DCTN2

Summary

DCTN2 (dynactin subunit 2, HGNC:2712) is a protein-coding gene on chromosome 12q13.3, encoding Dynactin subunit 2 (Q13561). Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules. It is a common-essential gene (DepMap: required in 93.0% of cancer cell lines).

This gene encodes a 50-kD subunit of dynactin, a macromolecular complex consisting of 10-11 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. It is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit is present in 4-5 copies per dynactin molecule. It contains three short alpha-helical coiled-coil domains that may mediate association with self or other dynactin subunits. It may interact directly with the largest subunit (p150) of dynactin and may affix p150 in place. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 10540 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 47 total
• Cancer dependency (DepMap): dependent in 93.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001261413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2712
Approved symbol	DCTN2
Name	dynactin subunit 2
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	RBP50, DCTN-50
Ensembl gene	ENSG00000175203
Ensembl biotype	protein_coding
OMIM	607376
Entrez	10540

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 20 protein_coding, 12 retained_intron, 6 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000434715, ENST00000543672, ENST00000546559, ENST00000546670, ENST00000546758, ENST00000546965, ENST00000547345, ENST00000547480, ENST00000548249, ENST00000548736, ENST00000548949, ENST00000549394, ENST00000549712, ENST00000550086, ENST00000550201, ENST00000550576, ENST00000550750, ENST00000550954, ENST00000550988, ENST00000551142, ENST00000551400, ENST00000551611, ENST00000551872, ENST00000552390, ENST00000676646, ENST00000676956, ENST00000678247, ENST00000678322, ENST00000678505, ENST00000678521, ENST00000678653, ENST00000678990, ENST00000679307, ENST00000858279, ENST00000858280, ENST00000858281, ENST00000939636, ENST00000939637, ENST00000946068, ENST00000946069, ENST00000946070, ENST00000946071, ENST00000946072

RefSeq mRNA: 7 — MANE Select: NM_001261413 NM_001261412, NM_001261413, NM_001348065, NM_001348066, NM_001348067, NM_001348068, NM_006400

CCDS: CCDS44930, CCDS58245, CCDS73489, CCDS91711

Canonical transcript exons

ENST00000548249 — 14 exons

Exon	Start	End
ENSE00002389583	57547028	57547192
ENSE00002406685	57530051	57530775
ENSE00003492152	57532984	57533022
ENSE00003503431	57534292	57534452
ENSE00003508658	57535749	57535845
ENSE00003514635	57532733	57532810
ENSE00003526516	57532572	57532643
ENSE00003569308	57533953	57534097
ENSE00003592045	57535056	57535154
ENSE00003597085	57532015	57532106
ENSE00003599468	57546028	57546096
ENSE00003628823	57533238	57533303
ENSE00003631919	57532213	57532315
ENSE00003660833	57535484	57535545

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 124.1995 / max 509.6753, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131707	121.6805	1827
131708	2.5190	1405

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.17	gold quality
ganglionic eminence	UBERON:0004023	99.13	gold quality
ventricular zone	UBERON:0003053	98.87	gold quality
body of pancreas	UBERON:0001150	98.59	gold quality
stromal cell of endometrium	CL:0002255	98.54	gold quality
lower esophagus	UBERON:0013473	98.43	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.43	gold quality
body of uterus	UBERON:0009853	98.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.35	gold quality
cerebellar cortex	UBERON:0002129	98.32	gold quality
cerebellar hemisphere	UBERON:0002245	98.32	gold quality
right frontal lobe	UBERON:0002810	98.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.32	gold quality
mucosa of transverse colon	UBERON:0004991	98.31	gold quality
skin of leg	UBERON:0001511	98.30	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.28	gold quality
mucosa of stomach	UBERON:0001199	98.26	gold quality
esophagus	UBERON:0001043	98.24	gold quality
right adrenal gland cortex	UBERON:0035827	98.24	gold quality
metanephros cortex	UBERON:0010533	98.23	gold quality
lower esophagus mucosa	UBERON:0035834	98.23	gold quality
transverse colon	UBERON:0001157	98.22	gold quality
body of stomach	UBERON:0001161	98.20	gold quality
right adrenal gland	UBERON:0001233	98.20	gold quality
left adrenal gland	UBERON:0001234	98.15	gold quality
islet of Langerhans	UBERON:0000006	98.14	gold quality
prefrontal cortex	UBERON:0000451	98.14	gold quality
embryo	UBERON:0000922	98.14	gold quality
right coronary artery	UBERON:0001625	98.12	gold quality
popliteal artery	UBERON:0002250	98.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.51
E-HCAD-5	no	2.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting DCTN2, 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-9-5P	100.00	72.28	2361
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-153-5P	99.89	73.86	6317
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-3146	98.85	66.77	601
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-3613-5P	98.40	68.91	604
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-6514-3P	97.52	66.50	808
HSA-MIR-571	95.38	66.54	671

