TFG

Summary

TFG (trafficking from ER to golgi regulator, HGNC:11758) is a protein-coding gene on chromosome 3q12.2, encoding Protein TFG (Q92734). Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules.

There are several documented fusion oncoproteins encoded partially by this gene. This gene also participates in several oncogenic rearrangements resulting in anaplastic lymphoma and mixoid chondrosarcoma, and may play a role in the NF-kappaB pathway. Multiple transcript variants have been found for this gene.

Source: NCBI Gene 10342 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary motor and sensory neuropathy, Okinawa type (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 502 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 69
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_006070

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11758
Approved symbol	TFG
Name	trafficking from ER to golgi regulator
Location	3q12.2
Locus type	gene with protein product
Status	Approved
Aliases	TF6, FLJ36137, SPG57
Ensembl gene	ENSG00000114354
Ensembl biotype	protein_coding
OMIM	602498
Entrez	10342

Gene structure

Transcript identifiers

Ensembl transcripts: 60 — 51 protein_coding, 6 nonsense_mediated_decay, 3 retained_intron

ENST00000240851, ENST00000418917, ENST00000463568, ENST00000476228, ENST00000479672, ENST00000481203, ENST00000487505, ENST00000490574, ENST00000615993, ENST00000620299, ENST00000674615, ENST00000674645, ENST00000674699, ENST00000674758, ENST00000674798, ENST00000675011, ENST00000675047, ENST00000675243, ENST00000675246, ENST00000675420, ENST00000675499, ENST00000675543, ENST00000675553, ENST00000675586, ENST00000675591, ENST00000675692, ENST00000675890, ENST00000675958, ENST00000676010, ENST00000676054, ENST00000676111, ENST00000676276, ENST00000676308, ENST00000676395, ENST00000676431, ENST00000676455, ENST00000873435, ENST00000873436, ENST00000873437, ENST00000873438, ENST00000873439, ENST00000873440, ENST00000873441, ENST00000873442, ENST00000873443, ENST00000917750, ENST00000917751, ENST00000917752, ENST00000917753, ENST00000917754, ENST00000917755, ENST00000917756, ENST00000917757, ENST00000917758, ENST00000917759, ENST00000917760, ENST00000917761, ENST00000972367, ENST00000972368, ENST00000972369

RefSeq mRNA: 4 — MANE Select: NM_006070 NM_001007565, NM_001195478, NM_001195479, NM_006070

CCDS: CCDS2939, CCDS56266

Canonical transcript exons

ENST00000240851 — 8 exons

Exon	Start	End
ENSE00000774677	100728712	100728858
ENSE00000774688	100744833	100744931
ENSE00000823251	100732508	100732672
ENSE00000823252	100736576	100736716
ENSE00000967215	100713643	100713869
ENSE00000967216	100719975	100720058
ENSE00001335030	100709494	100709721
ENSE00001896758	100748149	100748964

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 107.2378 / max 1218.7475, expressed in 1826 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37633	81.1279	1825
37634	9.4983	1660
37635	5.4407	1486
37630	3.9587	1466
37632	3.7688	1440
37629	2.4883	1121
37628	0.5290	326
37631	0.4261	216

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.76	gold quality
jejunal mucosa	UBERON:0000399	98.71	gold quality
gingival epithelium	UBERON:0001949	98.34	gold quality
oocyte	CL:0000023	98.31	gold quality
gingiva	UBERON:0001828	98.08	gold quality
duodenum	UBERON:0002114	97.78	gold quality
tibia	UBERON:0000979	97.69	gold quality
parietal pleura	UBERON:0002400	97.59	gold quality
stromal cell of endometrium	CL:0002255	97.55	gold quality
smooth muscle tissue	UBERON:0001135	97.39	gold quality
rectum	UBERON:0001052	97.37	gold quality
oral cavity	UBERON:0000167	97.27	gold quality
pleura	UBERON:0000977	97.22	gold quality
mucosa of transverse colon	UBERON:0004991	96.98	gold quality
gall bladder	UBERON:0002110	96.97	gold quality
ventricular zone	UBERON:0003053	96.90	gold quality
cartilage tissue	UBERON:0002418	96.86	gold quality
tongue squamous epithelium	UBERON:0006919	96.85	gold quality
esophagus mucosa	UBERON:0002469	96.76	gold quality
visceral pleura	UBERON:0002401	96.75	gold quality
right atrium auricular region	UBERON:0006631	96.73	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.70	gold quality
adrenal tissue	UBERON:0018303	96.70	gold quality
body of pancreas	UBERON:0001150	96.65	gold quality
corpus epididymis	UBERON:0004359	96.65	gold quality
islet of Langerhans	UBERON:0000006	96.59	gold quality
colonic mucosa	UBERON:0000317	96.52	gold quality
right adrenal gland	UBERON:0001233	96.46	gold quality
adenohypophysis	UBERON:0002196	96.46	gold quality
right lobe of liver	UBERON:0001114	96.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1

miRNA regulators (miRDB)

45 targeting TFG, 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-4778-3P	99.93	70.40	1818
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-4705	99.10	69.10	1091

Literature-anchored findings (GeneRIF, showing 39)

• TFG was fused to NOR1 is a patient with extraskeletal myxoid chondrosarcoma. (PMID:15188455)
• TFG is a novel protein able to modulate SHP-1 activity. (PMID:15557341)
• TFG enhances the effect of TNF-alpha, TANK, TNF receptor-associated factor (TRAF)2, and TRAF6 in inducing NF-kappaB activity; it is suggested that TFG is a novel member of the NF-kappaB pathway (PMID:16547966)
• A polymorphic gene fusion consisting of TRK-fused gene and G-protein-coupled receptor 128 is identified in healthy individuals and in patients with lymphoma and soft tissue neoplasms. (PMID:19797732)
• Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma. (PMID:22250051)
• results suggest that the oncogenic effect of the t(3;9) translocation may be due to the TFG-TEC chimeric protein and that fusion of the TFG (NTD) to the TEC protein produces a gain-of-function chimeric product (PMID:22581839)
• The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. (PMID:22883144)
• Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. (PMID:23479643)
• Whole-exome sequencing reveals that HMSN-P is caused by a mutation in the TRK-fused gene on chromosome 3q13.2 (PMID:23553329)
• TFG plays a pivotal role in negative regulation of RNA-sensing, RIG-I-like receptor (RLR) family signaling pathways. (PMID:23810392)
• Study demonstrates that TFG1 physiologically functions to inhibit the protein degradation system, resulting in an increase in ER resident proteins and ER stress; the P285L mutant substantially enhances these consequences (PMID:24613659)
• TRIM68 targets TFG, a novel regulator of IFN production, and in doing so turns off and limits type I IFN production in response to anti-viral detection systems (PMID:24999993)
• TFG plays an important role in the protein secretory pathways that are essential for proper functioning of the human peripheral nervous system. (PMID:25098539)
• TFG functions at the endoplasmic reticulum (ER)/ER-Golgi intermediate compartments (ERGIC) interface to locally concentrate COPII-coated transport carriers and link exit sites on the ER to ERGIC membranes. (PMID:25586378)
• HMSN-P caused by p.Pro285Leu mutation in TFG is not confined to patients with Far East ancestry. (PMID:25725944)
• TFG organizes transitional ER (tER) and ER exit sites (ERESs) into larger structures. (PMID:27184855)
• Results identified two TFG variants associated with hereditary spastic paraplegias (HSP) (c.316C>T and c.317G> A) confirming the causal nature of bi-allelic TFG mutations for HSP, and suggest that that mitochondrial impairment represents a pathomechanistic link to other neurodegenerative conditions. (PMID:27492651)
• We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. (PMID:27601211)
• This study finding p.Gly269Val in a newly identified Iranian pedigree affected with hereditary motor and sensory neuropathy with proximal predominance. (PMID:27653917)
• The results suggest that ALG-2 acts as a Ca2+-sensitive adaptor to concentrate and polymerize TFG at endoplasmic reticulum exit sites, supporting a potential role for ALG-2 in COPII-dependent trafficking from the endoplasmic reticulum. (PMID:27813252)
• Differences in the severity of the disorder as well as new clinical findings. These include presence of clonus, undeveloped speech, and sleep disturbances. these findings extend the phenotypic spectrum associated with the TFG mutations in Hereditary spastic paraplegia. (PMID:28124177)
• Study suggests that a genetic variant in an intron of TFG may be associated with skin aging in Korean females, and TFG may be an interesting new candidate gene for exploring individual differences in the molecular bases of collagen and MMP production. (PMID:28882477)
• This study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking. (PMID:29971521)
• Data highlight a key role for TFG-mediated protein transport in the pathogenesis of HSP. (PMID:30157421)
• TFG homozygous mutation is associated with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. (PMID:30467354)
• Tropomyosin-receptor kinase fused gene (TFG) regulates lipid production in human sebocytes. (PMID:31036933)
• Continuum of phenotypes in hereditary motor and sensory neuropathy with proximal predominance and Charcot-Marie-Tooth patients with TFG mutation has been described. (PMID:31111683)
• A novel TFG c.793C>G mutation in a Chinese pedigree with Charcot-Marie-Tooth disease 2. (PMID:32666699)
• TFG-maintaining stability of overlooked FANCD2 confers early DNA-damage response. (PMID:33099537)
• Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature. (PMID:33767317)
• TFG binds LC3C to regulate ULK1 localization and autophagosome formation. (PMID:33932238)
• Deregulation of CLTC interacts with TFG, facilitating osteosarcoma via the TGF-beta and AKT/mTOR signaling pathways. (PMID:34185412)
• A Novel TFG Mutation in a Korean Family with alpha-Synucleinopathy and Amyotrophic Lateral Sclerosis. (PMID:34779525)
• Mutation Screening of TFG in alpha-Synucleinopathy and Amyotrophic Lateral Sclerosis. (PMID:35642252)
• TFG mutation induces haploinsufficiency and drives axonal Charcot-Marie-Tooth disease by causing neurite degeneration. (PMID:35986567)
• TFG::MET-rearranged soft tissue tumor: A rare infantile neoplasm with a distinct low-grade triphasic morphology. (PMID:36464850)
• Novel TFG mutation causes autosomal-dominant spastic paraplegia and defects in autophagy. (PMID:37890998)
• Hereditary motor sensory neuropathy with proximal involvement (HMSN-P) associated with TFG p.Pro285Leu variant in an Italian family with a motor neuron disease-like clinical picture. (PMID:38533668)
• Characterization of a novel TFG variant causing autosomal recessive pure hereditary spastic paraplegia. (PMID:38837630)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfg	ENSDARG00000003641
mus_musculus	Tfg	ENSMUSG00000022757
rattus_norvegicus	Tfg	ENSRNOG00000001633
caenorhabditis_elegans	tfg-1	WBGENE00006565
caenorhabditis_elegans	Y71A12B.10	WBGENE00013507

Protein

Protein identifiers

Protein TFG — Q92734 (reviewed: Q92734)

Alternative names: TRK-fused gene protein

All UniProt accessions (13): A0A6Q8PF40, A0A6Q8PF51, A0A6Q8PFC4, A0A6Q8PFY7, A0A6Q8PG00, A0A6Q8PG04, A0A6Q8PGS4, A0A6Q8PH27, A0A6Q8PH89, C9JJP5, C9JTY3, C9JUE0, Q92734

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules. Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus.

Subunit / interactions. Self-associates to form an oligomeric complex. Interacts with PDCD6; promoting localization and polymerization of TFG at endoplasmic reticulum exit site. Interacts with SEC16B.

Subcellular location. Endoplasmic reticulum.

Tissue specificity. Ubiquitous.

Disease relevance. A chromosomal aberration involving TFG is found in papillary thyroid carcinomas (PTCs). Translocation t(1;3)(q21;q11) with NTRK1. The TFG sequence is fused to the 3’-end of NTRK1 generating the TRKT3 (TRK-T3) fusion transcript. Neuropathy, hereditary motor and sensory, Okinawa type (HMSNO) [MIM:604484] A neurodegenerative disorder characterized by young adult onset of proximal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. The disorder is slowly progressive and clinically resembles amyotrophic lateral sclerosis. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 57, autosomal recessive (SPG57) [MIM:615658] A complicated form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
Q92734-1	1	yes
Q92734-2	2
Q92734-3	3
Q92734-4	4

RefSeq proteins (4): NP_001007566, NP_001182407, NP_001182408, NP_006061* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000270	PB1_dom	Domain
IPR033512	TFG	Family
IPR034857	PB1_TFG	Domain
IPR053793	PB1-like	Domain

Pfam: PF00564

UniProt features (38 total): strand 8, sequence variant 7, modified residue 5, compositionally biased region 5, splice variant 3, helix 3, region of interest 2, chain 1, domain 1, site 1, sequence conflict 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9E7C	X-RAY DIFFRACTION	1.91
8TER	ELECTRON MICROSCOPY	2.59
8TEQ	ELECTRON MICROSCOPY	2.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92734-F1	60.51	0.21

Functional residue map

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

Catalytic / active sites (1): 193–194 (breakpoint for translocation to form trk-t3)

Post-translational modifications (5): 1, 50, 197, 385, 400

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-1643685	Disease
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-597592	Post-translational protein modification
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-9700206	Signaling by ALK in cancer

MSigDB gene sets: 300 (showing top): GOBP_VESICLE_LOCALIZATION, GOBP_VESICLE_ORGANIZATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_VESICLE_TARGETING, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, KEGG_PATHWAYS_IN_CANCER, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_MEMBRANE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, ACEVEDO_LIVER_CANCER_UP, GOBP_ORGANELLE_LOCALIZATION

GO Biological Process (4): endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), COPII vesicle coat assembly (GO:0048208), vesicle-mediated transport (GO:0016192)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), endoplasmic reticulum exit site (GO:0070971), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	1
Signaling by ALK in cancer	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1
Asparagine N-linked glycosylation	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
vesicle coat assembly	1
protein-containing complex assembly	1
COPII-coated vesicle budding	1
transport	1
cellular process	1
protein binding	1
binding	1
intracellular anatomical structure	1
endoplasmic reticulum	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

340 interactions, top by confidence:

A	B	Type	Score
HIF1AN	APBA3	psi-mi:“MI:0914”(association)	0.850
TFG	TFG	psi-mi:“MI:0915”(physical association)	0.820
TFG	VPS37C	psi-mi:“MI:0915”(physical association)	0.720
TFG	CSTF2	psi-mi:“MI:0915”(physical association)	0.720
CEP55	TFG	psi-mi:“MI:0915”(physical association)	0.720
TFG	MAPK1IP1L	psi-mi:“MI:0915”(physical association)	0.720
TFG	MAGED1	psi-mi:“MI:0915”(physical association)	0.720
SPG21	TFG	psi-mi:“MI:0915”(physical association)	0.720
PEF1	TFG	psi-mi:“MI:0915”(physical association)	0.720
MAGED1	TFG	psi-mi:“MI:0915”(physical association)	0.720
TFG	SPG21	psi-mi:“MI:0915”(physical association)	0.720
CSTF2	TFG	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (334): TFG (Two-hybrid), TFG (Two-hybrid), TFG (Two-hybrid), TFG (Two-hybrid), TFG (Two-hybrid), TFG (Two-hybrid), SEC24A (Two-hybrid), RBPMS (Two-hybrid), ARHGEF16 (Two-hybrid), SPG21 (Two-hybrid), VPS37C (Two-hybrid), CEP55 (Two-hybrid), BOLL (Two-hybrid), MAPK1IP1L (Two-hybrid), RIPPLY2 (Two-hybrid)

ESM2 similar proteins: A0A1P8AS03, A3LX75, A5DDB7, D5MCN2, F4IUY8, F4K1Z0, G4NID8, M2TGT8, M2U3Z7, O13987, O17670, O60167, O61708, O74345, O74412, O95677, P25644, P34643, P53297, P97767, Q05672, Q07998, Q08400, Q09750, Q09801, Q10655, Q10667, Q18273, Q20374, Q20870, Q2L4W6, Q3MK94, Q3S405, Q61X54, Q6E3D2, Q6E3D4, Q6FLG1, Q6FSQ6, Q75BK1, Q7ZT82

Diamond homologs: Q92734, Q9U1W1

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TFG	up-regulates	SEC16A	binding
TFG	up-regulates	SEC16B	binding
TRIM68	“down-regulates quantity by destabilization”	TFG	ubiquitination
TRIM68	“down-regulates quantity”	TFG	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 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
Cargo recognition for clathrin-mediated endocytosis	6	9.7×	8e-03
Neddylation	11	8.0×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	6	23.1×	1e-04
G1/S transition of mitotic cell cycle	6	12.9×	2e-03

Disease & clinical

Cancer significance

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	240
Likely benign	178
Benign	50

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
100909	NM_006070.6(TFG):c.316C>T (p.Arg106Cys)	Pathogenic
1452866	NM_006070.6(TFG):c.64C>T (p.Arg22Trp)	Pathogenic
425303	NM_006070.6(TFG):c.337C>T (p.Arg113Ter)	Likely pathogenic
4819724	NM_006070.6(TFG):c.124C>G (p.Arg42Gly)	Likely pathogenic

SpliceAI

1679 predictions. Top by Δscore:

Variant	Effect	Δscore
3:100713867:AAGGT:A	donor_loss	1.0000
3:100713868:AGGTA:A	donor_loss	1.0000
3:100713870:G:C	donor_loss	1.0000
3:100713871:T:A	donor_loss	1.0000
3:100728705:A:AG	acceptor_gain	1.0000
3:100728707:TTCA:T	acceptor_loss	1.0000
3:100728709:CA:C	acceptor_loss	1.0000
3:100728709:CAG:C	acceptor_gain	1.0000
3:100728710:A:AC	acceptor_loss	1.0000
3:100728710:A:AG	acceptor_gain	1.0000
3:100728711:G:GT	acceptor_gain	1.0000
3:100728711:GT:G	acceptor_gain	1.0000
3:100728711:GTT:G	acceptor_gain	1.0000
3:100728711:GTTA:G	acceptor_gain	1.0000
3:100728711:GTTAA:G	acceptor_gain	1.0000
3:100728855:AATGG:A	donor_loss	1.0000
3:100728859:G:GG	donor_gain	1.0000
3:100728859:GTAA:G	donor_loss	1.0000
3:100728860:T:C	donor_loss	1.0000
3:100732498:A:AG	acceptor_gain	1.0000
3:100732502:TTACA:T	acceptor_loss	1.0000
3:100732503:TACAG:T	acceptor_loss	1.0000
3:100732504:ACAG:A	acceptor_loss	1.0000
3:100732505:CAGA:C	acceptor_loss	1.0000
3:100732506:A:AG	acceptor_gain	1.0000
3:100732506:A:AT	acceptor_loss	1.0000
3:100732507:G:GG	acceptor_gain	1.0000
3:100732507:GAT:G	acceptor_gain	1.0000
3:100732507:GATA:G	acceptor_gain	1.0000
3:100732667:TTTC:T	donor_gain	1.0000

AlphaMissense

2594 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:100713705:T:A	L7Q	1.000
3:100713705:T:C	L7P	1.000
3:100713710:G:T	G9W	1.000
3:100713711:G:A	G9E	1.000
3:100713711:G:T	G9V	1.000
3:100713713:A:G	K10E	1.000
3:100713715:G:C	K10N	1.000
3:100713715:G:T	K10N	1.000
3:100713717:T:A	L11Q	1.000
3:100713717:T:C	L11P	1.000
3:100713720:T:A	I12N	1.000
3:100713720:T:C	I12T	1.000
3:100713720:T:G	I12S	1.000
3:100713723:T:A	I13N	1.000
3:100713723:T:C	I13T	1.000
3:100713723:T:G	I13S	1.000
3:100713725:A:C	K14Q	1.000
3:100713725:A:G	K14E	1.000
3:100713726:A:T	K14I	1.000
3:100713727:A:C	K14N	1.000
3:100713727:A:T	K14N	1.000
3:100713728:G:C	A15P	1.000
3:100713729:C:A	A15D	1.000
3:100713732:A:C	Q16P	1.000
3:100713735:T:C	L17P	1.000
3:100713743:G:C	D20H	1.000
3:100713747:T:A	I21N	1.000
3:100713749:C:G	R22G	1.000
3:100713750:G:C	R22P	1.000
3:100713753:G:C	R23P	1.000

dbSNP variants (sampled 300 via entrez): RS1000049398 (3:100709505 A>C,G), RS1000065596 (3:100746232 G>A), RS1000205812 (3:100726788 T>C), RS1000397631 (3:100737696 T>C), RS1000440475 (3:100739969 G>A), RS1000510105 (3:100727527 A>G), RS1000817178 (3:100714128 T>G), RS1000934242 (3:100715839 G>A), RS1000986683 (3:100716057 C>A), RS1001005465 (3:100732041 G>A,C,T), RS1001022528 (3:100748744 C>A,T), RS1001053691 (3:100748362 C>G,T), RS1001256856 (3:100726370 C>T), RS1001290783 (3:100710209 G>A), RS1001378922 (3:100714739 A>C,G)

Disease associations

OMIM: gene MIM:602498 | disease phenotypes: MIM:604484, MIM:615658, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary motor and sensory neuropathy, Okinawa type	Strong	Autosomal dominant
hereditary spastic paraplegia 57	Strong	Autosomal recessive
autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation	Supportive	Autosomal dominant

Mondo (4): hereditary motor and sensory neuropathy, Okinawa type (MONDO:0011468), hereditary spastic paraplegia 57 (MONDO:0014295), Charcot-Marie-Tooth disease (MONDO:0015626), autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation (MONDO:0018567)

Orphanet (3): Autosomal recessive spastic paraplegia type 57 (Orphanet:431329), Hereditary motor and sensory neuropathy, Okinawa type (Orphanet:90117), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000079	Abnormality of the urinary system
HP:0000572	Visual loss
HP:0000648	Optic atrophy
HP:0000763	Sensory neuropathy
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity
HP:0002094	Dyspnea
HP:0002171	Gliosis
HP:0002378	Hand tremor
HP:0002380	Fasciculations
HP:0002398	Degeneration of anterior horn cells
HP:0002445	Tetraplegia
HP:0002483	Bulbar signs
HP:0002505	Loss of ambulation
HP:0002540	Inability to walk
HP:0002878	Respiratory failure
HP:0002936	Distal sensory impairment
HP:0003074	Hyperglycemia
HP:0003077	Hyperlipidemia
HP:0003134	Abnormality of peripheral nerve conduction
HP:0003236	Elevated circulating creatine kinase concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_434	Refractive error	5.000000e-25

MeSH disease descriptors (2)

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
C535717	Neuropathy, hereditary motor and sensory, Okinawa type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465388 (CHIMERIC PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance, decreases expression	2
sodium arsenite	affects methylation, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment, decreases expression	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects expression	1
cobaltous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Arsenic	decreases methylation, increases abundance	1
Aspirin	increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5363002	Binding	Inhibition of ALK-TFG (unknown origin) assessed as residual activity at 1 uM relative to control	Discovery of pyrazolo[3,4-b]pyridine derivatives as novel and potent Mps1 inhibitors for the treatment of cancer. — Eur J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2IE	Abcam HeLa TFG KO	Cancer cell line	Female
CVCL_D8C7	Ubigene A-549 TFG KO	Cancer cell line	Male
CVCL_TS20	HAP1 TFG (-) 1	Cancer cell line	Male
CVCL_XU17	HAP1 TFG (-) 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