PRX

Summary

PRX (periaxin, HGNC:13797) is a protein-coding gene on chromosome 19q13.2, encoding Periaxin (Q9BXM0). Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells.

This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy.

Source: NCBI Gene 57716 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease type 4 (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 1,460 total — 50 pathogenic, 21 likely-pathogenic
• MANE Select transcript: NM_181882

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13797
Approved symbol	PRX
Name	periaxin
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1620
Ensembl gene	ENSG00000105227
Ensembl biotype	protein_coding
OMIM	605725
Entrez	57716

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 17 protein_coding_CDS_not_defined, 14 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000291825, ENST00000324001, ENST00000599513, ENST00000673881, ENST00000674005, ENST00000674642, ENST00000674773, ENST00000674781, ENST00000674899, ENST00000674912, ENST00000674978, ENST00000675021, ENST00000675099, ENST00000675156, ENST00000675300, ENST00000675339, ENST00000675369, ENST00000675484, ENST00000675511, ENST00000675517, ENST00000675541, ENST00000676042, ENST00000676047, ENST00000676076, ENST00000676078, ENST00000676230, ENST00000676260, ENST00000676316, ENST00000676330, ENST00000676344, ENST00000903445, ENST00000903446, ENST00000903447

RefSeq mRNA: 3 — MANE Select: NM_181882 NM_001411127, NM_020956, NM_181882

CCDS: CCDS12556, CCDS33028, CCDS92620

Canonical transcript exons

ENST00000324001 — 7 exons

Exon	Start	End
ENSE00000951887	40403706	40403862
ENSE00001293982	40398620	40398816
ENSE00001342950	40408158	40408256
ENSE00001342954	40408340	40408383
ENSE00001409504	40393768	40397970
ENSE00003049167	40413338	40413378
ENSE00003499628	40407906	40408031

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.0562 / max 221.7615, expressed in 1172 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180985	1.7199	1084
180986	1.3264	227
180987	0.0099	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	99.61	gold quality
trigeminal ganglion	UBERON:0001675	99.26	gold quality
sural nerve	UBERON:0015488	99.03	gold quality
nerve	UBERON:0001021	99.01	gold quality
tibial nerve	UBERON:0001323	99.01	gold quality
dorsal root ganglion	UBERON:0000044	98.58	gold quality
pancreatic ductal cell	CL:0002079	96.45	gold quality
right lung	UBERON:0002167	96.41	gold quality
upper lobe of left lung	UBERON:0008952	94.05	gold quality
upper lobe of lung	UBERON:0008948	92.42	gold quality
type B pancreatic cell	CL:0000169	89.99	silver quality
diaphragm	UBERON:0001103	88.97	gold quality
triceps brachii	UBERON:0001509	88.86	gold quality
tongue squamous epithelium	UBERON:0006919	88.06	silver quality
gluteal muscle	UBERON:0002000	87.55	gold quality
lung	UBERON:0002048	85.61	gold quality
right lobe of thyroid gland	UBERON:0001119	84.66	gold quality
left lobe of thyroid gland	UBERON:0001120	84.47	gold quality
epithelial cell of pancreas	CL:0000083	83.74	silver quality
thyroid gland	UBERON:0002046	83.62	gold quality
vastus lateralis	UBERON:0001379	83.39	silver quality
cerebellar vermis	UBERON:0004720	83.34	gold quality
vena cava	UBERON:0004087	83.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.77	gold quality
buccal mucosa cell	CL:0002336	82.70	silver quality
quadriceps femoris	UBERON:0001377	82.67	silver quality
inferior olivary complex	UBERON:0002127	81.89	gold quality
parotid gland	UBERON:0001831	81.67	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	81.13	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	80.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	1993.87
E-ANND-3	yes	10.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2L2

miRNA regulators (miRDB)

217 targeting PRX, 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-4692	100.00	67.32	2066
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6780B-5P	99.96	69.60	2562

Literature-anchored findings (GeneRIF, showing 14)

• Results indicate a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein. (PMID:12112076)
• Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease (PMID:15197604)
• S399fsX410 mutation in the PRX gene and its effects at the protein level, which was identified in an 8-year-old patient with early-onsetCharcot-Marie-Tooth type 4F disease. (PMID:16534116)
• A PRX mutation in Japanese patients is presented. (PMID:16770524)
• Data show that the mutations in the periaxin (PRX) gene is associated with early-onset demyelinating AR-CMT and severe sensory loss. (PMID:18504680)
• Thirty sequence variants have been found in the analysed genes from patients with Charcot-Marie-Tooth disorders: 5 pathogenic mutations in the GDAP1 gene and 2 pathogenic mutations in the PRX gene. (PMID:19837996)
• novel mutation in vocal cord paralysis (PMID:19950375)
• In this review, periaxin protein is required for the maintenance of peripheral nerve myelin; however, patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease or Dejerine-Sottas neuropathy. (PMID:21079185)
• Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes. (PMID:21741241)
• a variation of clinical phenotypes for CMT4F caused by a novel, nonsense PRX mutation, was shown. (PMID:22847150)
• Study of the periaxin gene should be considered in patients with severe demyelinating neuropathy associated with early infantile scoliosis. (PMID:24011642)
• we were able to simplify this complex phenotype and identified a causative mutation (p.R1070*) in the gene periaxin (PRX), a gene previously shown to cause peripheral neuropathy (Dejerine-Sottas syndrome) when this mutation is present (PMID:26059842)
• results offer a possible mechanism to the formation of periaxin complexes, improvement of complex stability, and establishment of a link between the extracellular matrix and the cytoskeleton (PMID:26940996)
• The study identified a variant of periaxin in a Chinese family with congenital cataract by exome sequencing. (PMID:27081207)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Prx	ENSMUSG00000053198
rattus_norvegicus	Prx	ENSRNOG00000018369

Paralogs (2): AHNAK (ENSG00000124942), AHNAK2 (ENSG00000185567)

Protein

Protein identifiers

Periaxin — Q9BXM0 (reviewed: Q9BXM0)

All UniProt accessions (9): Q9BXM0, A0A669KBF1, A0A6Q8PFM7, A0A6Q8PFP7, A0A6Q8PFW6, A0A6Q8PGB6, A0A6Q8PGK2, A0A6Q8PH11, A0A6Q8PHM6

UniProt curated annotations — full annotation on UniProt →

Function. Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells. Required for the maintenance of the peripheral myelin sheath that is essential for normal transmission of nerve impulses and normal perception of sensory stimuli. Required for normal transport of MBP mRNA from the perinuclear to the paranodal regions. Required for normal remyelination after nerve injury. Required for normal elongation of Schwann cells and normal length of the internodes between the nodes of Ranvier. The demyelinated nodes of Ranvier permit saltatory transmission of nerve impulses; shorter internodes cause slower transmission of nerve impulses. Required for the formation of appositions between the abaxonal surface of the myelin sheath and the Schwann cell plasma membrane; the Schwann cell cytoplasm is restricted to regions between these appositions. Required for the formation of Cajal bands and of Schmidt-Lanterman incisures that correspond to short, cytoplasm-filled regions on myelinated nerves. Recruits DRP2 to the Schwann cell plasma membrane. Required for normal protein composition of the eye lens fiber cell plasma membrane and normal eye lens fiber cell morphology.

Subunit / interactions. Homodimer (via PDZ domain). Interacts with SCN10A. Found in a complex with SCN10A. Interacts with DRP2. Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1. Detected in a complex composed of at least EZR, AHNAK, PPL and PRX. Identified in a complex with EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, VIM and spectrin.

Subcellular location. Cell membrane. Nucleus. Cytoplasm Cytoplasm Cell membrane. Cell junction.

Tissue specificity. Detected in spinal cord. Isoform 1 and isoform 2 are found in sciatic nerve and Schwann cells.

Disease relevance. Dejerine-Sottas syndrome (DSS) [MIM:145900] A severe degenerating neuropathy of the demyelinating Charcot-Marie-Tooth disease category, with onset by age 2 years. Characterized by motor and sensory neuropathy with very slow nerve conduction velocities, increased cerebrospinal fluid protein concentrations, hypertrophic nerve changes, delayed age of walking as well as areflexia. There are both autosomal dominant and autosomal recessive forms of Dejerine-Sottas syndrome. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, demyelinating, type 4F (CMT4F) [MIM:614895] 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. CMT4F is characterized by distal sensory impairment and distal muscle weakness and atrophy affecting the lower more than the upper limbs. The age at onset is variable and can range from childhood to adult years. When the onset is in infancy, the phenotype is characterized as Dejerine-Sottas syndrome. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Has a remarkable domain of repetitive pentameric units sometimes followed by a tripeptide spacer, it may separate two functional basic and acidic domains. The Arg/Lys-rich basic domain functions as a tripartite nuclear localization signal. The PDZ domain contains the signal for export from the nucleus. The N-terminal region including the PDZ domain is required for the formation of Cajal bands on myelinated nerves.