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 93.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 11)

• Altered levels of Cep135 and p50 by RNAi and protein overexpression caused the release of endogenous partner molecules from centrosomes. (PMID:14983524)
• the Sec23p component of the COPII complex directly interacts with the dynactin complex through the carboxy-terminal cargo-binding domain of p150(Glued). (PMID:15580264)
• DCTN2 is required in the earliest stages of peroxisome biogenesis. (PMID:15813749)
• study does not support a major role for DCTN2 overexpression in carcinogenesis (PMID:16369996)
• Data show how dynamitin’s different structural domains contribute to its ability to self-associate, interact with dynactin and assemble into a complex with its close binding partner, p24. (PMID:18182012)
• The interaction between ZW10 and dynamitin showed that the N-terminal region of ZW10 is the major binding site for dynamitin and, like full-length ZW10, could move along microtubules to the centrosomal area in a dynein-dynactin-dependent manner. (PMID:18782227)
• the determinants of p50/DM required for self-oligomerization of the protein and for interactions with other subunits of the dynactin complex (PMID:20463029)
• dynamitin is involved in the regulation of Nav1.5 cell-surface density (PMID:25088759)
• This is the first time a haplotype on chromosome 12 containing sequence variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A has been linked to an inherited neuropathy in humans. (PMID:26517670)
• Binding between ROCK1 and DCTN2 triggers diabetesassociated centrosome amplification in colon cancer cells. (PMID:34080666)
• Pan-cancer analysis of DCTN2 and its tumour-promoting role in HCC by modulating the AKT pathway. (PMID:38842133)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dctn2	ENSDARG00000031388
mus_musculus	Dctn2	ENSMUSG00000025410
rattus_norvegicus	Dctn2	ENSRNOG00000025481
drosophila_melanogaster	DCTN2-p50	FBGN0021825
caenorhabditis_elegans		WBGENE00001018

Protein

Protein identifiers

Dynactin subunit 2 — Q13561 (reviewed: Q13561)

Alternative names: 50 kDa dynein-associated polypeptide, Dynactin complex 50 kDa subunit, p50 dynamitin

All UniProt accessions (16): A0A384MDU9, A0A7I2V2Z2, A0A7I2V390, A0A7I2V4H4, A0A7I2V4Y9, A0A7I2V5R4, A8K8J9, Q13561, F8VRV7, F8VW18, F8VX93, F8W0U6, F8W1I6, H0YHL1, H0YI98, V9HW58

UniProt curated annotations — full annotation on UniProt →

Function. Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules. In the dynactin soulder domain, binds the ACTR1A filament and acts as a molecular ruler to determine the length. Modulates cytoplasmic dynein binding to an organelle, and plays a role in prometaphase chromosome alignment and spindle organization during mitosis. Involved in anchoring microtubules to centrosomes. May play a role in synapse formation during brain development.

Subunit / interactions. Subunit of dynactin, a multiprotein complex part of a tripartite complex with dynein and a adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built around ACTR1A/ACTB filament and consists of an actin-related filament composed of a shoulder domain, a pointed end and a barbed end. Its length is defined by its flexible shoulder domain. The soulder is composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. The 4 DCNT2 (via N-terminus) bind the ACTR1A filament and act as molecular rulers to determine the length. The pointed end is important for binding dynein-dynactin cargo adapters and consists of 4 subunits: ACTR10, DCNT4, DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB heterodimers, which binds ACTR1A/ACTB filament and dynactin and stabilizes dynactin. Interacts with BICD2 and CEP135. Interacts with DYNAP. Interacts with ECPAS. Interacts with MAPRE1.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Membrane.

Similarity. Belongs to the dynactin subunit 2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13561-1	1	yes
Q13561-2	2
Q13561-3	3

RefSeq proteins (7): NP_001248341, NP_001248342, NP_001334994, NP_001334995, NP_001334996, NP_001334997, NP_006391 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028133	Dynamitin	Family

Pfam: PF04912

UniProt features (15 total): modified residue 7, coiled-coil region 3, splice variant 2, initiator methionine 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9B85	ELECTRON MICROSCOPY	3.47
9B7J	ELECTRON MICROSCOPY	3.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13561-F1	77.22	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 (7): 134, 198, 320, 2, 6, 83, 86

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-2132295	MHC class II antigen presentation
R-HSA-2565942	Regulation of PLK1 Activity at G2/M Transition
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-380259	Loss of Nlp from mitotic centrosomes
R-HSA-380270	Recruitment of mitotic centrosome proteins and complexes
R-HSA-380284	Loss of proteins required for interphase microtubule organization from the centrosome
R-HSA-380320	Recruitment of NuMA to mitotic centrosomes
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic
R-HSA-8854518	AURKA Activation by TPX2

MSigDB gene sets: 241 (showing top): MORF_MTA1, GOBP_CHROMOSOME_ORGANIZATION, MYAATNNNNNNNGGC_UNKNOWN, AP1_01, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_PIGMENT_GRANULE_LOCALIZATION, GOBP_VESICLE_LOCALIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_CHROMOSOME_LOCALIZATION, MORF_RAD21, HSIAO_HOUSEKEEPING_GENES, GOBP_CELLULAR_PIGMENTATION, TGACCTY_ERR1_Q2, REACTOME_MEMBRANE_TRAFFICKING, GOCC_MICROTUBULE_ORGANIZING_CENTER

GO Biological Process (5): mitotic spindle organization (GO:0007052), mitotic metaphase chromosome alignment (GO:0007080), melanosome transport (GO:0032402), protein localization to centrosome (GO:0071539), microtubule-based process (GO:0007017)

GO Molecular Function (4): protein kinase binding (GO:0019901), spectrin binding (GO:0030507), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (12): kinetochore (GO:0000776), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), dynactin complex (GO:0005869), microtubule (GO:0005874), membrane (GO:0016020), dynein complex (GO:0030286), growth cone (GO:0030426), vesicle (GO:0031982), extracellular exosome (GO:0070062), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
G2/M Transition	2
Centrosome maturation	2
Adaptive Immune System	1
Cellular responses to stress	1
Loss of proteins required for interphase microtubule organization from the centrosome	1
Mitotic Prometaphase	1
Assembly of the 9+0 primary cilium	1
ER to Golgi Anterograde Transport	1
Golgi-to-ER retrograde transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
mitotic cell cycle	2
intracellular membraneless organelle	2
microtubule associated complex	2
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
mitotic sister chromatid segregation	1
metaphase chromosome alignment	1
mitotic cell cycle process	1
melanosome localization	1
establishment of melanosome localization	1
pigment granule transport	1
protein localization to microtubule organizing center	1
cellular process	1
kinase binding	1
cytoskeletal protein binding	1
protein-containing complex binding	1
protein binding	1
binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
actin cytoskeleton	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
catalytic complex	1
site of polarized growth	1
distal axon	1
membrane-bounded organelle	1
extracellular vesicle	1

Protein interactions and networks

STRING

2098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DCTN2	DCTN1	Q14203	999
DCTN2	ACTR10	Q9NZ32	971
DCTN2	TPPP	O94811	968
DCTN2	DCTN4	Q9UJW0	929
DCTN2	ACTR3C	Q9C0K3	912
DCTN2	ZW10	O43264	911
DCTN2	ACTR3B	Q9P1U1	907
DCTN2	BICD2	Q8TD16	852
DCTN2	DCTN3	O75935	832
DCTN2	CAPZA2	P47755	822
DCTN2	CAPZA1	P52907	821
DCTN2	DYNC1H1	Q14204	807
DCTN2	ACTR1A	P42024	761
DCTN2	DCTN6	O00399	759
DCTN2	DYNC1I2	Q13409	753

IntAct

296 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
MAPRE1	CLASP2	psi-mi:“MI:0914”(association)	0.850
DCTN1	DCTN6	psi-mi:“MI:0914”(association)	0.780
GADD45A	DCTN2	psi-mi:“MI:0915”(physical association)	0.740
DCTN2	DCTN6	psi-mi:“MI:0914”(association)	0.730
MAPT	ANXA2	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CCDC172	DCTN2	psi-mi:“MI:0915”(physical association)	0.670
DCTN2	CCDC172	psi-mi:“MI:0915”(physical association)	0.670
DCTN2	DCTN2	psi-mi:“MI:0915”(physical association)	0.670
DCTN2	BORCS6	psi-mi:“MI:0915”(physical association)	0.670
HTT	DCTN2	psi-mi:“MI:0915”(physical association)	0.670
DCTN2	CEP44	psi-mi:“MI:0915”(physical association)	0.660
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
HAUS1	DCTN2	psi-mi:“MI:0915”(physical association)	0.560
DCTN2	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
DCTN2	BLOC1S6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (528): DCTN2 (Two-hybrid), DCTN2 (Two-hybrid), BLOC1S6 (Two-hybrid), HAUS1 (Two-hybrid), CCDC172 (Two-hybrid), DCTN2 (Affinity Capture-RNA), DCTN2 (Affinity Capture-MS), DCTN2 (Affinity Capture-MS), ACTR1B (Affinity Capture-MS), ACTR1A (Affinity Capture-MS), DCTN1 (Affinity Capture-MS), DCTN3 (Affinity Capture-MS), ACTR10 (Affinity Capture-MS), DCTN4 (Affinity Capture-MS), EXD2 (Affinity Capture-MS)

ESM2 similar proteins: A0A5G2QD80, A8E5U3, A9ULY7, O75934, Q13503, Q13561, Q16891, Q1HQF2, Q28DG8, Q28HX4, Q28Y46, Q2TBU8, Q3ZCF0, Q4R6N3, Q4V909, Q5EA95, Q5FW42, Q5PPY2, Q5R561, Q5RAX7, Q5RE46, Q5REX6, Q5RKQ0, Q5U1Z0, Q5ZKJ4, Q66J30, Q6AYH5, Q6DF11, Q6DFL5, Q6IRB3, Q6IVW0, Q6NY52, Q6PBE2, Q6TA25, Q7K2D2, Q7PZ25, Q7T3H1, Q7ZXA8, Q8BMG7, Q8BXG3

Diamond homologs: A0A5G2QD80, Q13561, Q1HQF2, Q28Y46, Q3ZCF0, Q5FW42, Q66J30, Q6AYH5, Q6IRB3, Q7K2D2, Q7PZ25, Q7T3H1, Q99KJ8, Q9PTG6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ZW10	“up-regulates activity”	DCTN2	relocalization
“RZZ complex”	“up-regulates activity”	DCTN2	relocalization
DCTN2	“up-regulates activity”	Cytoplasmic_Dynein	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
COPI-independent Golgi-to-ER retrograde traffic	12	30.8×	1e-12
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	12	28.7×	2e-12
COPI-mediated anterograde transport	13	17.6×	5e-11
Loss of Nlp from mitotic centrosomes	8	15.7×	3e-06
Loss of proteins required for interphase microtubule organization from the centrosome	8	15.7×	3e-06
MHC class II antigen presentation	14	15.4×	5e-11
AURKA Activation by TPX2	8	15.0×	4e-06
Anchoring of the basal body to the plasma membrane	10	14.0×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
mitotic spindle organization	7	18.8×	9e-05
synapse organization	5	13.9×	3e-03
cell division	11	5.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1941 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57532010:CACA:C	donor_loss	1.0000
12:57532011:ACACC:A	donor_loss	1.0000
12:57532013:ACCTG:A	donor_loss	1.0000
12:57532102:CATGG:C	acceptor_gain	1.0000
12:57532103:ATGG:A	acceptor_gain	1.0000
12:57532104:TGG:T	acceptor_gain	1.0000
12:57532105:GG:G	acceptor_gain	1.0000
12:57532107:C:CC	acceptor_gain	1.0000
12:57532439:T:A	donor_gain	1.0000
12:57532565:T:TA	donor_gain	1.0000
12:57532571:CCTTG:C	donor_gain	1.0000
12:57532640:CACT:C	acceptor_gain	1.0000
12:57532642:CT:C	acceptor_gain	1.0000
12:57532644:C:CC	acceptor_gain	1.0000
12:57533951:A:AC	donor_gain	1.0000
12:57533952:C:CC	donor_gain	1.0000
12:57534287:CCCA:C	donor_gain	1.0000
12:57534290:A:AC	donor_gain	1.0000
12:57534290:ACTTA:A	donor_loss	1.0000
12:57534291:C:CT	donor_gain	1.0000
12:57534291:CTTAG:C	donor_gain	1.0000
12:57534294:A:AC	donor_gain	1.0000
12:57534294:AG:A	donor_gain	1.0000
12:57534294:AGC:A	donor_gain	1.0000
12:57534295:G:C	donor_gain	1.0000
12:57534449:TCGT:T	acceptor_gain	1.0000
12:57534450:CGT:C	acceptor_gain	1.0000
12:57534450:CGTC:C	acceptor_gain	1.0000
12:57534453:C:CC	acceptor_gain	1.0000
12:57534456:G:GC	acceptor_gain	1.0000

AlphaMissense

2603 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57535081:A:G	L113P	1.000
12:57535102:A:G	L106P	1.000
12:57535781:A:G	F57S	1.000
12:57532737:A:G	L283P	0.999
12:57535105:C:G	R105P	0.999
12:57535541:G:C	F69L	0.999
12:57535541:G:T	F69L	0.999
12:57535543:A:G	F69L	0.999
12:57535780:G:C	F57L	0.999
12:57535780:G:T	F57L	0.999
12:57535782:A:G	F57L	0.999
12:57535793:G:T	A53D	0.999
12:57535794:C:G	A53P	0.999
12:57535808:A:T	V48D	0.999
12:57546081:C:G	D18H	0.999
12:57547038:A:G	L9P	0.999
12:57547038:A:T	L9H	0.999
12:57547048:A:G	Y6H	0.999
12:57535106:G:T	R105S	0.998
12:57535509:C:T	G80E	0.998
12:57535542:A:G	F69S	0.998
12:57535782:A:T	F57I	0.998
12:57535831:G:C	S40R	0.998
12:57535831:G:T	S40R	0.998
12:57535833:T:G	S40R	0.998
12:57546068:G:A	T22I	0.998
12:57546075:A:C	Y20D	0.998
12:57546075:A:G	Y20H	0.998
12:57547033:C:G	G11R	0.998
12:57547047:T:C	Y6C	0.998

dbSNP variants (sampled 300 via entrez): RS1000362429 (12:57548608 A>G), RS1001001143 (12:57538972 T>C), RS1001058228 (12:57536430 C>T), RS1001128732 (12:57546539 G>A), RS1001154646 (12:57543630 G>A,T), RS1001222476 (12:57545749 T>G), RS1001365699 (12:57531416 C>T), RS1001663785 (12:57542373 T>C), RS1001852487 (12:57538882 G>A), RS1002000982 (12:57543815 T>G), RS1002229648 (12:57536792 GCATGTC>G), RS1002348631 (12:57530110 C>T), RS1002362317 (12:57545462 C>A,T), RS1002582073 (12:57537158 A>G), RS1002599912 (12:57546008 G>C)

Disease associations

OMIM: gene MIM:607376 | disease phenotypes: MIM:118220, MIM:615486, MIM:616280

GenCC curated gene-disease

Mondo (3): Charcot-Marie-Tooth disease (MONDO:0015626), severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (MONDO:0014206), Charcot-Marie-Tooth disease axonal type 2U (MONDO:0014566)

Orphanet (3): Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Autosomal dominant Charcot-Marie-Tooth disease type 2U (Orphanet:397735), Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (Orphanet:440427)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_209	Brain morphology (MOSTest)	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Doxorubicin	increases expression, affects expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Smoke	decreases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	increases abundance, increases palmitoylation, decreases expression, decreases reaction	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
decabromobiphenyl ether	decreases expression	1
tetrahydropalmatine	decreases expression	1
tetrabromobisphenol A	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Irinotecan	increases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Benztropine	increases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Caffeine	affects phosphorylation	1
Dactinomycin	affects cotreatment, increases secretion	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT