SH3TC2

Summary

SH3TC2 (SH3 domain and tetratricopeptide repeats 2, HGNC:29427) is a protein-coding gene on chromosome 5q32, encoding SH3 domain and tetratricopeptide repeat-containing protein 2 (Q8TF17). Is involved in nerve myelination and is required for the integrity of nodes of Ranvier.

This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons.

Source: NCBI Gene 79628 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete autosomal recessive hereditary demyelinating motor and sensory neuropathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 1,866 total — 104 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 75
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_024577

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29427
Approved symbol	SH3TC2
Name	SH3 domain and tetratricopeptide repeats 2
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1985, CMT4C
Ensembl gene	ENSG00000169247
Ensembl biotype	protein_coding
OMIM	608206
Entrez	79628

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 12 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 4 protein_coding, 3 retained_intron

ENST00000323829, ENST00000502274, ENST00000503071, ENST00000504091, ENST00000504517, ENST00000504690, ENST00000510350, ENST00000510779, ENST00000511307, ENST00000511949, ENST00000512049, ENST00000513340, ENST00000513604, ENST00000515229, ENST00000515425, ENST00000643113, ENST00000674655, ENST00000674983, ENST00000675793, ENST00000676056, ENST00000676367, ENST00000867060, ENST00000964176

RefSeq mRNA: 1 — MANE Select: NM_024577 NM_024577

CCDS: CCDS4293

Canonical transcript exons

ENST00000515425 — 17 exons

Exon	Start	End
ENSE00002076902	148982150	149004902
ENSE00003462716	149031554	149031687
ENSE00003475519	149012584	149012734
ENSE00003485845	149010270	149010392
ENSE00003499340	149044533	149044638
ENSE00003560392	149062971	149063062
ENSE00003577342	149028677	149028718
ENSE00003589546	149041416	149041617
ENSE00003614111	149047862	149047989
ENSE00003623485	149008851	149009001
ENSE00003659865	149040604	149040677
ENSE00003659962	149038295	149038490
ENSE00003663775	149026860	149028554
ENSE00003671943	149052142	149052240
ENSE00003675790	149026572	149026752
ENSE00003680299	149006881	149007077
ENSE00003691283	149042694	149042837

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 87.82.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4023 / max 137.6501, expressed in 224 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64112	1.3340	209
64114	0.4339	199
64113	0.0683	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	87.82	gold quality
sural nerve	UBERON:0015488	85.74	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.15	gold quality
spinal cord	UBERON:0002240	82.17	gold quality
medial globus pallidus	UBERON:0002477	81.13	gold quality
placenta	UBERON:0001987	81.09	gold quality
endothelial cell	CL:0000115	79.38	gold quality
tibial nerve	UBERON:0001323	77.42	gold quality
globus pallidus	UBERON:0001875	77.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.01	gold quality
right testis	UBERON:0004534	73.96	gold quality
apex of heart	UBERON:0002098	73.15	gold quality
cranial nerve II	UBERON:0000941	73.05	gold quality
left testis	UBERON:0004533	72.36	gold quality
lower esophagus mucosa	UBERON:0035834	71.66	gold quality
substantia nigra	UBERON:0002038	71.18	gold quality
testis	UBERON:0000473	71.13	gold quality
monocyte	CL:0000576	70.80	gold quality
mononuclear cell	CL:0000842	70.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	70.36	gold quality
midbrain	UBERON:0001891	70.28	gold quality
leukocyte	CL:0000738	69.99	gold quality
inferior vagus X ganglion	UBERON:0005363	69.96	silver quality
prefrontal cortex	UBERON:0000451	69.91	gold quality
olfactory bulb	UBERON:0002264	69.72	gold quality
amygdala	UBERON:0001876	69.51	gold quality
subthalamic nucleus	UBERON:0001906	68.95	silver quality
putamen	UBERON:0001874	68.40	gold quality
right atrium auricular region	UBERON:0006631	68.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	67.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.28
E-MTAB-7303	no	12.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

903 targeting SH3TC2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 25)