Similarity. Belongs to the periaxin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BXM0-1	1, L-periaxin	yes
Q9BXM0-2	2, S-periaxin
Q9BXM0-3	3

RefSeq proteins (3): NP_001398056, NP_066007, NP_870998* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR052082	Myelin_sheath_structural	Family

UniProt features (98 total): repeat 55, sequence variant 13, modified residue 10, strand 6, splice variant 3, region of interest 2, short sequence motif 2, compositionally biased region 2, helix 2, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4CMZ	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXM0-F1	35.74	0.00

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 (10): 7, 133, 900, 1082, 1349, 1351, 1363, 1401, 1407, 1439

Mutagenesis-validated functional residues (1):

Position	Phenotype
81–83	nearly abolishes export from the nucleus.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9619665	EGR2 and SOX10-mediated initiation of Schwann cell myelination

MSigDB gene sets: 253 (showing top): RNGTGGGC_UNKNOWN, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_NEUROGENESIS, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, AP1_Q4_01, GOBP_ENSHEATHMENT_OF_NEURONS, TGCTGAY_UNKNOWN, CCTGTGA_MIR513, BACH2_01, TGTGTGA_MIR377, GOBP_RNA_SPLICING, AIYAR_COBRA1_TARGETS_DN, HFH3_01, TGANTCA_AP1_C

GO Biological Process (3): axon ensheathment (GO:0008366), peripheral nervous system myelin maintenance (GO:0032287), regulation of RNA splicing (GO:0043484)

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

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), anchoring junction (GO:0070161), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nervous system development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
ensheathment of neurons	1
myelination in peripheral nervous system	1
myelin maintenance	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

1530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRX	DRP2	Q13474	988
PRX	PPL	O60437	973
PRX	EZR	P15311	944
PRX	AHNAK	Q09666	938
PRX	GJB1	P08034	893
PRX	PMP2	P02689	867
PRX	EGR2	P11161	852
PRX	MPZL1	O95297	817
PRX	MTMR2	Q13614	799
PRX	PMP22	Q01453	784
PRX	DMD	P11532	719
PRX	MBP	P02686	710
PRX	RNMT	O43148	706
PRX	SOX10	P56693	647
PRX	UTRN	P46939	638

IntAct

16 interactions, top by confidence:

A	B	Type	Score
PRX	TERF2IP	psi-mi:“MI:0915”(physical association)	0.510
PRX	CDK6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PRX	ABL1	psi-mi:“MI:0915”(physical association)	0.400
CRK	PRX	psi-mi:“MI:0915”(physical association)	0.400
PRX	FYN	psi-mi:“MI:0915”(physical association)	0.400
PRX	NCK1	psi-mi:“MI:0915”(physical association)	0.400
PRX	TUFM	psi-mi:“MI:0915”(physical association)	0.400
NYAP1	PRX	psi-mi:“MI:0915”(physical association)	0.400
PRX	AHNAK	psi-mi:“MI:0915”(physical association)	0.400
PRX	H1-4	psi-mi:“MI:0915”(physical association)	0.400
PRX	SMC3	psi-mi:“MI:0915”(physical association)	0.400
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
GPC3	PXDNL	psi-mi:“MI:0914”(association)	0.350
PRX	TERF2IP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): PRX (Affinity Capture-MS), PRX (Affinity Capture-MS), PRX (Proximity Label-MS), SMC3 (Proximity Label-MS), PRX (Proximity Label-MS), PRX (Proximity Label-MS), PRX (Proximity Label-MS), PRX (Reconstituted Complex), DAG1 (Affinity Capture-Western), DRP2 (Affinity Capture-Western), PRX (Two-hybrid), PRX (Affinity Capture-Western), PRX (Reconstituted Complex), PRX (Negative Genetic), PRX (Affinity Capture-MS)

ESM2 similar proteins: A0A8I5ZN27, A6NNT2, D3ZEN0, E1AZ71, E1BM58, O15061, O15446, O55103, O88737, O88778, P08855, P0C671, P10636, P10637, P12036, P16884, P19246, P19332, P27816, P34926, P36225, P53814, P62521, P78559, Q06002, Q09666, Q0VA45, Q28181, Q3TN34, Q3UH66, Q4R729, Q5S6V2, Q5STT6, Q5T0Z8, Q5YCV9, Q5YCW0, Q5YCW1, Q63425, Q76KJ5, Q7Z2K8

