FGD4

Summary

FGD4 (FYVE, RhoGEF and PH domain containing 4, HGNC:19125) is a protein-coding gene on chromosome 12p11.21, encoding FYVE, RhoGEF and PH domain-containing protein 4 (Q96M96). Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP.

This gene encodes a protein that is involved in the regulation of the actin cytoskeleton and cell shape. This protein contains an actin filament-binding domain, which together with its Dbl homology domain and one of its pleckstrin homology domains, can form microspikes. This protein can activate MAPK8 independently of the actin filament-binding domain, and it is also involved in the activation of CDC42 via the exchange of bound GDP for free GTP. The activation of CDC42 also enables this protein to play a role in mediating the cellular invasion of Cryptosporidium parvum, an intracellular parasite that infects the gastrointestinal tract. Mutations in this gene can cause Charcot-Marie-Tooth disease type 4H (CMT4H), a disorder of the peripheral nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 121512 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 817 total — 41 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 21
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001370298

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19125
Approved symbol	FGD4
Name	FYVE, RhoGEF and PH domain containing 4
Location	12p11.21
Locus type	gene with protein product
Status	Approved
Aliases	FRABP, frabin, ZFYVE6, CMT4H
Ensembl gene	ENSG00000139132
Ensembl biotype	protein_coding
OMIM	611104
Entrez	121512

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 9 protein_coding, 4 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000395740, ENST00000427716, ENST00000472289, ENST00000473513, ENST00000479023, ENST00000493087, ENST00000494275, ENST00000494977, ENST00000497153, ENST00000525053, ENST00000531134, ENST00000534526, ENST00000546442, ENST00000550091, ENST00000551984, ENST00000583694, ENST00000682739, ENST00000683182, ENST00000683515, ENST00000684033

RefSeq mRNA: 15 — MANE Select: NM_001370298 NM_001304481, NM_001304483, NM_001304484, NM_001330373, NM_001330374, NM_001370297, NM_001370298, NM_001384126, NM_001384127, NM_001384128, NM_001384130, NM_001384131, NM_001384132, NM_001385118, NM_139241

CCDS: CCDS76544, CCDS81679, CCDS8727, CCDS91680, CCDS91681

Canonical transcript exons

ENST00000534526 — 17 exons

Exon	Start	End
ENSE00001268783	32640276	32646050
ENSE00002394375	32399558	32399959
ENSE00003473693	32633549	32633689
ENSE00003489351	32638655	32638795
ENSE00003490384	32610776	32610834
ENSE00003493151	32625654	32625779
ENSE00003501153	32624422	32624452
ENSE00003536907	32619698	32619870
ENSE00003539180	32611137	32611283
ENSE00003583095	32601278	32601423
ENSE00003597189	32602161	32602317
ENSE00003614286	32581960	32582467
ENSE00003628523	32598497	32598586
ENSE00003631270	32576266	32576449
ENSE00003632385	32564137	32564289
ENSE00003637197	32607957	32608095
ENSE00003639849	32624976	32625068

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 95.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4773 / max 787.3759, expressed in 1520 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124991	6.7601	384
124983	3.5988	839
124997	3.2747	765
124985	2.4111	580
124995	1.5372	340
124994	1.4367	392
124998	1.0837	458
124992	0.4856	157
124981	0.3306	131
124982	0.2400	118

