SBF2

Summary

SBF2 (SET binding factor 2, HGNC:2135) is a protein-coding gene on chromosome 11p15.4, encoding Myotubularin-related protein 13 (Q86WG5). Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28.

This gene encodes a pseudophosphatase and member of the myotubularin-related protein family. This gene maps within the CMT4B2 candidate region of chromosome 11p15 and mutations in this gene have been associated with Charcot-Marie-Tooth Disease, type 4B2.

Source: NCBI Gene 81846 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease type 4B2 (Definitive, ClinGen)
• GWAS associations: 47
• Clinical variants (ClinVar): 1,076 total — 43 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 57
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_030962

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2135
Approved symbol	SBF2
Name	SET binding factor 2
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1766, MTMR13, DENND7B
Ensembl gene	ENSG00000133812
Ensembl biotype	protein_coding
OMIM	607697
Entrez	81846

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 20 protein_coding, 13 retained_intron, 12 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000256190, ENST00000420722, ENST00000524961, ENST00000525040, ENST00000526353, ENST00000527019, ENST00000528478, ENST00000529587, ENST00000530741, ENST00000532095, ENST00000533584, ENST00000533661, ENST00000533770, ENST00000675281, ENST00000676324, ENST00000676387, ENST00000685217, ENST00000686079, ENST00000686677, ENST00000687210, ENST00000687256, ENST00000687300, ENST00000688206, ENST00000688344, ENST00000688417, ENST00000688739, ENST00000689128, ENST00000689258, ENST00000689342, ENST00000689356, ENST00000689597, ENST00000689674, ENST00000689940, ENST00000690003, ENST00000690234, ENST00000690437, ENST00000690806, ENST00000690944, ENST00000690959, ENST00000691616, ENST00000692068, ENST00000692716, ENST00000693022, ENST00000693181, ENST00000693201, ENST00000693212, ENST00000693541, ENST00000856971

RefSeq mRNA: 6 — MANE Select: NM_030962 NM_001386339, NM_001386342, NM_001424318, NM_001425069, NM_001425070, NM_030962

CCDS: CCDS31427, CCDS91439, CCDS91440

Canonical transcript exons

ENST00000256190 — 40 exons

Exon	Start	End
ENSE00000910974	9790556	9790683
ENSE00000910975	9795831	9795957
ENSE00001121731	9787634	9787738
ENSE00001214325	9839498	9839696
ENSE00001217509	9778668	9780516
ENSE00001312343	9789109	9789342
ENSE00001339668	9812532	9812708
ENSE00001339673	9829356	9829496
ENSE00001339674	9832224	9832420
ENSE00001339834	10193902	10193987
ENSE00003459508	10031048	10031170
ENSE00003461562	10028452	10028557
ENSE00003466782	9785125	9785318
ENSE00003482651	9998266	9998379
ENSE00003486864	9808000	9808185
ENSE00003497061	9784351	9784438
ENSE00003502157	9853540	9853712
ENSE00003523607	10002557	10002689
ENSE00003531915	9993921	9993998
ENSE00003537024	9852676	9852749
ENSE00003537964	10000914	10001022
ENSE00003544856	9968341	9968545
ENSE00003555818	9992990	9993103
ENSE00003556172	9842625	9842770
ENSE00003556920	9850023	9850218
ENSE00003589548	9989497	9989595
ENSE00003606233	9992415	9992543
ENSE00003609265	9845565	9845740
ENSE00003620893	9808901	9809002
ENSE00003626191	9816840	9817024
ENSE00003629061	9781507	9781638
ENSE00003634742	9963773	9963882
ENSE00003641234	10029765	10029875
ENSE00003642394	9858226	9858396
ENSE00003645445	9895943	9896011
ENSE00003667228	9856458	9856720
ENSE00003669156	9846956	9847083
ENSE00003679273	9961957	9962106
ENSE00003681770	10042844	10042981
ENSE00003900171	10294015	10294219

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 97.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.5813 / max 425.8024, expressed in 1800 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118596	27.0508	1799
118583	0.2684	122
118594	0.2179	61
118593	0.0185	9
118595	0.0155	6
118592	0.0102	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	97.18	silver quality
colonic epithelium	UBERON:0000397	95.99	gold quality
calcaneal tendon	UBERON:0003701	95.77	gold quality
sural nerve	UBERON:0015488	95.45	gold quality
cortical plate	UBERON:0005343	95.32	gold quality
germinal epithelium of ovary	UBERON:0001304	93.40	gold quality
ventricular zone	UBERON:0003053	93.16	gold quality
seminal vesicle	UBERON:0000998	92.63	gold quality
mucosa of stomach	UBERON:0001199	92.59	gold quality
adrenal tissue	UBERON:0018303	92.48	gold quality
pancreatic ductal cell	CL:0002079	92.38	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.25	gold quality
tibial nerve	UBERON:0001323	92.08	gold quality
corpus callosum	UBERON:0002336	91.91	gold quality
adipose tissue	UBERON:0001013	91.84	gold quality
oviduct epithelium	UBERON:0004804	91.76	gold quality
uterine cervix	UBERON:0000002	91.72	gold quality
palpebral conjunctiva	UBERON:0001812	91.44	gold quality
ectocervix	UBERON:0012249	91.44	gold quality
left ventricle myocardium	UBERON:0006566	91.41	silver quality
gingival epithelium	UBERON:0001949	91.38	gold quality
kidney epithelium	UBERON:0004819	91.36	silver quality
ganglionic eminence	UBERON:0004023	91.27	gold quality
endocervix	UBERON:0000458	91.23	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.18	silver quality
left ovary	UBERON:0002119	90.96	gold quality
eye	UBERON:0000970	90.80	gold quality
urinary bladder	UBERON:0001255	90.60	gold quality
stromal cell of endometrium	CL:0002255	90.51	gold quality
thoracic mammary gland	UBERON:0005200	90.41	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	20.86
E-CURD-46	yes	14.43
E-GEOD-137537	yes	8.63
E-ANND-3	yes	6.78
E-GEOD-111727	no	1259.15
E-MTAB-6524	no	159.89
E-MTAB-7606	no	60.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

154 targeting SBF2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-656-3P	100.00	72.15	2788
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
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-5011-5P	100.00	83.46	5820
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-9983-3P	99.94	71.48	3631

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 14)

• Mutations in MTMR13 were associated with a syndrome of demyelinating Charcot-Marie-Tooth disease and early onset glaucoma; MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork (PMID:12687498)
• A loss-of-function mutation in SBF2/MTMR13 causes CMT4B with early-onset glaucoma, possibly by degradation of SBF2 mRNA thru the nonsense mutation decay pathway. (PMID:15304601)
• The first evidence of a mutation in the splicing site of the SBF2 gene, confirming that mutations in the SBF2 gene are causative of the CMT4B2 subtype of Charcot-Marie-Tooth disease. (PMID:15477569)
• Loss of MTMR13 (SBF2) function in Charcot-Marie-Tooth disease type 4B patients may lead to alterations in MTMR2 function and subsequent alterations in 3-phosphoinositide signaling. (PMID:15998640)
• review of the role of MTMR2 and MTMR13 and their involvement in the biology of Schwann cell and CMT4B neuropathies (PMID:17880751)
• REVIEW : MTMR13 and homologous proteins are mutated in several neuromuscular diseases (PMID:18429927)
• A phylogenetic study revealing co-evolution of myotubularins with PI 3-kinase class III complex (PMID:18774718)
• FLNB and SBF2 are associated with human stature. (PMID:19039035)
• Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. (PMID:23180869)
• Identification of a novel SBF2 missense mutation associated with a rare case of thrombocytopenia using whole-exome sequencing. (PMID:23334996)
• SBF2 frameshift mutation is associated with charcot-marie-tooth disease type 4B2. (PMID:25462154)
• Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion. (PMID:25648148)
• Rare variants in SBF2 predict an increased risk of taxane-induced peripheral neuropathy in African American breast cancer patients receiving paclitaxel. (PMID:27732968)
• The impact of SBF2 on taxane-induced peripheral neuropathy. (PMID:34986146)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	sbf2	ENSDARG00000059460
mus_musculus	Sbf2	ENSMUSG00000038371
rattus_norvegicus	Sbf2	ENSRNOG00000009812
drosophila_melanogaster	mtm	FBGN0025742
drosophila_melanogaster	Sbf	FBGN0025802
drosophila_melanogaster	Mtmr6	FBGN0028497
drosophila_melanogaster	CG14411	FBGN0030582
drosophila_melanogaster	CG3632	FBGN0030735
drosophila_melanogaster	CG5026	FBGN0035945
caenorhabditis_elegans	mtm-1	WBGENE00003475
caenorhabditis_elegans		WBGENE00003476
caenorhabditis_elegans		WBGENE00003477
caenorhabditis_elegans		WBGENE00003478
caenorhabditis_elegans		WBGENE00003479
caenorhabditis_elegans	mtm-10	WBGENE00021683