• This paper presents an analysis of the SH3TC2 promoter after identifying a read-through transcript of the SH3TC2 and HTR4 loci. Available data suggests HTR4 is a separate locus with its own promoter, and not the product of a bi-cistronic transcript. (PMID:11716477)
• mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy (PMID:14574644)
• a founder mutation, p.Arg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes (PMID:16326826)
• the SH3TC2 p.R1109X mutation is associated with a conserved haplotype and, therefore, may be a private founder mutation for the Gypsy population (PMID:17470135)
• Linkage analysis confirmed that all families are linked to CMT4C locus on chromosome 5q32 (multipoint LOD score of 9.06). Haplotype analysis suggests that two SH3TC2 mutations are present in this cohort (PMID:18511281)
• Structural alterations to the SH3TC2 gene could possibly predispose to peripheral nerve inflammation. (PMID:19272779)
• Missense mutations in the SH3TC2 causing Charcot-Marie-Tooth disease type 4C affect its localization to plasma membrane. (PMID:19744956)
• Mistargeting of SH3TC2 away from the recycling endosome is the fundamental molecular defect that leads to Charcot-Marie-Tooth disease type 4C. (PMID:20028792)
• Mutations in the SH3TC2 gene are a frequent cause of HMSN I in Czech patients. (PMID:21291453)
• This study presented evidence that mutations c.279G –> A and c.3676-8G –>A in the SH3TC2 gene cause aberrant splicing and are therefore pathogenic and causal for CMT4C. (PMID:22950825)
• Data indicate that the most frequent form is SH3TC2 gene (CMT4C; 57.14%), followed by HK1 gene causative of CMT4G (CMT4G/HMSN-Russe 25%) and NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom; 17.86%). (PMID:22978647)
• SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes. (PMID:24833716)
• The novelty of our data is the relatively high frequency of SH3TC2 and GDAP1 mutations in demyelinating and axonal forms, respectively, of Charcot-Marie-Tooth disease (PMID:25429913)
• DNA sequence analysis in a French-Canadian family revealed a novel combination of 2 known recessive mutations, p.R904X and p.R954X, in the SH3TC2 gene. (PMID:25737037)
• A homozygous missense mutation c.1894G>A of SH3TC2 is associated with Charcot-Marie-Tooth disease type 4C. (PMID:26829735)
• In this series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR-CMT type. (PMID:27231023)
• Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating form of CMT characterized clinically by early onset and severe spinal deformities, and is caused by mutations in SH3TC2. (PMID:27882734)
• This present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2. (PMID:28981955)
• SH3TC2, PMP2, and BSCL2 pathogenic variants might be rare in Chinese Charcot-Marie-Tooth (CMT) patients. (PMID:29336362)
• Mutations in SH3TC2 are responsible for 26% of Greek patients with suspected CMT4C. (PMID:30653784)
• Compound heterozygous mutations of SH3TC2 in Charcot-Marie-Tooth disease type 4C patients. (PMID:31227790)
• Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants. (PMID:31634715)
• Screening for SH3TC2 variants in Charcot-Marie-Tooth disease in a cohort of Chinese patients. (PMID:33587240)
• Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy. (PMID:37372933)
• Characterisation of Patients with SH3TC2 Associated Neuropathy in an Indian Cohort. (PMID:37929431)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3tc2	ENSDARG00000089917
mus_musculus	Sh3tc2	ENSMUSG00000045629
rattus_norvegicus	Sh3tc2	ENSRNOG00000019305

Paralogs (1): SH3TC1 (ENSG00000125089)

Protein

Protein identifiers

SH3 domain and tetratricopeptide repeat-containing protein 2 — Q8TF17 (reviewed: Q8TF17)

All UniProt accessions (11): Q8TF17, A0A2R8YCS9, A0A514TP98, A0A6Q8PFZ4, A0A6Q8PHT4, A0A7I2Y4M9, D6RA65, D6RFX2, E9PDF1, H0Y8Q9, H0Y9E7

UniProt curated annotations — full annotation on UniProt →

Function. Is involved in nerve myelination and is required for the integrity of nodes of Ranvier. It probably functions as a Rab effector in the regulation of endocytic recycling.

Subunit / interactions. Can form homodimers. Interacts with RAB11A.

Subcellular location. Cell membrane. Recycling endosome.

Tissue specificity. Strongly expressed in brain and spinal cord. Expressed at equal level in spinal cord and sciatic nerve. Weakly expressed in striated muscle.

Post-translational modifications. Myristoylated; myristoylation is required for localization to the cell membrane.

Disease relevance. Charcot-Marie-Tooth disease, demyelinating, type 4C (CMT4C) [MIM:601596] 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. CMT4C is characterized by onset in childhood, early-onset scoliosis and a distinct Schwann cell pathology. The disease is caused by variants affecting the gene represented in this entry. Mononeuropathy of the median nerve mild (MNMN) [MIM:613353] A disease characterized by median nerve mononeuropathy at the wrist. The clinical presentation ranges from a mild phenotype, consistent with carpal tunnel syndrome, to a severe median nerve mononeuropathy at the wrist associated with evidence of a more widespread axonal polyneuropathy. The latter phenotype is similar to that of patients with hereditary neuropathy with liability to pressure palsies. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8TF17-1	1	yes
Q8TF17-2	2
Q8TF17-3	3
Q8TF17-4	4
Q8TF17-5	5

RefSeq proteins (1): NP_078853* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR042772	SH3TC1/SH3TC2	Family

Pfam: PF00018

UniProt features (42 total): sequence variant 15, repeat 8, splice variant 7, region of interest 2, domain 2, mutagenesis site 2, sequence conflict 2, initiator methionine 1, chain 1, compositionally biased region 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TF17-F1	78.63	0.29

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 (1): 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
659	no effect on interaction with rab11a.
1201–1288	fails to localize to the recycling endosome and has a non-specific cytosolic distribution. loss of interaction with rab1

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 398 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_GLIAL_CELL_DEVELOPMENT, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, KOYAMA_SEMA3B_TARGETS_UP, GOBP_ERBB_SIGNALING_PATHWAY, GOBP_ENSHEATHMENT_OF_NEURONS, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOBP_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION

GO Biological Process (5): peripheral nervous system myelin maintenance (GO:0032287), regulation of intracellular protein transport (GO:0033157), regulation of ERBB signaling pathway (GO:1901184), regulation of endocytic recycling (GO:2001135), myelination in peripheral nervous system (GO:0022011)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), recycling endosome (GO:0055037), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of intracellular transport	2
myelination in peripheral nervous system	1
myelin maintenance	1
intracellular protein transport	1
regulation of protein transport	1
regulation of signal transduction	1
ERBB signaling pathway	1
endocytic recycling	1
regulation of vesicle-mediated transport	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
myelination	1
binding	1
membrane	1
cell periphery	1
endosome	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

568 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3TC2	GJB1	P08034	832
SH3TC2	GDAP1	Q8TB36	801
SH3TC2	SBF2	Q86WG5	789
SH3TC2	MTMR2	Q13614	779
SH3TC2	FIG4	Q92562	740
SH3TC2	FGD4	Q96M96	732
SH3TC2	PMP22	Q01453	725
SH3TC2	RNMT	O43148	718
SH3TC2	RAB11A	P24410	711
SH3TC2	LITAF	Q99732	705
SH3TC2	TTR	P02766	646
SH3TC2	IGHMBP2	P38935	631
SH3TC2	LRSAM1	Q6UWE0	623
SH3TC2	SBF1	O95248	610
SH3TC2	NDRG1	Q92597	599

IntAct

0 interactions, top by confidence:

BioGRID (1): SH3TC2 (Affinity Capture-MS)

ESM2 similar proteins: A0JMF1, A2CI97, A3KNA7, A6NE52, B2GV47, E7FAW3, P60330, Q06ZW3, Q0VDN7, Q12769, Q1M161, Q2NKJ3, Q2YDQ5, Q3SYW0, Q3T1I9, Q3U6Q4, Q4FZR5, Q5EE38, Q5PNP6, Q5RDX3, Q5SUQ9, Q5TYP4, Q5ZIB8, Q6AYM1, Q6DG91, Q6IRN0, Q6NSI4, Q6NYX6, Q6P4K6, Q6PH58, Q6ZNJ1, Q6ZPG2, Q6ZQA0, Q7T006, Q7ZVM9, Q80TE0, Q80VA5, Q8BJW5, Q8BMG1, Q8C779

Diamond homologs: Q80VA5, Q8TE82, Q8TF17

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1866 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	104
Likely pathogenic	44
Uncertain significance	864
Likely benign	474
Benign	115

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1011026	NM_024577.4(SH3TC2):c.3508_3516del (p.His1170_Leu1172del)	Pathogenic
1030852	NM_024577.4(SH3TC2):c.383T>G (p.Leu128Ter)	Pathogenic
1066688	NM_024577.4(SH3TC2):c.3327+1G>A	Pathogenic
1068543	NM_024577.4(SH3TC2):c.676C>T (p.Gln226Ter)	Pathogenic
1070097	NM_024577.4(SH3TC2):c.3078C>A (p.Cys1026Ter)	Pathogenic
1073106	NM_024577.4(SH3TC2):c.1556_1557insCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAANNNNNNNNNNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAAAAGAAAGTGGGCCAAG (p.Lys519delinsAsnGlyTrpIleMetArgSerGlyAspArgAspHisProGlyTer)	Pathogenic
1075273	NM_024577.4(SH3TC2):c.1557_1558insGCCGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGGCCGAAGCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACAAGGTGAAACCCCGTCTCTACTAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAGTGGGCCAAG (p.Lys520delinsAlaGlyArgGlyGlySerCysLeuTer)	Pathogenic
1075741	NC_000005.9:g.(?148360713)(148443737_?)del	Pathogenic
1076119	NM_024577.4(SH3TC2):c.1546A>T (p.Lys516Ter)	Pathogenic
1076648	NM_024577.4(SH3TC2):c.2775G>A (p.Trp925Ter)	Pathogenic
1120206	NM_024577.4(SH3TC2):c.233_239del (p.Leu78fs)	Pathogenic
1162982	NM_024577.4(SH3TC2):c.798T>G (p.Tyr266Ter)	Pathogenic
1172758	NM_024577.4(SH3TC2):c.2599C>T (p.Gln867Ter)	Pathogenic
1323592	NM_024577.4(SH3TC2):c.1737C>A (p.Tyr579Ter)	Pathogenic
1356429	NM_024577.4(SH3TC2):c.2211C>A (p.Cys737Ter)	Pathogenic
1426548	NC_000005.9:g.(?148420147)(148420260_?)del	Pathogenic
1444894	NM_024577.4(SH3TC2):c.3627T>A (p.Tyr1209Ter)	Pathogenic
1453733	NM_024577.4(SH3TC2):c.2083C>T (p.Gln695Ter)	Pathogenic
1454168	NM_024577.4(SH3TC2):c.1005del (p.Ser335fs)	Pathogenic
1457295	NM_024577.4(SH3TC2):c.620C>G (p.Ser207Ter)	Pathogenic
1457760	NM_024577.4(SH3TC2):c.1090del (p.Leu364fs)	Pathogenic
1686184	NM_024577.4(SH3TC2):c.731+2T>G	Pathogenic
1687474	NM_024577.4(SH3TC2):c.929dup (p.Ser312fs)	Pathogenic
1727798	NM_024577.4(SH3TC2):c.3115del (p.Glu1039fs)	Pathogenic
1966232	NM_024577.4(SH3TC2):c.2253_2256dup (p.Ser754fs)	Pathogenic
1972877	NM_024577.4(SH3TC2):c.307C>T (p.Gln103Ter)	Pathogenic
2030348	NM_024577.4(SH3TC2):c.1829dup (p.His611fs)	Pathogenic
2032655	NM_024577.4(SH3TC2):c.1462_1465dup (p.Phe489Ter)	Pathogenic
2152006	NM_024577.4(SH3TC2):c.1679del (p.Gly560fs)	Pathogenic
216119	NM_024577.4(SH3TC2):c.1662del (p.Ile555fs)	Pathogenic

SpliceAI

3529 predictions. Top by Δscore:

Variant	Effect	Δscore
5:149008847:CCA:C	donor_loss	1.0000
5:149008849:ACCTG:A	donor_loss	1.0000
5:149008850:C:CA	donor_loss	1.0000
5:149010264:ACTT:A	donor_loss	1.0000
5:149010265:CTT:C	donor_loss	1.0000
5:149010267:TA:T	donor_loss	1.0000
5:149010268:A:AC	donor_gain	1.0000
5:149010269:C:CA	donor_gain	1.0000
5:149010269:CT:C	donor_gain	1.0000
5:149010269:CTCG:C	donor_gain	1.0000
5:149010389:CTGC:C	acceptor_gain	1.0000
5:149010393:C:CC	acceptor_gain	1.0000
5:149012578:GCCTA:G	donor_loss	1.0000
5:149012579:CCTA:C	donor_loss	1.0000
5:149012580:CTA:C	donor_loss	1.0000
5:149012581:TACCT:T	donor_loss	1.0000
5:149012582:A:AT	donor_loss	1.0000
5:149012583:C:CG	donor_loss	1.0000
5:149012612:T:TA	donor_gain	1.0000
5:149012735:C:CA	acceptor_loss	1.0000
5:149031552:A:AC	donor_gain	1.0000
5:149031553:C:CC	donor_gain	1.0000
5:149031553:CTGAG:C	donor_gain	1.0000
5:149038293:A:AC	donor_gain	1.0000
5:149038294:C:CC	donor_gain	1.0000
5:149038366:T:A	donor_gain	1.0000
5:149038487:CTGC:C	acceptor_gain	1.0000
5:149038491:C:CC	acceptor_gain	1.0000
5:149041414:A:AC	donor_gain	1.0000
5:149041415:C:CC	donor_gain	1.0000

AlphaMissense

8379 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:149028128:C:T	G535D	0.988
5:149028147:G:T	R529S	0.985
5:149028187:T:A	R515S	0.985
5:149028187:T:G	R515S	0.985
5:149028146:C:G	R529P	0.984
5:149038334:A:T	V321D	0.984
5:149041421:G:C	F242L	0.984
5:149041421:G:T	F242L	0.984
5:149041423:A:G	F242L	0.984
5:149044552:G:C	F122L	0.984
5:149044552:G:T	F122L	0.984
5:149044554:A:G	F122L	0.984
5:149028139:G:C	C531W	0.983
5:149044579:G:C	F113L	0.983
5:149044579:G:T	F113L	0.983
5:149044581:A:G	F113L	0.983
5:149007044:C:G	R1171P	0.982
5:149028072:C:G	A554P	0.982
5:149028129:C:G	G535R	0.982
5:149044553:A:G	F122S	0.982
5:149044560:A:G	W120R	0.979
5:149044560:A:T	W120R	0.979
5:149044592:A:G	F109S	0.979
5:149010325:C:T	G1091D	0.978
5:149010329:C:G	A1090P	0.978
5:149028179:G:T	A518D	0.978
5:149040676:A:G	W245R	0.977
5:149040676:A:T	W245R	0.977
5:149027826:A:G	C636R	0.976
5:149028141:A:G	C531R	0.976

dbSNP variants (sampled 300 via entrez): RS1000040898 (5:149062182 C>T), RS1000086928 (5:148995685 T>A), RS1000153937 (5:149061872 C>T), RS1000158718 (5:149014424 C>T), RS1000163572 (5:149019242 G>A), RS1000164932 (5:149011234 A>G), RS1000211445 (5:149014667 A>G), RS1000216698 (5:149019609 A>C), RS1000236992 (5:149049647 T>A,C), RS1000351456 (5:148985423 C>T), RS1000370879 (5:149013524 T>C), RS1000385415 (5:149020179 T>C), RS1000438413 (5:149062140 T>A), RS1000439556 (5:149055640 G>A), RS1000450989 (5:149049961 C>A)

Disease associations

OMIM: gene MIM:608206 | disease phenotypes: MIM:601596, MIM:613353, MIM:118220, MIM:181500, MIM:303350, MIM:617468, MIM:118200

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 4C	Definitive	Autosomal recessive
autosomal recessive hereditary demyelinating motor and sensory neuropathy	Definitive	Autosomal recessive
susceptibility to mononeuropathy of the median nerve, mild	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
obsolete autosomal recessive hereditary demyelinating motor and sensory neuropathy	Definitive	AR

Mondo (18): Charcot-Marie-Tooth disease type 4C (MONDO:0011113), Charcot-Marie-Tooth disease type 4 (MONDO:0018995), susceptibility to mononeuropathy of the median nerve, mild (MONDO:0013237), peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease (MONDO:0015626), schizophrenia (MONDO:0005090), distal hereditary motor neuropathy (MONDO:0018894), hereditary spastic paraplegia (MONDO:0019064), scoliosis (MONDO:0005392), arthrogryposis multiplex congenita (MONDO:0015168), congenital contractures (MONDO:0022823), hereditary motor and sensory neuropathy (MONDO:0015358), hereditary motor neuron disease (MONDO:0024257), ependymoma (MONDO:0016698), Charcot-Marie-Tooth disease type 1 (MONDO:0019011)

Orphanet (13): Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Charcot-Marie-Tooth disease type 4C (Orphanet:99949), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Distal hereditary motor neuropathy (Orphanet:53739), Hereditary spastic paraplegia (Orphanet:685), Arthrogryposis multiplex congenita (Orphanet:1037), Genetic motor neuron disease (Orphanet:98505), Ependymoma (Orphanet:251636), Charcot-Marie-Tooth disease type 1 (Orphanet:65753), Charcot-Marie-Tooth disease type 1B (Orphanet:101082), Autosomal dominant intermediate Charcot-Marie-Tooth disease (Orphanet:90114), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), OBSOLETE: Hereditary motor and sensory neuropathy (Orphanet:140450)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000183	Tongue muscle weakness
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000587	Abnormal optic nerve morphology
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000651	Diplopia
HP:0000764	Peripheral axonal degeneration
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001291	Abnormal cranial nerve morphology
HP:0001308	Tongue fasciculations
HP:0001385	Hip dysplasia
HP:0001508	Failure to thrive
HP:0001604	Vocal cord paresis
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0001765	Hammertoe
HP:0002066	Gait ataxia
HP:0002093	Respiratory insufficiency
HP:0002307	Drooling
HP:0002346	Head tremor

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003273_17	Diastolic blood pressure	7.000000e-11
GCST004777_9	Diastolic blood pressure	3.000000e-06
GCST007094_132	Diastolic blood pressure	7.000000e-19
GCST007098_3	Diastolic blood pressure	1.000000e-07
GCST007098_4	Diastolic blood pressure	4.000000e-06
GCST007099_57	Systolic blood pressure	1.000000e-13
GCST007267_208	Systolic blood pressure	2.000000e-10
GCST012488_19	L1-L4 bone mineral density x serum urate levels interaction	8.000000e-06
GCST90002388_326	Lymphocyte count	1.000000e-10
GCST90002401_24	Platelet distribution width	9.000000e-10
GCST90002407_471	White blood cell count	5.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004531	urate measurement
EFO:0007701	spine bone mineral density
EFO:0004587	lymphocyte count
EFO:0007984	platelet component distribution width

MeSH disease descriptors (6)

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
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D015417	Hereditary Sensory and Motor Neuropathy	C10.500.300; C10.574.500.495; C10.668.829.800.300; C16.131.666.300; C16.320.400.375
D012600	Scoliosis	C05.116.900.800.875
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C535423	Charcot-Marie-Tooth disease, Type 4C (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, decreases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases methylation, increases expression	2
Silicon Dioxide	increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
titanium dioxide	increases expression	1
sulforaphane	increases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Lipopolysaccharides	decreases expression, decreases reaction	1
Methotrexate	increases expression	1
Naled	affects expression	1
Niclosamide	decreases expression	1
Oxygen	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
Urethane	decreases expression	1
Vanadates	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_HQ49	GM25515	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.