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.93	gold quality
calcaneal tendon	UBERON:0003701	95.49	gold quality
ileal mucosa	UBERON:0000331	94.65	gold quality
pigmented layer of retina	UBERON:0001782	94.60	gold quality
kidney epithelium	UBERON:0004819	93.94	gold quality
epithelial cell of pancreas	CL:0000083	93.85	gold quality
trabecular bone tissue	UBERON:0002483	93.80	gold quality
visceral pleura	UBERON:0002401	93.28	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.33	gold quality
lower lobe of lung	UBERON:0008949	92.03	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.86	gold quality
buccal mucosa cell	CL:0002336	91.52	gold quality
cardia of stomach	UBERON:0001162	91.01	gold quality
pancreatic ductal cell	CL:0002079	90.80	gold quality
bone marrow cell	CL:0002092	90.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.62	gold quality
deltoid	UBERON:0001476	90.56	gold quality
jejunum	UBERON:0002115	90.40	gold quality
tendon	UBERON:0000043	90.20	gold quality
sural nerve	UBERON:0015488	90.04	gold quality
biceps brachii	UBERON:0001507	89.99	gold quality
corpus callosum	UBERON:0002336	89.87	gold quality
colonic epithelium	UBERON:0000397	89.49	gold quality
caput epididymis	UBERON:0004358	89.04	gold quality
parietal pleura	UBERON:0002400	88.88	gold quality
pylorus	UBERON:0001166	88.80	gold quality
oral cavity	UBERON:0000167	88.71	gold quality
monocyte	CL:0000576	88.67	gold quality
oviduct epithelium	UBERON:0004804	88.62	gold quality
tibialis anterior	UBERON:0001385	88.60	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-124858	yes	80.34
E-HCAD-35	yes	36.94
E-ANND-3	yes	20.54
E-HCAD-25	yes	14.60
E-MTAB-5061	yes	14.47
E-GEOD-81608	yes	7.63
E-ENAD-27	no	3.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

280 targeting FGD4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• role of frabin, a guanine nucleotide exchange factor specific for Cdc42, in the activation of Cdc42 during Cryptosporidium parvum infection of biliary epithelial cells (PMID:15133042)
• The identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in families with Charcot-Marie-Tooth type 4H. (PMID:17564959)
• We report that disruption of frabin/FGD4, a GEF for the Rho GTPase cell-division cycle 42 (Cdc42), causes peripheral nerve demyelination in patients with autosomal recessive Charcot-Marie-Tooth (CMT) neuropathy. (PMID:17564972)
• A novel homozygous Frabin (FGD4) nonsense mutation p.R275X is identified in a family with Charcot-Marie Tooth disease (CMT4H) from Northern Ireland. (PMID:19221294)
• Genetic heterogeneity of FGD4 demonstrates that CMT4H has variable functional impairment and suggests that frabin plays a crucial role during myelin formation. (PMID:19332693)
• differentialy expressed in dendritic cells upon stimulation of with with the major house dust mite allergen Der p 1 (PMID:19494521)
• susceptibility genes associated with alcohol drinking (PMID:22295116)
• LMP1, through its transmembrane domains, directly bound FGD4 and enhanced FGD4 activity toward Cdc42, leading to actin cytoskeleton rearrangement and increased motility of NPC cells. (PMID:22589722)
• we have identified two novel missense mutations in FGD4 in two patients affected by autosomal recessive demyelinating Charcot-Marie-Tooth disease (PMID:22734899)
• A single nucleotide polymorphism in FGD4 was associated with the onset of paclitaxel-induced sensory peripheral neuropathy. (PMID:22843789)
• Our results suggest that FGD4 should be screened in other early-onset CMT subtypes, regardless of the severity of the phenotype, and particularly in patients of consanguineous descent. (PMID:23550889)
• identified two different pairs of novel compound heterozygous mutations in the FGD4 gene from nonconsanguineous Korean Charcot-Marie-Tooth disease type 4H families (PMID:26400421)
• FGD4 c.2044-236 A-allele carriers had an increased risk of paclitaxel dose reduction (HR per A-allele=1.38, P=0.036) when adjusted for total cumulative paclitaxel dose (PMID:27736846)
• Results show that the expression of FGD4 is upregulated in cancerous prostates compared to the luminal cells in benign prostatic hyperplasia and demonstrate a tumor promoting and a cell migratory function of FGD4 in prostate cancer cells. Its inhibition enhances the response for both androgen-dependent and independent prostate cancer cells towards currently used prostate cancer drugs. (PMID:30558664)
• Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease. (PMID:31852984)
• Circular RNA circFGD4 suppresses gastric cancer progression via modulating miR-532-3p/APC/beta-catenin signalling pathway. (PMID:32633323)
• MiR-23a induced the activation of CDC42/PAK1 pathway and cell cycle arrest in human cov434 cells by targeting FGD4. (PMID:32772928)
• Polymorphism of FGD4 and myelosuppression in patients with esophageal squamous cell carcinoma. (PMID:33709789)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgd4b	ENSDARG00000060248
danio_rerio	fgd4a	ENSDARG00000101471
mus_musculus	Fgd4	ENSMUSG00000022788
rattus_norvegicus	Fgd4	ENSRNOG00000059491
caenorhabditis_elegans		WBGENE00001366
caenorhabditis_elegans		WBGENE00001490

Paralogs (10): FARP2 (ENSG00000006607), FGD1 (ENSG00000102302), FGD3 (ENSG00000127084), ARHGEF39 (ENSG00000137135), FGD2 (ENSG00000146192), FARP1 (ENSG00000152767), FGD5 (ENSG00000154783), FRMD7 (ENSG00000165694), FGD6 (ENSG00000180263), ECT2L (ENSG00000203734)

Protein

Protein identifiers

FYVE, RhoGEF and PH domain-containing protein 4 — Q96M96 (reviewed: Q96M96)

Alternative names: Actin filament-binding protein frabin, FGD1-related F-actin-binding protein, Zinc finger FYVE domain-containing protein 6

All UniProt accessions (11): Q96M96, A0A804HK93, B7Z493, E9PJX4, E9PNX0, E9PQT1, F8VVF1, F8VWL3, F8W1R0, H0YDQ0, J3KSS3

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. Activates MAPK8.

Subunit / interactions. Homooligomer.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Filopodium.

Tissue specificity. Expressed in different tissues, including brain, cerebellum, peripheral nerve, skeletal muscle, heart, uterus, placenta and testis.

Disease relevance. Charcot-Marie-Tooth disease, demyelinating, type 4H (CMT4H) [MIM:609311] A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The part of the protein spanning the actin filament-binding domain together with the DH domain and the first PH domain is necessary and sufficient for microspike formation. Activation of MAPK8 requires the presence of all domains with the exception of the actin filament-binding domain.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96M96-1	1	yes
Q96M96-2	2
Q96M96-3	3

RefSeq proteins (15): NP_001291410, NP_001291412, NP_001291413, NP_001317302, NP_001317303, NP_001357226, NP_001357227, NP_001371055, NP_001371056, NP_001371057, NP_001371059, NP_001371060, NP_001371061, NP_001372047, NP_640334 (=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
IPR035941	FGD1-4_PH2	Domain
IPR037742	FDG4_N_PH	Domain
IPR051092	FYVE_RhoGEF_PH	Family

Pfam: PF00169, PF00621, PF01363

UniProt features (33 total): binding site 8, splice variant 5, region of interest 5, compositionally biased region 4, domain 3, modified residue 2, sequence variant 2, sequence conflict 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96M96-F1	70.85	0.36

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): 565; 568; 582; 585; 590; 593; 611; 614

Post-translational modifications (2): 702, 716

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: 317 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, WHITEHURST_PACLITAXEL_SENSITIVITY, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOCC_RUFFLE, GOMF_GTPASE_BINDING, AAAYRNCTG_UNKNOWN, chr12p11, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5

GO Biological Process (8): cytoskeleton organization (GO:0007010), regulation of cell shape (GO:0008360), actin cytoskeleton organization (GO:0030036), regulation of GTPase activity (GO:0043087), filopodium assembly (GO:0046847), regulation of small GTPase mediated signal transduction (GO:0051056), lamellipodium assembly (GO:0030032), microspike assembly (GO:0030035)

GO Molecular Function (5): actin binding (GO:0003779), 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), lamellipodium (GO:0030027), filopodium (GO:0030175), 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
plasma membrane bounded cell projection assembly	3
cellular anatomical structure	3
cell leading edge	2
plasma membrane bounded cell projection	2
cytoplasm	2
organelle organization	1
regulation of cell morphogenesis	1
regulation of biological quality	1
cytoskeleton organization	1
actin filament-based process	1
GTPase activity	1
regulation of hydrolase activity	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
lamellipodium organization	1
cytoskeletal protein binding	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
actin-based cell projection	1