Paralogs (13): MTMR7 (ENSG00000003987), MTMR11 (ENSG00000014914), MTMR1 (ENSG00000063601), MTMR2 (ENSG00000087053), SBF1 (ENSG00000100241), MTMR3 (ENSG00000100330), MTMR8 (ENSG00000102043), MTMR9 (ENSG00000104643), MTMR4 (ENSG00000108389), MTMR6 (ENSG00000139505), MTMR12 (ENSG00000150712), MTMR10 (ENSG00000166912), MTM1 (ENSG00000171100)

Protein

Protein identifiers

Myotubularin-related protein 13 — Q86WG5 (reviewed: Q86WG5)

Alternative names: Inactive phosphatidylinositol 3-phosphatase 13, SET-binding factor 2

All UniProt accessions (28): A0A6Q8PH13, A0A6Q8PH87, A0A6Q8PHP8, A0A8I5KNS4, A0A8I5KQ02, Q86WG5, A0A8I5KQC6, A0A8I5KRP8, A0A8I5KRQ5, A0A8I5KSD8, A0A8I5KT45, A0A8I5KT92, A0A8I5KTA9, A0A8I5KTX3, A0A8I5KUI7, A0A8I5KUI9, A0A8I5KUN8, A0A8I5KVJ0, A0A8I5KWJ6, A0A8I5KWU9, A0A8I5KWY5, A0A8I5KXJ7, A0A8I5KY55, A0A8I5QJN8, A0A8I5QKS9, A0A8I5QL20, H0Y767, H0YD05

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. In response to starvation-induced autophagy, activates RAB21 which in turn binds to and regulates SNARE protein VAMP8 endolysosomal transport required for SNARE-mediated autophagosome-lysosome fusion. Acts as an adapter for the phosphatase MTMR2. Increases MTMR2 catalytic activity towards phosphatidylinositol 3,5-bisphosphate and to a lesser extent towards phosphatidylinositol 3-phosphate.

Subunit / interactions. Homodimer. Heterotetramer consisting of one MTMR2 dimer and one SBF2/MTMR13 dimer; stabilizes SBF2/MTMR13 at the membranes and increases MTMR2 catalytic activity towards phosphatidylinositol 3,5-bisphosphate and to a lesser extent towards phosphatidylinositol 3-phosphate. Interacts with SBF1/MTMR5; the interaction seems to be independent of the coiled-coil and PH domain of SBF2/MTMR13 and independent of MTMR2. Interacts with class II PI3-kinase PIK3C2A. Interacts (via DENN domain) with RAB21 (in GDP-bound form) in response to starvation; the interaction activates RAB21. Interacts with VAMP8 in response to starvation.

Subcellular location. Cytoplasm. Perinuclear region. Membrane. Endosome membrane. Cell projection. Axon.

Tissue specificity. Widely expressed. Expressed in spinal cord.

Disease relevance. Charcot-Marie-Tooth disease, demyelinating, type 4B2 (CMT4B2) [MIM:604563] 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 C-terminal domain mediates homodimerization. By mediating SBF2/MTMR13 homodimerization, indirectly involved in SBF2/MTMR13 and MTMR2 heterotetramerization. The GRAM domain mediates binding to phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 3,5-biphosphate and phosphatidylinositol 3,4,5-trisphosphate. The PH domain binds preferentially phosphatidylinositol 3,4,5-trisphosphate. Appears to be dispensable for localization to membranes.

Similarity. Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86WG5-1	1	yes
Q86WG5-3	3

RefSeq proteins (6): NP_001373268, NP_001373271, NP_001411247, NP_001411998, NP_001411999, NP_112224* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001194	cDENN_dom	Domain
IPR001849	PH_domain	Domain
IPR004182	GRAM	Domain
IPR005112	dDENN_dom	Domain
IPR005113	uDENN_dom	Domain
IPR010569	Myotubularin-like_Pase_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR022096	SBF1/SBF2	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR030564	Myotubularin	Family
IPR037516	Tripartite_DENN	Domain
IPR037823	MTMR13_PH-GRAM	Domain
IPR043153	DENN_C	Homologous_superfamily

Pfam: PF00169, PF02141, PF02893, PF03456, PF06602, PF12335

UniProt features (18 total): domain 6, sequence variant 3, modified residue 2, splice variant 2, sequence conflict 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86WG5-F1	73.74	0.27

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 (2): 1279, 1127

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs
R-HSA-1430728	Metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-199991	Membrane Trafficking
R-HSA-556833	Metabolism of lipids
R-HSA-5653656	Vesicle-mediated transport
R-HSA-9007101	Rab regulation of trafficking

MSigDB gene sets: 338 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOCC_VACUOLAR_MEMBRANE, TTTGTAG_MIR520D, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, REACTOME_MEMBRANE_TRAFFICKING, GGGTGGRR_PAX4_03, ATGTTAA_MIR302C, CEBP_Q2, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_ENSHEATHMENT_OF_NEURONS, HFH1_01, RYTTCCTG_ETS2_B, BASAKI_YBX1_TARGETS_DN, GOCC_NEURON_PROJECTION, PTF1BETA_Q6

GO Biological Process (2): autophagy (GO:0006914), myelination (GO:0042552)

GO Molecular Function (6): guanyl-nucleotide exchange factor activity (GO:0005085), phosphatase regulator activity (GO:0019208), phosphatase binding (GO:0019902), phosphatidylinositol binding (GO:0035091), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), vacuolar membrane (GO:0005774), cytosol (GO:0005829), endosome membrane (GO:0010008), membrane (GO:0016020), axon (GO:0030424), perinuclear region of cytoplasm (GO:0048471), endosome (GO:0005768), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
PI Metabolism	1
Rab regulation of trafficking	1
Phospholipid metabolism	1
Metabolism of lipids	1
Vesicle-mediated transport	1
Metabolism	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
bounding membrane of organelle	2
cytoplasm	2
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
axon ensheathment	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
phosphatase activity	1
phosphatase binding	1
enzyme regulator activity	1
enzyme binding	1
anion binding	1
protein binding	1
binding	1
intracellular anatomical structure	1
vacuole	1
endosome	1
cytoplasmic vesicle membrane	1
neuron projection	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

915 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SBF2	MTMR2	Q13614	919
SBF2	SH3TC2	Q8TF17	789
SBF2	FGD4	Q96M96	748
SBF2	GDAP1	Q8TB36	742
SBF2	FIG4	Q92562	738
SBF2	ADGRD1	Q6QNK2	719
SBF2	ADGRG6	Q86SQ4	714
SBF2	NPR3	P17342	673
SBF2	RAB21	Q9UL25	668
SBF2	LIN28B	Q6ZN17	649
SBF2	GJB1	P08034	590
SBF2	MCM6	Q14566	589
SBF2	FLNB	O75369	587
SBF2	LITAF	Q99732	571
SBF2	RNMT	O43148	570

IntAct

26 interactions, top by confidence:

A	B	Type	Score
MTMR2	CCDC22	psi-mi:“MI:0914”(association)	0.730
RBPMS	SBF2	psi-mi:“MI:0915”(physical association)	0.560
FHL3	SBF2	psi-mi:“MI:0915”(physical association)	0.560
MTMR1	GMNN	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
SBF2	SBF1	psi-mi:“MI:0914”(association)	0.420
SBF2	HNRNPU	psi-mi:“MI:0915”(physical association)	0.400
Mtmr2	SBF1	psi-mi:“MI:0914”(association)	0.350
HNRNPD	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
SYNCRIP	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
BAG6	CNOT1	psi-mi:“MI:0914”(association)	0.350
SORT1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MTMR2	LUC7L3	psi-mi:“MI:0914”(association)	0.350
LSM7	GEMIN2	psi-mi:“MI:0914”(association)	0.350
INF2	PIPSL	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
DHFR	FANCA	psi-mi:“MI:0914”(association)	0.350
SBF2	PMPCB	psi-mi:“MI:2364”(proximity)	0.270
DISC1	SBF2	psi-mi:“MI:0915”(physical association)	0.000
SBF2	FHL3	psi-mi:“MI:0915”(physical association)	0.000
SBF2	FOS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (53): SBF2 (Two-hybrid), SBF2 (Affinity Capture-MS), SBF2 (Affinity Capture-MS), SBF2 (Synthetic Growth Defect), SBF2 (Affinity Capture-MS), SBF2 (Affinity Capture-MS), SBF2 (Affinity Capture-MS), SBF2 (Affinity Capture-MS), SBF2 (Affinity Capture-MS), SBF2 (Affinity Capture-MS), SBF2 (Affinity Capture-MS), MTMR1 (Affinity Capture-MS), MTMR2 (Affinity Capture-MS), SBF1 (Affinity Capture-MS), MTMR2 (Proximity Label-MS)

ESM2 similar proteins: A0JMD0, A1A535, A1ZAB5, A2AIV2, A8E7C5, A8PJX4, A8XAA9, B0W2S0, B3MIW0, B3NPV8, B4GAM1, B4JW99, B4KT50, B4LQ23, B4MY63, B4P6P7, D3YVL2, E9PXF8, F4HS99, F4HZK4, F4J5S1, F4JKH6, O60502, O75153, O88379, P34466, P69735, Q0IHW8, Q0VA04, Q15042, Q17N71, Q291J5, Q5PQS3, Q5SW19, Q5TYW4, Q5U430, Q69YN4, Q6NTN5, Q6ZT12, Q7PZD5

Diamond homologs: A0A0G2JXT6, A0JMK5, A6QLT2, A6QLT4, A7MB43, F4J3T8, F4JWB3, G5ED68, O13819, P47147, Q13496, Q13613, Q13614, Q13615, Q22712, Q2KJ24, Q52KU6, Q54GQ1, Q55E58, Q5EB32, Q5F452, Q5PQT2, Q5R6F6, Q5R9S3, Q5REB9, Q5ZIV1, Q6AXQ4, Q6TEL0, Q7ZXF1, Q86WG5, Q8K296, Q8VE11, Q91XS1, Q965W9, Q96EF0, Q96QG7, Q9N589, Q9NYA4, Q9Y216, Q9Y217

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1076 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	17
Uncertain significance	491
Likely benign	388
Benign	58

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072400	NC_000011.9:g.(?9989878)(9990102_?)del	Pathogenic
1072401	NC_000011.9:g.(?10215443)(10215540_?)del	Pathogenic
1076239	NC_000011.9:g.(?9809171)(9812240_?)del	Pathogenic
1453531	NM_030962.4(SBF2):c.444del (p.Asn149fs)	Pathogenic
1459048	NC_000011.9:g.(?9864152)(9871785_?)del	Pathogenic
1686137	NM_030962.4(SBF2):c.4877del (p.Pro1626fs)	Pathogenic
1734143	NM_030962.4(SBF2):c.3706C>T (p.Gln1236Ter)	Pathogenic
1789225	NM_030962.4(SBF2):c.229C>T (p.Arg77Ter)	Pathogenic
2022380	NM_030962.4(SBF2):c.4296T>G (p.Tyr1432Ter)	Pathogenic
2032532	NM_030962.4(SBF2):c.4297dup (p.Arg1433fs)	Pathogenic
2033308	NM_030962.4(SBF2):c.613C>T (p.Gln205Ter)	Pathogenic
2044685	NM_030962.4(SBF2):c.952C>T (p.Gln318Ter)	Pathogenic
2063142	NM_030962.4(SBF2):c.610C>T (p.Gln204Ter)	Pathogenic
2066168	NM_030962.4(SBF2):c.331C>T (p.Gln111Ter)	Pathogenic
2426959	NC_000011.9:g.(?9809161)(9812250_?)del	Pathogenic
245894	NM_030962.4(SBF2):c.4315C>T (p.Gln1439Ter)	Pathogenic
2728844	NM_030962.4(SBF2):c.4363C>T (p.Gln1455Ter)	Pathogenic
2730910	NM_030962.4(SBF2):c.387T>A (p.Tyr129Ter)	Pathogenic
2740044	NM_030962.4(SBF2):c.958C>T (p.Gln320Ter)	Pathogenic
2817938	NM_030962.4(SBF2):c.724G>T (p.Glu242Ter)	Pathogenic
2899750	NM_030962.4(SBF2):c.1516del (p.Gln506fs)	Pathogenic
2909	NM_030962.4(SBF2):c.1088_1296+646del	Pathogenic
2910	NM_030962.4(SBF2):c.2875C>T (p.Gln959Ter)	Pathogenic
2911	NM_030962.4(SBF2):c.3586C>T (p.Arg1196Ter)	Pathogenic
2912	NM_030962.4(SBF2):c.1459C>T (p.Arg487Ter)	Pathogenic
2960159	NM_030962.4(SBF2):c.4187dup (p.Ser1397fs)	Pathogenic
3236699	NM_030962.4(SBF2):c.620G>T (p.Gly207Val)	Pathogenic
3244699	NC_000011.9:g.(?10013942)(10022589_?)del	Pathogenic
3244700	NC_000011.9:g.(?9878231)(9902092_?)del	Pathogenic
3706892	NM_030962.4(SBF2):c.4547C>G (p.Ser1516Ter)	Pathogenic

SpliceAI

8113 predictions. Top by Δscore:

Variant	Effect	Δscore
11:10000905:AATAC:A	donor_loss	1.0000
11:10000906:ATACT:A	donor_loss	1.0000
11:10000907:TACTT:T	donor_loss	1.0000
11:10000908:ACT:A	donor_loss	1.0000
11:10000909:CTTA:C	donor_loss	1.0000
11:10000910:T:TG	donor_loss	1.0000
11:10000911:T:TG	donor_loss	1.0000
11:10000912:A:AC	donor_gain	1.0000
11:10000913:C:CT	donor_gain	1.0000
11:10000913:CA:C	donor_gain	1.0000
11:10000913:CAA:C	donor_gain	1.0000
11:10000913:CAAG:C	donor_gain	1.0000
11:10000913:CAAGT:C	donor_gain	1.0000
11:10001018:GATAA:G	acceptor_gain	1.0000
11:10001019:ATAA:A	acceptor_gain	1.0000
11:10001020:TAA:T	acceptor_gain	1.0000
11:10001021:AA:A	acceptor_gain	1.0000
11:10001023:C:CC	acceptor_gain	1.0000
11:10029762:TACCT:T	donor_loss	1.0000
11:10029764:CCTGA:C	donor_loss	1.0000
11:10029820:T:A	donor_gain	1.0000
11:10029871:CAAGC:C	acceptor_gain	1.0000
11:10029872:AAGC:A	acceptor_gain	1.0000
11:10029873:AGC:A	acceptor_gain	1.0000
11:10029873:AGCC:A	acceptor_loss	1.0000
11:10029874:GC:G	acceptor_gain	1.0000
11:10029875:CC:C	acceptor_gain	1.0000
11:10029876:C:CC	acceptor_gain	1.0000
11:10029876:CT:C	acceptor_loss	1.0000
11:10042977:CAAAA:C	acceptor_gain	1.0000

AlphaMissense

12176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:9780456:A:G	W1838R	1.000
11:9780456:A:T	W1838R	1.000
11:9780488:A:G	F1827S	1.000
11:9781637:A:G	L1774P	1.000
11:9784376:A:G	F1765S	1.000
11:9784392:A:G	W1760R	1.000
11:9784392:A:T	W1760R	1.000
11:9784414:T:A	K1752N	1.000
11:9784414:T:G	K1752N	1.000
11:9784416:T:C	K1752E	1.000
11:9858339:A:G	W663R	1.000
11:9858339:A:T	W663R	1.000
11:10000951:C:T	G275E	0.999
11:10002626:G:A	S228F	0.999
11:10002635:A:G	L225P	0.999
11:10002638:A:T	V224D	0.999
11:10002668:A:G	L214P	0.999
11:10042963:A:G	W54R	0.999
11:10042963:A:T	W54R	0.999
11:9780454:C:A	W1838C	0.999
11:9780454:C:G	W1838C	0.999
11:9780495:A:C	Y1825D	0.999
11:9780515:A:G	L1818P	0.999
11:9781511:A:G	F1816S	0.999
11:9781634:C:G	R1775P	0.999
11:9784352:T:G	Q1773P	0.999
11:9784375:A:C	F1765L	0.999
11:9784375:A:T	F1765L	0.999
11:9784377:A:G	F1765L	0.999
11:9784382:C:G	R1763P	0.999

dbSNP variants (sampled 300 via entrez): RS1000007040 (11:10213186 C>T), RS1000016415 (11:9965050 C>A,T), RS1000017461 (11:10132776 G>T), RS1000017820 (11:9790444 G>A), RS1000018250 (11:9836881 G>T), RS1000020239 (11:10226393 A>G), RS1000026965 (11:10293745 G>A,C), RS1000029161 (11:10030475 C>A), RS1000031501 (11:10071072 G>A), RS1000032838 (11:10253352 C>A), RS1000044772 (11:10259477 C>G), RS1000045953 (11:10092114 T>C), RS1000047444 (11:10171302 A>G), RS1000059443 (11:10031220 C>T), RS1000060794 (11:10186366 T>G)

Disease associations

OMIM: gene MIM:607697 | disease phenotypes: MIM:604563, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 4B2	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 4B2	Definitive	AR

Mondo (3): Charcot-Marie-Tooth disease type 4 (MONDO:0018995), Charcot-Marie-Tooth disease type 4B2 (MONDO:0011475), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (3): Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Charcot-Marie-Tooth disease type 4B2 (Orphanet:99956), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000183	Tongue muscle weakness
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000557	Buphthalmos
HP:0000648	Optic atrophy
HP:0000729	Autistic behavior
HP:0001026	Penetrating foot ulcers
HP:0001087	Developmental glaucoma
HP:0001171	Split hand
HP:0001178	Ulnar claw
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001328	Specific learning disability
HP:0001337	Tremor
HP:0001605	Vocal cord paralysis
HP:0001618	Dysphonia
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0001765	Hammertoe
HP:0002093	Respiratory insufficiency
HP:0002460	Distal muscle weakness
HP:0002522	Areflexia of lower limbs
HP:0002540	Inability to walk

GWAS associations

47 associations (top):

Study	Trait	p-value
GCST001749_7	Pancreatic cancer	2.000000e-07
GCST003770_37	Neuroticism	3.000000e-09
GCST004485_21	Survival in pancreatic cancer	2.000000e-07
GCST004601_153	Red blood cell count	3.000000e-27
GCST004604_64	Hematocrit	9.000000e-39
GCST004604_65	Hematocrit	5.000000e-27
GCST004615_69	Hemoglobin concentration	3.000000e-32
GCST004615_70	Hemoglobin concentration	1.000000e-23
GCST004744_42	Lung adenocarcinoma	2.000000e-06
GCST005575_32	Moyamoya disease	8.000000e-09
GCST005983_37	Serum uric acid levels	2.000000e-08
GCST006586_30	Urinary albumin excretion	3.000000e-09
GCST007725_27	Serum uric acid levels	1.000000e-08
GCST007929_97	Medication use (calcium channel blockers)	3.000000e-08
GCST008058_270	Estimated glomerular filtration rate	5.000000e-08
GCST008059_160	Estimated glomerular filtration rate	7.000000e-11
GCST008790_40	Urinary albumin-to-creatinine ratio	6.000000e-10
GCST008794_32	Urinary albumin-to-creatinine ratio	1.000000e-09
GCST009640_40	Urinary albumin-to-creatinine ratio	2.000000e-08
GCST009685_3	Hypertension	3.000000e-12
GCST010083_102	Hemoglobin levels	1.000000e-54
GCST010083_253	Hemoglobin levels	1.000000e-28
GCST010727_27	Deep white matter hyperintensities	6.000000e-07
GCST011011_18	Youthful appearance (self-reported)	5.000000e-13
GCST011346_65	Total cholesterol levels	4.000000e-08
GCST012227_659	Hip circumference adjusted for BMI	4.000000e-10
GCST012228_405	Waist-hip index	4.000000e-10
GCST012228_406	Waist-hip index	3.000000e-11
GCST012228_407	Waist-hip index	2.000000e-09
GCST012230_26	Waist-to-hip ratio adjusted for BMI	6.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0000638	overall survival
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004761	uric acid measurement
EFO:0004285	albuminuria
EFO:0009930	Calcium channel blocker use measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0005665	white matter hyperintensity measurement
EFO:0004574	total cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004980	appendicular lean mass

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
C535421	Charcot-Marie-Tooth disease, Type 4B2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11042725	ADM, SBF2	3	3.25	1	paroxetine

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, increases expression	6
Benzo(a)pyrene	affects methylation, decreases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, decreases expression	1
aflatoxin B2	decreases methylation	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Panobinostat	increases expression	1
Cisplatin	decreases expression	1

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
NCT05902351	Not specified	RECRUITING	Natural History Study for 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