PI3K/AKT signaling pathway. (PMID:34783295)
• Novel truncating variants in FGD1 detected in two Danish families with Aarskog-Scott syndrome and myopathic features. (PMID:35388608)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgd1	ENSDARG00000100402
mus_musculus	Fgd1	ENSMUSG00000025265
rattus_norvegicus	Fgd1	ENSRNOG00000038970
caenorhabditis_elegans		WBGENE00001366
caenorhabditis_elegans		WBGENE00001490

Paralogs (10): FARP2 (ENSG00000006607), FGD3 (ENSG00000127084), ARHGEF39 (ENSG00000137135), FGD4 (ENSG00000139132), FGD2 (ENSG00000146192), FARP1 (ENSG00000152767), FGD5 (ENSG00000154783), FRMD7 (ENSG00000165694), FGD6 (ENSG00000180263), ECT2L (ENSG00000203734)

Protein

Protein identifiers

FYVE, RhoGEF and PH domain-containing protein 1 — P98174 (reviewed: P98174)

Alternative names: Faciogenital dysplasia 1 protein, Rho/Rac guanine nucleotide exchange factor FGD1, Zinc finger FYVE domain-containing protein 3

All UniProt accessions (1): P98174

UniProt curated annotations — full annotation on UniProt →

Function. Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Plays a role in regulating the actin cytoskeleton and cell shape.

Subunit / interactions. Interacts with DBNL/ABP1 and CTTN. May interact with CCPG1. Binds CDC42.

Subcellular location. Cytoplasm. Cell projection. Lamellipodium. Ruffle. Cytoskeleton.

Tissue specificity. Expressed in fetal heart, brain, lung, kidney and placenta. Less expressed in liver; adult heart, brain, lung, pancreas and skeletal muscle.

Disease relevance. Aarskog-Scott syndrome (AAS) [MIM:305400] An X-linked recessive, rare multisystemic disorder characterized by disproportionately short stature, and by facial, skeletal and urogenital anomalies. Some patients manifest intellectual disability, attention deficit disorder and hyperactivity. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The DH domain is involved in interaction with CCPG1.

RefSeq proteins (1): NP_004454* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000306	Znf_FYVE	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR035939	FGD1_PH1	Domain
IPR035941	FGD1-4_PH2	Domain
IPR051092	FYVE_RhoGEF_PH	Family

Pfam: PF00169, PF00621, PF01363

UniProt features (40 total): compositionally biased region 11, binding site 8, sequence variant 6, modified residue 4, domain 3, region of interest 3, sequence conflict 2, chain 1, zinc finger region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98174-F1	66.18	0.30

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 (8): 736; 739; 753; 756; 761; 764; 782; 785

Post-translational modifications (4): 48, 205, 711, 715

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-9013148	CDC42 GTPase cycle

MSigDB gene sets: 326 (showing top): GOBP_REGULATION_OF_CELL_MORPHOGENESIS, PAX4_01, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOCC_RUFFLE, AP2_Q3, GOMF_GTPASE_BINDING, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, WANG_RESPONSE_TO_BEXAROTENE_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2, AML_Q6, GUO_HEX_TARGETS_UP, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (8): cytoskeleton organization (GO:0007010), signal transduction (GO:0007165), regulation of cell shape (GO:0008360), animal organ morphogenesis (GO:0009887), actin cytoskeleton organization (GO:0030036), regulation of GTPase activity (GO:0043087), filopodium assembly (GO:0046847), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), small GTPase binding (GO:0031267), metal ion binding (GO:0046872)

GO Cellular Component (8): ruffle (GO:0001726), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), lamellipodium (GO:0030027), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell leading edge	2
plasma membrane bounded cell projection	2
cytoplasm	2
organelle organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of cell morphogenesis	1
regulation of biological quality	1
anatomical structure morphogenesis	1
animal organ development	1
cytoskeleton organization	1
actin filament-based process	1
GTPase activity	1
regulation of hydrolase activity	1
plasma membrane bounded cell projection assembly	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
transition metal ion binding	1
GTPase binding	1
cation binding	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGD1	CDC42	P21181	768
FGD1	CTTN	Q14247	765
FGD1	DBNL	P84070	694
FGD1	TUBB2B	Q9BVA1	686
FGD1	PLEK2	Q9NYT0	661
FGD1	PLEK	P08567	661
FGD1	OPHN1	O60890	655
FGD1	MC2R	Q01718	640
FGD1	ARHGEF3	Q9NR81	631
FGD1	HCLS1	P14317	622
FGD1	MRAP	Q8TCY5	609
FGD1	WNK2	Q9Y3S1	573
FGD1	WASL	O00401	569
FGD1	RABIF	P47224	534
FGD1	DDN	O94850	528

IntAct

11 interactions, top by confidence:

A	B	Type	Score
	FGD1	psi-mi:“MI:0915”(physical association)	0.560
SH3PXD2A	FGD1	psi-mi:“MI:0914”(association)	0.530
FGD1	RPL7	psi-mi:“MI:0915”(physical association)	0.400
FGD1		psi-mi:“MI:0914”(association)	0.350
FGD1	MECP2	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
OSBPL8	FABP6	psi-mi:“MI:0914”(association)	0.350
FGFR4	SH3PXD2B	psi-mi:“MI:2364”(proximity)	0.270
FGD1		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (47): GGCX (Affinity Capture-MS), STX3 (Affinity Capture-MS), TAP2 (Affinity Capture-MS), PITPNM1 (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), INTS7 (Affinity Capture-MS), MRPL18 (Affinity Capture-MS), FBXL19 (Affinity Capture-MS), ESYT2 (Affinity Capture-MS), MICALL2 (Affinity Capture-MS), SH3RF1 (Two-hybrid), FGD1 (Proximity Label-MS), FGD1 (Proximity Label-MS), FGD1 (FRET), CWC15 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JXN2, A2AWP8, O88842, O95267, P29590, P52734, P98174, Q1LY10, Q29RM4, Q2TBA3, Q3TAA7, Q3U0J8, Q3UTZ3, Q496Y0, Q4VX76, Q568M3, Q58D15, Q5BIM1, Q5JSP0, Q5R5M3, Q5R5T1, Q5REJ9, Q5W0U4, Q68FF6, Q69Z89, Q69ZK0, Q6PFY8, Q7TNM2, Q7Z4K8, Q7Z5H3, Q7Z6J4, Q80V85, Q8BY35, Q8BZ52, Q8C190, Q8N1F8, Q8TCU6, Q8WVR3, Q96JH8, Q99N48

Diamond homologs: A2AWP8, E9PSK7, O15013, P34609, P52734, P98174, Q07139, Q1ZXH8, Q29RM4, Q58A65, Q5R5M3, Q8C033, Q9ESN9, Q9H8V3, Q9HCE6, Q9UPT6, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A3LX75, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, O13821, O14964, O59722, O76902, O88387

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FGD1	“up-regulates activity”	CDC42	“guanine nucleotide exchange factor”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	33
Uncertain significance	219
Likely benign	129
Benign	44

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10824	NM_004463.3(FGD1):c.1392dup (p.Lys465fs)	Pathogenic
10825	NM_004463.3(FGD1):c.1829G>A (p.Arg610Gln)	Pathogenic
10827	NG_008054.1:g.(35701_?)_(?_50820)del	Pathogenic
10831	NM_004463.3(FGD1):c.2192del (p.Lys731fs)	Pathogenic
10832	NM_004463.3(FGD1):c.1328G>T (p.Arg443Leu)	Pathogenic
10833	NM_004463.3(FGD1):c.944dup (p.Ala316fs)	Pathogenic
10834	NM_004463.3(FGD1):c.1396A>G (p.Met466Val)	Pathogenic
1299192	NM_004463.3(FGD1):c.419del (p.Pro140fs)	Pathogenic
1327174	NM_004463.3(FGD1):c.278_285del (p.Ser92_Tyr93insTer)	Pathogenic
1454559	NM_004463.3(FGD1):c.1088del (p.Gln363fs)	Pathogenic
1700172	NM_004463.3(FGD1):c.1327C>T (p.Arg443Cys)	Pathogenic
1757212	NM_004463.3(FGD1):c.710del (p.Gly237fs)	Pathogenic
194218	NM_004463.3(FGD1):c.2016-2A>G	Pathogenic
1995490	NM_004463.3(FGD1):c.1699C>T (p.Arg567Ter)	Pathogenic
2232264	NM_004463.3(FGD1):c.1076del (p.Leu359fs)	Pathogenic
2425123	NC_000023.10:g.(?54481861)(54483020_?)del	Pathogenic
2808503	NM_004463.3(FGD1):c.578del (p.Arg193fs)	Pathogenic
2811382	NM_004463.3(FGD1):c.1075del (p.Pro358_Leu359insTer)	Pathogenic
2849341	NM_004463.3(FGD1):c.1784del (p.Gly595fs)	Pathogenic
29974	NM_004463.3(FGD1):c.1966C>T (p.Arg656Ter)	Pathogenic
3046497	NM_004463.3(FGD1):c.482-2A>G	Pathogenic
3075723	NM_004463.3(FGD1):c.2016-36A>T	Pathogenic
3254768	NM_004463.3(FGD1):c.1564dup (p.Arg522fs)	Pathogenic
3255138	NM_004463.3(FGD1):c.1341G>A (p.Trp447Ter)	Pathogenic
3356860	NM_004463.3(FGD1):c.1204C>T (p.Arg402Trp)	Pathogenic
3905980	NC_000023.11:g.54450302del	Pathogenic
4073652	NM_004463.3(FGD1):c.1531del (p.His511fs)	Pathogenic
4074389	NM_004463.3(FGD1):c.1192-1G>A	Pathogenic
421839	NM_004463.3(FGD1):c.26dup (p.Ala10fs)	Pathogenic
4494033	NM_004463.3(FGD1):c.1489G>T (p.Glu497Ter)	Pathogenic

SpliceAI

2509 predictions. Top by Δscore:

Variant	Effect	Δscore
X:54447455:C:CC	acceptor_gain	1.0000
X:54448800:TCTTA:T	donor_loss	1.0000
X:54448801:CTTAC:C	donor_loss	1.0000
X:54448802:TTAC:T	donor_loss	1.0000
X:54448803:TACC:T	donor_loss	1.0000
X:54448804:A:AC	donor_gain	1.0000
X:54448804:A:AT	donor_loss	1.0000
X:54448804:ACCT:A	donor_gain	1.0000
X:54448805:C:CC	donor_gain	1.0000
X:54448805:CCT:C	donor_gain	1.0000
X:54448805:CCTC:C	donor_gain	1.0000
X:54448964:CCAC:C	acceptor_gain	1.0000
X:54448965:CACC:C	acceptor_gain	1.0000
X:54448967:CCTGG:C	acceptor_loss	1.0000
X:54449135:ACACT:A	donor_loss	1.0000
X:54449137:ACTCA:A	donor_loss	1.0000
X:54449138:CTCA:C	donor_loss	1.0000
X:54449139:TCA:T	donor_loss	1.0000
X:54449141:A:AC	donor_gain	1.0000
X:54449142:C:CA	donor_loss	1.0000
X:54449142:C:CC	donor_gain	1.0000
X:54449142:CATG:C	donor_gain	1.0000
X:54449166:G:A	donor_gain	1.0000
X:54449222:T:TA	donor_gain	1.0000
X:54449265:CGTT:C	acceptor_gain	1.0000
X:54449266:GTTC:G	acceptor_loss	1.0000
X:54449267:TT:T	acceptor_gain	1.0000
X:54449268:TC:T	acceptor_loss	1.0000
X:54449269:C:CC	acceptor_gain	1.0000
X:54449269:CT:C	acceptor_loss	1.0000

AlphaMissense

6233 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:54446259:C:A	W912C	1.000
X:54446259:C:G	W912C	1.000
X:54446261:A:G	W912R	1.000
X:54446261:A:T	W912R	1.000
X:54446293:A:G	F901S	1.000
X:54446326:A:G	F890S	1.000
X:54446380:C:T	G872D	1.000
X:54446381:C:G	G872R	1.000
X:54446386:A:G	L870P	1.000
X:54446386:A:T	L870H	1.000
X:54446394:G:C	S867R	1.000
X:54446394:G:T	S867R	1.000
X:54446396:T:G	S867R	1.000
X:54446404:G:T	A864D	1.000
X:54446413:T:G	D861A	1.000
X:54446414:C:G	D861H	1.000
X:54447325:A:C	Y856D	1.000
X:54447333:A:G	L853P	1.000
X:54447367:A:G	W842R	1.000
X:54447367:A:T	W842R	1.000
X:54447379:A:G	W838R	1.000
X:54447379:A:T	W838R	1.000
X:54448887:G:C	C785W	1.000
X:54448888:C:A	C785F	1.000
X:54448888:C:G	C785S	1.000
X:54448888:C:T	C785Y	1.000
X:54448889:A:G	C785R	1.000
X:54448889:A:T	C785S	1.000
X:54448896:G:C	C782W	1.000
X:54448897:C:A	C782F	1.000

dbSNP variants (sampled 300 via entrez): RS1000031569 (X:54445097 C>A), RS1000052643 (X:54466063 C>A), RS1000065787 (X:54479245 G>C), RS1000120971 (X:54462108 G>A), RS1000276012 (X:54455668 A>G), RS1000325464 (X:54454486 C>T), RS1000371921 (X:54466151 A>C,G), RS1000568966 (X:54475870 C>T), RS1000707615 (X:54496177 T>G), RS1000708366 (X:54463686 T>G), RS1000959788 (X:54474243 A>T), RS1001016369 (X:54483409 G>T), RS1001180519 (X:54478043 G>A), RS1001332909 (X:54467992 T>G), RS1001338907 (X:54451060 A>C)

Disease associations

OMIM: gene MIM:300546 | disease phenotypes: MIM:305400, MIM:180860, MIM:300534

GenCC curated gene-disease

Disease	Classification	Inheritance
Aarskog-Scott syndrome, X-linked	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Aarskog-Scott syndrome, X-linked	Definitive	XL

Mondo (5): Aarskog-Scott syndrome, X-linked (MONDO:0010589), intellectual disability (MONDO:0001071), Silver-Russell syndrome (MONDO:0008394), syndromic X-linked intellectual disability Claes-Jensen type (MONDO:0010355), polyhydramnios (MONDO:0004585)

Orphanet (4): Aarskog-Scott syndrome (Orphanet:915), Silver-Russell syndrome (Orphanet:813), KDM5C-related syndromic X-linked intellectual disability (Orphanet:85279), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

94 total (30 of 94 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000029	Testicular atrophy
HP:0000047	Hypospadias
HP:0000049	Shawl scrotum
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000307	Pointed chin
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000349	Widow’s peak
HP:0000358	Posteriorly rotated ears
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000485	Megalocornea
HP:0000486	Strabismus

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008860_37	Prostate cancer	7.000000e-09

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D006831	Polyhydramnios	C12.050.703.610
D056730	Silver-Russell Syndrome	C05.660.207.925; C16.131.077.855; C16.131.260.870; C16.320.180.870; C16.320.240.937; C16.320.447.750
C535331	Aarskog Syndrome (supp.)
C564494	Mental Retardation, X-Linked, Syndromic, Jarid1c-Related (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2862 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
coumarin	decreases phosphorylation	1
abrine	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Bucladesine	decreases expression, affects cotreatment	1
Estradiol	affects cotreatment, decreases expression	1
Niclosamide	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Medroxyprogesterone Acetate	affects cotreatment, decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Topotecan	affects response to substance	1
Particulate Matter	increases abundance, 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
CHEMBL878757	Binding	Binding affinity to uridine kinase from L1210. was determined from the dixon plot	Cyclopentenyluridine and cyclopentenylcytidine analogues as inhibitors of uridine-cytidine kinase. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT06457906	PHASE3	RECRUITING	SRS/SRT/Hypo-RT Versus HA-WBRT for No More Than 10 Brain Metastases in SCLC
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT04180501	PHASE2	UNKNOWN	SRS Sequential Sindilimab in Brain Metastasis of NSLSC
NCT04899908	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases
NCT07162246	PHASE2	RECRUITING	Combined Gamma Knife/Linac Radiosurgery for Large Brain Tumors / Metastases
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders