FBXO38

Summary

FBXO38 (F-box protein 38, HGNC:28844) is a protein-coding gene on chromosome 5q32, encoding F-box only protein 38 (Q6PIJ6). Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity.

This gene encodes a large protein that contains an F-box domain and may participate in protein ubiquitination. The encoded protein is a transcriptional co-activator of Krueppel-like factor 7 (Klf7). A heterozygous mutation in this gene was found in individuals with autosomal dominant distal hereditary motor neuronopathy type IID. There is a pseudogene for this gene on chromosome 4. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 81545 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronopathy, distal hereditary motor, type 2D (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 842 total — 2 pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_205836

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28844
Approved symbol	FBXO38
Name	F-box protein 38
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	MOKA, SP329, FLJ13962, Fbx38
Ensembl gene	ENSG00000145868
Ensembl biotype	protein_coding
OMIM	608533
Entrez	81545

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 18 protein_coding, 9 retained_intron, 7 protein_coding_CDS_not_defined

ENST00000296701, ENST00000340253, ENST00000394370, ENST00000502571, ENST00000502629, ENST00000503613, ENST00000504447, ENST00000504971, ENST00000505399, ENST00000508176, ENST00000508326, ENST00000508485, ENST00000508670, ENST00000509273, ENST00000509411, ENST00000509699, ENST00000511080, ENST00000513826, ENST00000514832, ENST00000521160, ENST00000851420, ENST00000851423, ENST00000851426, ENST00000851429, ENST00000851430, ENST00000851431, ENST00000928055, ENST00000949010, ENST00000949011, ENST00000949012, ENST00000949013, ENST00000949014, ENST00000949015, ENST00000949016

RefSeq mRNA: 3 — MANE Select: NM_205836 NM_001271723, NM_030793, NM_205836

CCDS: CCDS4290, CCDS43384, CCDS64285

Canonical transcript exons

ENST00000340253 — 22 exons

Exon	Start	End
ENSE00000000093	148383958	148384039
ENSE00001125484	148416994	148417204
ENSE00001293128	148423998	148424117
ENSE00001305718	148441124	148441237
ENSE00001421466	148427213	148427947
ENSE00003519094	148398999	148399132
ENSE00003525509	148402348	148402513
ENSE00003533671	148415928	148416070
ENSE00003542962	148438332	148438498
ENSE00003614921	148394714	148394904
ENSE00003640717	148410635	148410765
ENSE00003650005	148425522	148425701
ENSE00003658891	148440424	148440527
ENSE00003659896	148401982	148402145
ENSE00003663751	148433635	148433737
ENSE00003665240	148406257	148406394
ENSE00003668025	148433424	148433524
ENSE00003676122	148404685	148404822
ENSE00003681215	148439647	148439792
ENSE00003692720	148409124	148409217
ENSE00003693902	148414136	148414306
ENSE00003904131	148441969	148442836

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 95.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4972 / max 279.7789, expressed in 1803 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59314	14.8956	1783
59313	6.2749	1689
59317	0.2314	53
59315	0.0953	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.97	gold quality
adrenal tissue	UBERON:0018303	95.57	gold quality
endothelial cell	CL:0000115	95.31	gold quality
germinal epithelium of ovary	UBERON:0001304	92.85	gold quality
corpus callosum	UBERON:0002336	92.57	gold quality
colonic epithelium	UBERON:0000397	92.46	gold quality
blood	UBERON:0000178	91.84	gold quality
epithelium of nasopharynx	UBERON:0001951	91.57	gold quality
nasopharynx	UBERON:0001728	91.56	gold quality
bone marrow	UBERON:0002371	91.38	gold quality
sural nerve	UBERON:0015488	91.22	gold quality
stromal cell of endometrium	CL:0002255	90.94	gold quality
monocyte	CL:0000576	90.79	gold quality
rectum	UBERON:0001052	90.74	gold quality
bone marrow cell	CL:0002092	90.67	gold quality
mononuclear cell	CL:0000842	90.64	gold quality
leukocyte	CL:0000738	90.62	gold quality
ganglionic eminence	UBERON:0004023	90.55	gold quality
tibial nerve	UBERON:0001323	90.42	gold quality
tonsil	UBERON:0002372	90.39	gold quality
cortical plate	UBERON:0005343	90.31	gold quality
descending thoracic aorta	UBERON:0002345	90.06	gold quality
visceral pleura	UBERON:0002401	90.06	gold quality
spleen	UBERON:0002106	90.05	gold quality
minor salivary gland	UBERON:0001830	89.90	gold quality
ventricular zone	UBERON:0003053	89.90	gold quality
endometrium	UBERON:0001295	89.89	gold quality
ectocervix	UBERON:0012249	89.81	gold quality
mucosa of stomach	UBERON:0001199	89.80	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.79	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.35
E-GEOD-124858	no	248.67