Diamond homologs: E1BM58, O55103, Q63425, Q8IVF2, Q9BXM0, Q09666

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1460 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	21
Uncertain significance	829
Likely benign	408
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075484	NM_181882.3(PRX):c.1171del (p.Leu391fs)	Pathogenic
1075829	NM_181882.3(PRX):c.205C>T (p.Arg69Ter)	Pathogenic
1323502	NM_181882.3(PRX):c.2602del (p.Gln868fs)	Pathogenic
1324966	NM_181882.3(PRX):c.2581del (p.Leu861fs)	Pathogenic
1385857	NM_181882.3(PRX):c.2815_2816del (p.Ser939fs)	Pathogenic
1392880	NM_181882.3(PRX):c.3099_3100del (p.Glu1034fs)	Pathogenic
1423233	NM_181882.3(PRX):c.2050C>T (p.Gln684Ter)	Pathogenic
1686102	NM_181882.3(PRX):c.1552_1558del (p.Pro518fs)	Pathogenic
1908695	NM_181882.3(PRX):c.3054del (p.Arg1020fs)	Pathogenic
2703425	NM_181882.3(PRX):c.2362A>T (p.Lys788Ter)	Pathogenic
2777990	NM_181882.3(PRX):c.2180_2181del (p.Ile727fs)	Pathogenic
2787432	NM_181882.3(PRX):c.1552_1562delinsT (p.Pro518fs)	Pathogenic
2803049	NM_181882.3(PRX):c.3275del (p.Val1092fs)	Pathogenic
2806966	NM_181882.3(PRX):c.1657del (p.Glu553fs)	Pathogenic
2823989	NM_181882.3(PRX):c.3371C>G (p.Ser1124Ter)	Pathogenic
2851365	NM_181882.3(PRX):c.2301del (p.Leu768fs)	Pathogenic
2851657	NM_181882.3(PRX):c.1999del (p.Leu667fs)	Pathogenic
3018157	NM_181882.3(PRX):c.1001_1022del (p.Gly334fs)	Pathogenic
3248510	NC_000019.9:g.(?40913793)(40913839_?)del	Pathogenic
3611669	NM_181882.3(PRX):c.667del (p.Val223fs)	Pathogenic
3655356	NM_181882.3(PRX):c.2252C>G (p.Ser751Ter)	Pathogenic
3663633	NM_181882.3(PRX):c.3157del (p.Asp1053fs)	Pathogenic
3687942	NM_181882.3(PRX):c.1782_1783insTTCCTGAGATGAAA (p.Leu595delinsPheLeuArgTer)	Pathogenic
3690156	NM_181882.3(PRX):c.2447C>G (p.Ser816Ter)	Pathogenic
433553	NM_181882.3(PRX):c.1012del (p.Ala338fs)	Pathogenic
448140	NM_181882.3(PRX):c.3611del (p.Leu1204fs)	Pathogenic
4725896	NM_181882.3(PRX):c.1572_1650del (p.Val525fs)	Pathogenic
4787	NM_181882.3(PRX):c.2857C>T (p.Arg953Ter)	Pathogenic
4791	NM_181882.3(PRX):c.586C>T (p.Arg196Ter)	Pathogenic
549686	NM_181882.3(PRX):c.3703G>T (p.Glu1235Ter)	Pathogenic

SpliceAI

1068 predictions. Top by Δscore:

Variant	Effect	Δscore
19:40403704:ACCTT:A	donor_gain	1.0000
19:40403705:CCTTC:C	donor_gain	1.0000
19:40403708:T:TA	donor_gain	1.0000
19:40407901:CTCA:C	donor_loss	1.0000
19:40407902:TCACC:T	donor_loss	1.0000
19:40407903:CACCT:C	donor_loss	1.0000
19:40407904:A:AC	donor_gain	1.0000
19:40407904:A:T	donor_loss	1.0000
19:40407905:C:CC	donor_gain	1.0000
19:40407905:CCT:C	donor_gain	1.0000
19:40408029:AGCC:A	acceptor_loss	1.0000
19:40408032:CTGTG:C	acceptor_loss	1.0000
19:40408033:T:A	acceptor_loss	1.0000
19:40408179:T:TA	donor_gain	1.0000
19:40398619:CCAG:C	donor_gain	0.9900
19:40403701:CCCA:C	donor_loss	0.9900
19:40403702:CCACC:C	donor_loss	0.9900
19:40403703:CACCT:C	donor_loss	0.9900
19:40403704:A:C	donor_loss	0.9900
19:40403705:C:CA	donor_loss	0.9900
19:40403720:AGGCT:A	donor_gain	0.9900
19:40403724:T:TA	donor_gain	0.9900
19:40407904:AC:A	donor_gain	0.9900
19:40407905:CC:C	donor_gain	0.9900
19:40408028:GAGC:G	acceptor_gain	0.9900
19:40408030:GC:G	acceptor_gain	0.9900
19:40408031:CC:C	acceptor_gain	0.9900
19:40408032:C:CC	acceptor_gain	0.9900
19:40408382:CT:C	acceptor_gain	0.9900
19:40412327:T:TA	donor_gain	0.9900

AlphaMissense

9250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:40398714:A:G	L96P	0.999
19:40398750:A:G	L84P	0.999
19:40398798:G:T	A68D	0.999
19:40398720:A:G	F94S	0.998
19:40398753:A:G	L83P	0.998
19:40398786:A:G	F72S	0.998
19:40398807:A:G	L65P	0.998
19:40398709:G:T	R98S	0.997
19:40398726:A:T	V92D	0.997
19:40398763:C:G	A80P	0.997
19:40398799:C:G	A68P	0.997
19:40397879:A:G	F158S	0.996
19:40398708:C:G	R98P	0.996
19:40398741:G:T	A87D	0.996
19:40398759:A:G	L81P	0.996
19:40398792:A:T	V70E	0.996
19:40403759:A:T	V44D	0.996
19:40398795:C:G	R69P	0.995
19:40398804:A:G	L66P	0.995
19:40398807:A:T	L65Q	0.995
19:40403714:A:G	L59P	0.995
19:40398724:A:G	S93P	0.994
19:40398762:G:T	A80E	0.994
19:40398813:T:A	D63V	0.994
19:40403732:G:T	A53D	0.994
19:40403765:A:G	I42T	0.994
19:40397878:G:C	F158L	0.993
19:40397878:G:T	F158L	0.993
19:40397880:A:G	F158L	0.993
19:40398719:G:C	F94L	0.993

dbSNP variants (sampled 300 via entrez): RS1000026621 (19:40401807 G>A,C), RS1000133978 (19:40412970 T>C,G), RS1000191235 (19:40396657 T>A,C), RS1000304439 (19:40402365 A>G), RS1000357730 (19:40393663 G>A), RS1000539079 (19:40413934 C>T), RS1001047691 (19:40410700 G>A), RS1001505246 (19:40402938 G>A), RS1001563352 (19:40400012 T>C), RS1001661757 (19:40396752 G>A,T), RS1001867586 (19:40398681 A>C), RS1001898714 (19:40398403 T>C,G), RS1001903172 (19:40396349 G>C), RS1002049772 (19:40408786 A>G), RS1002049943 (19:40412186 G>A)

Disease associations

OMIM: gene MIM:605725 | disease phenotypes: MIM:614895, MIM:145900, MIM:118220, MIM:600361, MIM:617770

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 4	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease type 4F	Strong	Autosomal recessive
Charcot-Marie-Tooth disease type 3	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

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

Mondo (10): Charcot-Marie-Tooth disease type 4 (MONDO:0018995), Charcot-Marie-Tooth disease type 4F (MONDO:0013959), Charcot-Marie-Tooth disease type 3 (MONDO:0007790), Charcot-Marie-Tooth disease (MONDO:0015626), Charcot-Marie-Tooth disease type 5 (MONDO:0010877), Charcot-Marie-Tooth disease type 1 (MONDO:0019011), spinocerebellar ataxia 46 (MONDO:0033481), peripheral neuropathy (MONDO:0005244), distal hereditary motor neuropathy (MONDO:0018894), Gaucher disease (MONDO:0018150)

Orphanet (9): Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Charcot-Marie-Tooth disease type 4F (Orphanet:99952), Dejerine-Sottas syndrome (Orphanet:64748), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Spinocerebellar ataxia type 46 (Orphanet:589522), Hereditary motor and sensory neuropathy type 5 (Orphanet:64751), Charcot-Marie-Tooth disease type 1 (Orphanet:65753), Distal hereditary motor neuropathy (Orphanet:53739), Gaucher disease (Orphanet:355)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

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
D005776	Gaucher Disease	C10.228.140.163.100.435.825.400; C16.320.565.189.435.825.400; C16.320.565.398.641.803.441; C16.320.565.595.554.825.400; C18.452.132.100.435.825.400; C18.452.584.563.641.803.441; C18.452.648.189.435.825.400; C18.452.648.398.641.803.441; C18.452.648.595.554.825.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Dieldrin	decreases expression	1
Estradiol	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation	1
Selenium	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Triclosan	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Copper Sulfate	increases expression	1
Permethrin	decreases expression	1
S-Nitrosoglutathione	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

299 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)
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
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