Protein interactions and networks

STRING

848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGD4	SBF2	Q86WG5	748
FGD4	SH3TC2	Q8TF17	732
FGD4	CDC42	P21181	730
FGD4	MTMR2	Q13614	709
FGD4	GDAP1	Q8TB36	682
FGD4	FIG4	Q92562	608
FGD4	RABIF	P47224	591
FGD4	LRSAM1	Q6UWE0	589
FGD4	SBF1	O95248	586
FGD4	RAC2	P15153	580
FGD4	PLEK2	Q9NYT0	570
FGD4	PLEK	P08567	551
FGD4	LITAF	Q99732	530
FGD4	GJB1	P08034	514
FGD4	NDRG1	Q92597	507

IntAct

12 interactions, top by confidence:

A	B	Type	Score
	FGD4	psi-mi:“MI:0407”(direct interaction)	0.600
PRKCA	DUSP11	psi-mi:“MI:0914”(association)	0.530
FGD4	FGD3	psi-mi:“MI:0915”(physical association)	0.400
GOLM1	RAB19	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
FGD4	LANCL1	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): FGD4 (Affinity Capture-MS), FGD4 (Affinity Capture-MS), FGD3 (Affinity Capture-MS), FGD4 (Affinity Capture-MS), FGD4 (Affinity Capture-RNA), C9orf16 (Two-hybrid), FGD4 (Affinity Capture-MS), FGD4 (Affinity Capture-MS), FGD4 (FRET), DNAJC9 (Affinity Capture-MS), LANCL1 (Affinity Capture-MS), CCDC86 (Affinity Capture-MS), CTDSPL2 (Affinity Capture-MS), GSN (Affinity Capture-MS), NEFL (Affinity Capture-MS)

ESM2 similar proteins: A1L2W9, B2RQE8, B5XG43, G9CGD6, O08969, O88387, P59113, Q0V987, Q0VC85, Q1KKW7, Q1KKZ1, Q32LP0, Q3UUV5, Q3ZBA3, Q4V7G1, Q503L1, Q53GA4, Q5FVW6, Q5PQT7, Q5R8M5, Q5U597, Q5XGP7, Q5ZL23, Q6P0G8, Q6PG29, Q7Z628, Q7Z6J4, Q80VL0, Q80YS6, Q86UX7, Q86WV1, Q8AW35, Q8BY35, Q8IZC4, Q8K1B8, Q8N556, Q8VH46, Q91ZM9, Q91ZT5, Q925E0

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A3LX75, A4QTV1, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, O13821, O14964, O76902, O95405, O96838, P0CS26, P0CS27, P34657, P34756, P40343, Q05B78, Q0CJV3, Q0P4S0, Q0U4Z8, Q0V8S0, Q0WUR5, Q15075, Q17AN2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FGD4	“up-regulates activity”	CDC42	“guanine nucleotide exchange factor”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	11
Uncertain significance	390
Likely benign	231
Benign	95