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF7

miRNA regulators (miRDB)

43 targeting FBXO38, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-369-3P	99.85	70.52	2264
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-6074	98.89	69.64	2187

Literature-anchored findings (GeneRIF, showing 8)

• This publication identifies the F-box protein 38 mouse ortholog and characterizes its interaction with KLF7 during regulation of cell cycle progression. (PMID:14729953)
• Our findings provide direct evidence for the association of FBXO38 and AP3B2 with severe chronic periodontitis in the Han Chinese population. (PMID:26643602)
• data indicate that FBXO38 regulates PD-1 expression and highlight an alternative method to block the PD-1 pathway (PMID:30487606)
• USP7 Regulates Cytokinesis through FBXO38 and KIF20B. (PMID:30804394)
• Study found that a COPD associated alternative splicing variant of previously unknown function may contribute to the inclusion of a new exon in the FBXO38 gene. (PMID:31269066)
• FBXO38 regulates macrophage polarization to control the development of cancer and colitis. (PMID:37821621)
• FBXO38 deficiency promotes lysosome-dependent STING degradation and inhibits cGAS-STING pathway activation. (PMID:38277817)
• Identification of rare variants in the FBXO38 gene of patients with chronic inflammatory demyelinating polyradiculoneuropathy. (PMID:38823119)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo38	ENSDARG00000006924
mus_musculus	Fbxo38	ENSMUSG00000042211
rattus_norvegicus	Fbxo38	ENSRNOG00000019063

Protein

Protein identifiers

F-box only protein 38 — Q6PIJ6 (reviewed: Q6PIJ6)

All UniProt accessions (1): Q6PIJ6

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity. Required for anti-tumor activity of T-cells by promoting the degradation of PDCD1/PD-1; the PDCD1-mediated inhibitory pathway being exploited by tumors to attenuate anti-tumor immunity and facilitate tumor survival. May indirectly stimulate the activity of transcription factor KLF7, a regulator of neuronal differentiation, without promoting KLF7 ubiquitination.

Subunit / interactions. Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO38) composed of CUL1, SKP1, RBX1 and FBXO38. Interacts with KLF7. Interacts with PDCD1/PD-1.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Disease relevance. Neuronopathy, distal hereditary motor, autosomal dominant 6 (HMND6) [MIM:615575] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated by IL2. Down-regulated in tumor-infiltrating T-cells.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6PIJ6-1	1	yes
Q6PIJ6-2	2, a
Q6PIJ6-3	3

RefSeq proteins (3): NP_001258652, NP_110420, NP_995308* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR042354	FBX38	Family

Pfam: PF00646

UniProt features (35 total): compositionally biased region 7, modified residue 6, sequence conflict 6, region of interest 5, short sequence motif 4, sequence variant 3, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PIJ6-F1	67.97	0.46

Functional residue map

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

Post-translational modifications (6): 591, 598, 600, 606, 736, 740

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 252 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_CELL_ADHESION, GTGCCTT_MIR506, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GGAANCGGAANY_UNKNOWN

GO Biological Process (11): adaptive immune response (GO:0002250), positive regulation of T cell mediated immune response to tumor cell (GO:0002842), positive regulation of neuron projection development (GO:0010976), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), positive regulation of T cell activation (GO:0050870), protein K48-linked ubiquitination (GO:0070936), immune system process (GO:0002376), negative regulation of T cell mediated immune response to tumor cell (GO:0002841), protein ubiquitination (GO:0016567), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), negative regulation of T cell activation (GO:0050868)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
T cell mediated immune response to tumor cell	2
regulation of T cell mediated immune response to tumor cell	2
proteasome-mediated ubiquitin-dependent protein catabolic process	2
T cell activation	2
regulation of T cell activation	2
cellular anatomical structure	2
immune response	1
positive regulation of T cell mediated immunity	1
positive regulation of immune response to tumor cell	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
positive regulation of lymphocyte activation	1
positive regulation of leukocyte cell-cell adhesion	1
protein polyubiquitination	1
biological_process	1
negative regulation of T cell mediated immunity	1
negative regulation of immune response to tumor cell	1
protein modification by small protein conjugation	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
negative regulation of lymphocyte activation	1
negative regulation of leukocyte cell-cell adhesion	1
enzyme-substrate adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO38	KLF7	O75840	899
FBXO38	RNH1	P13489	844
FBXO38	TDRP	Q86YL5	616
FBXO38	CDC40	O60508	565
FBXO38	PPIL4	Q8WUA2	562
FBXO38	MON2	Q7Z3U7	559
FBXO38	TRIP12	Q14669	535
FBXO38	DHX40	Q8IX18	529
FBXO38	DNMT1	P26358	491
FBXO38	SMOC2	Q9H3U7	490
FBXO38	PAK1IP1	Q9NWT1	484
FBXO38	DDX24	Q9GZR7	481
FBXO38	TCF7	P36402	475
FBXO38	AP3D1	O14617	461
FBXO38	HTATSF1	O43719	450

IntAct

47 interactions, top by confidence:

A	B	Type	Score
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
ATXN7L3	USP27X	psi-mi:“MI:0914”(association)	0.640
KIR3DL2	METTL15	psi-mi:“MI:0914”(association)	0.530
ZNF331	USP9Y	psi-mi:“MI:0914”(association)	0.530
TANK	TRAF5	psi-mi:“MI:0914”(association)	0.530
PTGES3	AIP	psi-mi:“MI:0914”(association)	0.530
DNAJC3	DEDD	psi-mi:“MI:0914”(association)	0.530
FBXO38	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
Dynll1		psi-mi:“MI:0915”(physical association)	0.400
FBXO38	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
FBXO38	CDC37	psi-mi:“MI:0915”(physical association)	0.400
ABL2	FBXO38	psi-mi:“MI:0915”(physical association)	0.370
PPM1G	FBXO38	psi-mi:“MI:0915”(physical association)	0.370
RING1	FBXO38	psi-mi:“MI:0915”(physical association)	0.370
SOX30	FBXO38	psi-mi:“MI:0915”(physical association)	0.370
USP7	STIL	psi-mi:“MI:0914”(association)	0.350
METTL14	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
FGL1	DNM1L	psi-mi:“MI:0914”(association)	0.350
STYX	BANF1	psi-mi:“MI:0914”(association)	0.350
USP7		psi-mi:“MI:0914”(association)	0.350
STYX	PAK4	psi-mi:“MI:0914”(association)	0.350
GRK6	ILVBL	psi-mi:“MI:0914”(association)	0.350
ATXN7L1	USP27X	psi-mi:“MI:0914”(association)	0.350

BioGRID (185): FBXO38 (Affinity Capture-RNA), FBXO38 (Affinity Capture-RNA), FBXO38 (Affinity Capture-RNA), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Affinity Capture-MS), FBXO38 (Two-hybrid), KLF7 (Reconstituted Complex)

ESM2 similar proteins: A5WW08, D2H0Y8, O42354, O75113, O94972, P23804, P56273, P56950, P56951, Q00987, Q0IIM1, Q3T139, Q3UMB5, Q58WW2, Q5BLK4, Q5FWP4, Q5R9B8, Q5REL3, Q5VYS8, Q5XIK5, Q5XIN1, Q60524, Q6A037, Q6GQJ2, Q6I6G8, Q6IE82, Q6NRG0, Q6P256, Q6PCX9, Q6PIJ6, Q6PUR7, Q6ZMN7, Q70EL1, Q76N89, Q7YRZ8, Q7Z7J5, Q7ZUW7, Q7ZX20, Q7ZYI3, Q80VH0

Diamond homologs: Q6PIJ6, Q8BMI0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FBXO38	“up-regulates activity”	KLF7	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	431
Likely benign	312
Benign	51

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2431046	NM_205836.3(FBXO38):c.2215C>A (p.Pro739Thr)	Pathogenic
91854	NM_205836.3(FBXO38):c.616T>C (p.Cys206Arg)	Pathogenic

SpliceAI

3652 predictions. Top by Δscore:

Variant	Effect	Δscore
5:148394710:TCA:T	acceptor_loss	1.0000
5:148394713:G:A	acceptor_loss	1.0000
5:148394713:GGT:G	acceptor_gain	1.0000
5:148394713:GGTA:G	acceptor_gain	1.0000
5:148394713:GGTAC:G	acceptor_gain	1.0000
5:148394858:GACTA:G	donor_gain	1.0000
5:148394882:G:GT	donor_gain	1.0000
5:148402342:TTCTA:T	acceptor_loss	1.0000
5:148402343:TCTA:T	acceptor_loss	1.0000
5:148402344:CTAG:C	acceptor_loss	1.0000
5:148402345:TAGGG:T	acceptor_loss	1.0000
5:148402346:A:T	acceptor_loss	1.0000
5:148402346:AG:A	acceptor_gain	1.0000
5:148402347:G:GA	acceptor_loss	1.0000
5:148402347:GG:G	acceptor_gain	1.0000
5:148402347:GGGT:G	acceptor_gain	1.0000
5:148402510:GTTG:G	donor_gain	1.0000
5:148402515:T:G	donor_loss	1.0000
5:148404684:GGGGT:G	acceptor_gain	1.0000
5:148406390:ATCAG:A	donor_loss	1.0000
5:148406392:CAG:C	donor_loss	1.0000
5:148406393:AG:A	donor_loss	1.0000
5:148406394:GG:G	donor_loss	1.0000
5:148406395:G:GA	donor_loss	1.0000
5:148406396:T:G	donor_loss	1.0000
5:148409119:TTTA:T	acceptor_loss	1.0000
5:148409121:TA:T	acceptor_loss	1.0000
5:148409122:A:AG	acceptor_gain	1.0000
5:148409122:A:AT	acceptor_loss	1.0000
5:148409122:AGGT:A	acceptor_gain	1.0000

AlphaMissense

7872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:148394889:T:C	L38P	1.000
5:148399004:T:C	L45P	1.000
5:148399049:T:C	L60P	1.000
5:148399073:T:C	L68P	1.000
5:148402123:T:C	L135S	1.000
5:148402141:T:C	L141S	1.000
5:148402406:T:A	V162D	1.000
5:148402417:G:A	G166R	1.000
5:148402417:G:C	G166R	1.000
5:148402417:G:T	G166W	1.000
5:148402423:T:C	F168L	1.000
5:148402424:T:C	F168S	1.000
5:148402425:T:A	F168L	1.000
5:148402425:T:G	F168L	1.000
5:148402431:T:A	N170K	1.000
5:148402431:T:G	N170K	1.000
5:148402444:T:C	F175L	1.000
5:148402445:T:C	F175S	1.000
5:148402446:T:A	F175L	1.000
5:148402446:T:G	F175L	1.000
5:148402469:T:C	L183P	1.000
5:148402508:T:C	L196S	1.000
5:148402513:G:A	G198R	1.000
5:148402513:G:C	G198R	1.000
5:148402513:G:T	G198W	1.000
5:148404685:G:A	G198E	1.000
5:148404685:G:T	G198V	1.000
5:148404694:T:A	V201D	1.000
5:148404730:T:C	L213P	1.000
5:148404741:T:A	W217R	1.000

dbSNP variants (sampled 300 via entrez): RS1000026466 (5:148395447 T>G), RS1000029730 (5:148407854 G>A), RS1000047153 (5:148436231 GAA>G), RS1000062953 (5:148440901 G>C,T), RS1000268847 (5:148388829 A>G), RS1000318411 (5:148422114 A>G,T), RS1000334829 (5:148408460 A>G,T), RS1000371250 (5:148408850 C>T), RS1000448809 (5:148415452 A>G), RS1000451065 (5:148407593 ATTT>A,ATT,ATTTT,ATTTTT), RS1000481405 (5:148415069 C>G), RS1000575434 (5:148382448 G>C), RS1000651318 (5:148434758 C>T), RS1000715918 (5:148433232 G>A), RS1000815172 (5:148413666 C>G,T)

Disease associations

OMIM: gene MIM:608533 | disease phenotypes: MIM:615575, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronopathy, distal hereditary motor, type 2D	Strong	Autosomal dominant
distal hereditary motor neuropathy	Moderate	Autosomal dominant
distal hereditary motor neuropathy type 2	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
distal hereditary motor neuropathy	Moderate	AD

Mondo (4): distal hereditary motor neuropathy type 2 (MONDO:0015352), neuronopathy, distal hereditary motor, type 2D (MONDO:0014259), Charcot-Marie-Tooth disease (MONDO:0015626), distal hereditary motor neuropathy (MONDO:0018894)

Orphanet (3): Distal hereditary motor neuropathy type 2 (Orphanet:139525), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Distal hereditary motor neuropathy (Orphanet:53739)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001288	Gait disturbance
HP:0001761	Pes cavus
HP:0002380	Fasciculations
HP:0003394	Muscle spasm
HP:0003431	Decreased motor nerve conduction velocity
HP:0003444	EMG: chronic denervation signs
HP:0003677	Slowly progressive
HP:0003701	Proximal muscle weakness
HP:0003828	Variable expressivity
HP:0007210	Lower limb amyotrophy
HP:0007269	Spinal muscular atrophy
HP:0007340	Lower limb muscle weakness
HP:0009005	Weakness of the intrinsic hand muscles
HP:0009046	Difficulty running
HP:0009072	Decreased Achilles reflex
HP:0031108	Triceps weakness

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001588_14	Periodontal microbiota	2.000000e-06
GCST002934_17	Zinc levels	6.000000e-06
GCST007611_18	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	1.000000e-13
GCST009114_2	Lung function (FEV1/FVC) variance	7.000000e-10
GCST009119_2	Lung function (FEV1/FVC)	2.000000e-58
GCST011766_5	Chronic obstructive pulmonary disease	2.000000e-13
GCST90002396_312	Mean reticulocyte volume	8.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0010701	mean reticulocyte volume

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
C580044	Distal Hereditary Motor Neuropathy, Type II (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects expression, decreases expression	3
FR900359	affects phosphorylation	1
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
abrine	increases expression	1
Sunitinib	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Coumestrol	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Methotrexate	decreases expression	1
Nickel	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8FU	Abcam HCT 116 FBXO38 KO	Cancer cell line	Male
CVCL_B8VN	Abcam MCF-7 FBXO38 KO	Cancer cell line	Female
CVCL_B9I1	Abcam A-549 FBXO38 KO	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