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1011	NM_001370298.3(FGD4):c.1081C>T (p.Arg361Ter)	Pathogenic
1016	NM_001370298.3(FGD4):c.1234C>T (p.Arg412Ter)	Pathogenic
1072959	NM_001370298.3(FGD4):c.2079G>A (p.Trp693Ter)	Pathogenic
1075631	NM_001370298.3(FGD4):c.616del (p.Gln206fs)	Pathogenic
1075824	NM_001370298.3(FGD4):c.2252_2253del (p.Cys751fs)	Pathogenic
1184559	NM_001370298.3(FGD4):c.1097_1101del (p.Asp366fs)	Pathogenic
1402656	NM_001370298.3(FGD4):c.2083C>T (p.Arg695Ter)	Pathogenic
1454145	NM_001370298.3(FGD4):c.2444dup (p.Ala816fs)	Pathogenic
1454283	NM_001370298.3(FGD4):c.2583_2586del (p.Ser861fs)	Pathogenic
1457034	NC_000012.11:g.(?32729292)(32793467_?)del	Pathogenic
1458134	NM_001370298.3(FGD4):c.1135C>T (p.Arg379Ter)	Pathogenic
1778181	NM_001370298.3(FGD4):c.2104del (p.Cys702fs)	Pathogenic
2001493	NM_001370298.3(FGD4):c.2452dup (p.Gln818fs)	Pathogenic
2004242	NM_001370298.3(FGD4):c.2596C>T (p.Gln866Ter)	Pathogenic
2102422	NM_001370298.3(FGD4):c.994C>T (p.Gln332Ter)	Pathogenic
2170744	NM_001370298.3(FGD4):c.1869T>G (p.Tyr623Ter)	Pathogenic
2642835	NM_001370298.3(FGD4):c.875_878del (p.Ser292fs)	Pathogenic
265144	NM_001370298.3(FGD4):c.1808_1809del (p.Thr603fs)	Pathogenic
279806	NM_001370298.3(FGD4):c.1740C>A (p.Tyr580Ter)	Pathogenic
2829358	NM_001370298.3(FGD4):c.1497_1500del (p.Asp498_Tyr499insTer)	Pathogenic
3244341	NC_000012.11:g.(?32760871)(32761049_?)del	Pathogenic
3654646	NM_001370298.3(FGD4):c.1620_1621del (p.Leu541fs)	Pathogenic
3671318	NM_001370298.3(FGD4):c.601C>T (p.Gln201Ter)	Pathogenic
3689736	NM_001370298.3(FGD4):c.2058dup (p.Gly687fs)	Pathogenic
3696808	NM_001370298.3(FGD4):c.1073_1074dup (p.Val359fs)	Pathogenic
3716414	NM_001370298.3(FGD4):c.2452C>T (p.Gln818Ter)	Pathogenic
3727475	NM_001370298.3(FGD4):c.1993G>T (p.Glu665Ter)	Pathogenic
38445	NM_001370298.3(FGD4):c.1304T>G (p.Met435Arg)	Pathogenic
408261	NM_001370298.3(FGD4):c.2140C>T (p.Arg714Ter)	Pathogenic
408262	NM_001370298.3(FGD4):c.2452del (p.Gln818fs)	Pathogenic

SpliceAI

3726 predictions. Top by Δscore:

Variant	Effect	Δscore
12:32502336:AAG:A	donor_gain	1.0000
12:32511908:GA:G	donor_gain	1.0000
12:32511910:G:GG	donor_gain	1.0000
12:32598491:TTTTA:T	acceptor_loss	1.0000
12:32598492:TTTA:T	acceptor_loss	1.0000
12:32598494:TAGGA:T	acceptor_loss	1.0000
12:32598496:G:A	acceptor_loss	1.0000
12:32598496:GGA:G	acceptor_gain	1.0000
12:32598587:G:GA	donor_loss	1.0000
12:32598588:T:G	donor_loss	1.0000
12:32601273:TTCA:T	acceptor_loss	1.0000
12:32601275:CAG:C	acceptor_loss	1.0000
12:32601277:G:GC	acceptor_loss	1.0000
12:32601419:GAATG:G	donor_gain	1.0000
12:32602159:A:AG	acceptor_gain	1.0000
12:32602160:G:GG	acceptor_gain	1.0000
12:32602160:GGGAA:G	acceptor_gain	1.0000
12:32602314:TCAGG:T	donor_loss	1.0000
12:32602315:CAGGT:C	donor_loss	1.0000
12:32602316:AG:A	donor_loss	1.0000
12:32602317:GGTAA:G	donor_loss	1.0000
12:32602318:GTAAT:G	donor_loss	1.0000
12:32602319:T:A	donor_loss	1.0000
12:32608056:A:T	donor_gain	1.0000
12:32608096:G:GG	donor_gain	1.0000
12:32611127:A:AG	acceptor_gain	1.0000
12:32611128:A:G	acceptor_gain	1.0000
12:32611132:CCTA:C	acceptor_loss	1.0000
12:32611133:CTAG:C	acceptor_loss	1.0000
12:32611135:A:AG	acceptor_gain	1.0000

AlphaMissense

5951 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:32598537:T:C	L214P	1.000
12:32598570:T:C	L225P	1.000
12:32601402:T:C	L272P	1.000
12:32601411:G:C	R275P	1.000
12:32601422:T:A	W279R	1.000
12:32601422:T:C	W279R	1.000
12:32602181:G:A	G286E	1.000
12:32602207:T:C	F295L	1.000
12:32602209:C:A	F295L	1.000
12:32602209:C:G	F295L	1.000
12:32602211:T:C	L296P	1.000
12:32608000:T:C	L346P	1.000
12:32608009:T:A	V349D	1.000
12:32608013:G:C	Q350H	1.000
12:32608013:G:T	Q350H	1.000
12:32608015:G:C	R351P	1.000
12:32608036:T:C	L358P	1.000
12:32608039:T:C	L359P	1.000
12:32611238:A:C	K431N	1.000
12:32611238:A:T	K431N	1.000
12:32619861:T:C	L501P	1.000
12:32624444:T:A	W512R	1.000
12:32624444:T:C	W512R	1.000
12:32625693:G:C	D559H	1.000
12:32625711:T:A	C565S	1.000
12:32625711:T:C	C565R	1.000
12:32625712:G:A	C565Y	1.000
12:32625712:G:C	C565S	1.000
12:32625713:T:G	C565W	1.000
12:32625720:T:A	C568S	1.000

dbSNP variants (sampled 300 via entrez): RS1000003602 (12:32639787 G>T), RS1000012712 (12:32520750 A>G), RS1000018824 (12:32597712 T>C), RS1000026263 (12:32555985 G>A), RS1000059169 (12:32418652 G>C), RS1000076207 (12:32425246 G>A), RS1000081914 (12:32514317 G>T), RS1000082146 (12:32410342 T>A,G), RS1000085129 (12:32495956 G>C), RS1000093123 (12:32554867 G>A), RS1000124031 (12:32417186 G>A,T), RS1000148155 (12:32469506 C>G), RS1000168259 (12:32555535 G>C,T), RS1000178698 (12:32486703 A>G), RS1000180645 (12:32588342 A>T)

Disease associations

OMIM: gene MIM:611104 | disease phenotypes: MIM:609311, MIM:118220, MIM:214400

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease type 4H	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Definitive	AR

Mondo (4): Charcot-Marie-Tooth disease type 4 (MONDO:0018995), Charcot-Marie-Tooth disease type 4H (MONDO:0012250), Charcot-Marie-Tooth disease (MONDO:0015626), Charcot-Marie-Tooth disease type 4A (MONDO:0008961)

Orphanet (4): Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Charcot-Marie-Tooth disease type 4H (Orphanet:99954), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Charcot-Marie-Tooth disease type 4A (Orphanet:99948)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001245	Small thenar eminence
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0002317	Unsteady gait
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002936	Distal sensory impairment
HP:0003380	Decreased number of peripheral myelinated nerve fibers
HP:0003383	Onion bulb formation
HP:0003431	Decreased motor nerve conduction velocity
HP:0003484	Upper limb muscle weakness
HP:0007182	Peripheral hypomyelination
HP:0008944	Distal lower limb amyotrophy
HP:0009053	Distal lower limb muscle weakness
HP:0010487	Small hypothenar eminence
HP:0011463	Childhood onset
HP:0033748	Hypoesthesia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004599_185	Mean platelet volume	1.000000e-19
GCST008513_27	Health literacy	3.000000e-07
GCST009323_2	Figural/spatial cognitive ability	2.000000e-06
GCST009325_73	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	8.000000e-11
GCST010732_7	Sensory peripheral neuropathy in microtubule targeting agent-treated breast cancer	2.000000e-06
GCST90002395_121	Mean platelet volume	1.000000e-17

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010104	health literacy measurement
EFO:0008354	cognitive function measurement
EFO:0005260	response to antimicrotubule agent

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
C563740	Charcot-Marie-Tooth Disease, Type 4H (supp.)
C535419	Charcot-Marie-Tooth disease, Type 4A (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10771973	Toxicity	3	paclitaxel

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10771973	FGD4	3	3.00	1	paclitaxel
rs12823621	FGD4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	3
bisphenol A	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Dexamethasone	affects cotreatment, decreases expression, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tretinoin	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
decabromobiphenyl ether	increases expression	1
trichostatin A	increases expression	1
2-butenal	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SN46	HAP1 FGD4 (-) 1	Cancer cell line	Male
CVCL_SN47	HAP1 FGD4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT