GNB4

Summary

GNB4 (G protein subunit beta 4, HGNC:20731) is a protein-coding gene on chromosome 3q26.33, encoding Guanine nucleotide-binding protein subunit beta-4 (Q9HAV0). Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors.

Source: NCBI Gene 59345 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease dominant intermediate F (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 337 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 21
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_021629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20731
Approved symbol	GNB4
Name	G protein subunit beta 4
Location	3q26.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000114450
Ensembl biotype	protein_coding
OMIM	610863
Entrez	59345

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000232564, ENST00000465153, ENST00000466899, ENST00000468623, ENST00000497513, ENST00000674713, ENST00000674862, ENST00000674927, ENST00000675901, ENST00000676128, ENST00000856251, ENST00000856252, ENST00000958723, ENST00000958724, ENST00000958725, ENST00000958726

RefSeq mRNA: 1 — MANE Select: NM_021629 NM_021629

CCDS: CCDS3230

Canonical transcript exons

ENST00000232564 — 10 exons

Exon	Start	End
ENSE00000780684	179405190	179405406
ENSE00001139901	179396088	179401319
ENSE00001839333	179451346	179451470
ENSE00002207500	179426144	179426242
ENSE00002247155	179419399	179419505
ENSE00002287516	179413715	179413781
ENSE00002308335	179420889	179420927
ENSE00002317042	179414885	179415047
ENSE00002321573	179416493	179416556
ENSE00003672061	179413412	179413613

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.4027 / max 456.8134, expressed in 1662 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45724	23.7695	1646
45725	2.3512	1061
45726	2.2820	978

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	99.28	gold quality
secondary oocyte	CL:0000655	97.81	gold quality
upper leg skin	UBERON:0004262	97.61	gold quality
tibia	UBERON:0000979	97.35	gold quality
skin of hip	UBERON:0001554	96.91	gold quality
visceral pleura	UBERON:0002401	96.76	gold quality
parietal pleura	UBERON:0002400	96.39	gold quality
oocyte	CL:0000023	96.26	gold quality
layer of synovial tissue	UBERON:0007616	95.98	gold quality
saphenous vein	UBERON:0007318	95.66	gold quality
trigeminal ganglion	UBERON:0001675	95.44	gold quality
mammalian vulva	UBERON:0000997	95.32	gold quality
penis	UBERON:0000989	95.11	gold quality
trabecular bone tissue	UBERON:0002483	94.97	gold quality
superficial temporal artery	UBERON:0001614	94.88	gold quality
lower lobe of lung	UBERON:0008949	94.85	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.82	gold quality
germinal epithelium of ovary	UBERON:0001304	94.02	gold quality
synovial joint	UBERON:0002217	93.99	gold quality
calcaneal tendon	UBERON:0003701	93.99	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.96	gold quality
cortical plate	UBERON:0005343	93.78	gold quality
mammary duct	UBERON:0001765	93.65	gold quality
epithelium of mammary gland	UBERON:0003244	93.58	gold quality
dorsal root ganglion	UBERON:0000044	93.57	gold quality
cartilage tissue	UBERON:0002418	93.45	gold quality
heart right ventricle	UBERON:0002080	93.20	gold quality
gingiva	UBERON:0001828	93.04	gold quality
gingival epithelium	UBERON:0001949	92.81	gold quality
nipple	UBERON:0002030	92.76	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.23
E-CURD-11	no	177.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

252 targeting GNB4, 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-8485	100.00	77.57	4731
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 13)

• Gbeta4 subunit is coexpressed in physiologically ON-type cone bipolar cells with Ggamma13 and Gbeta3 but is not present in OFF-type bipolar cells. (PMID:12454992)
• Gbeta4 is widely expressed, located on chromosome 3 with a genomic structure like Gbeta1 to Gbeta3, but different from Gbeta5 (PMID:12782285)
• Intron-1 haplotypes of GNB4 may, thus, serve as predictive markers for progression and survival of patients suffering from bladder cancer. (PMID:18815590)
• Intron-1 haplotypes of GNB4 is associated with colorectal carcinoma. (PMID:19414374)
• Analysis of GNB4 in an additional 88 unrelated CMT individuals uncovered another de novo mutation. (PMID:23434117)
• Suggest Gbeta4gamma1 as a modulator of M3 muscarinic receptor signaling. (PMID:25916507)
• A novel missense GNB4 variant causes Charcot-Marie-Tooth disease F in two patients, who represent the first record of the disease in the Japanese population. (PMID:28642160)
• GNB4 is important for growth of breast cancer cells and a potential target for treatment (PMID:30103729)
• Guanine nucleotide-binding protein subunit beta-4 promotes gastric cancer progression via activating Erk1/2. (PMID:32747927)
• High G protein subunit beta 4 protein level is correlated to poor prognosis of urothelial carcinoma. (PMID:34398348)
• Prognostic and Immunological Value of GNB4 in Gastric Cancer by Analyzing TCGA Database. (PMID:35756485)
• Helicobacter pylori-induced aberrant demethylation and expression of GNB4 promotes gastric carcinogenesis via the Hippo-YAP1 pathway. (PMID:37016382)
• Plasma methylated GNB4 and Riplet as a novel dual-marker panel for the detection of hepatocellular carcinoma. (PMID:38154055)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	GNB4	ENSDARG00000019278
danio_rerio	gnb4b	ENSDARG00000115383
mus_musculus	Gnb4	ENSMUSG00000027669
rattus_norvegicus	Gnb4	ENSRNOG00000011070
drosophila_melanogaster	Gbeta13F	FBGN0001105
caenorhabditis_elegans		WBGENE00001679

Paralogs (4): GNB5 (ENSG00000069966), GNB1 (ENSG00000078369), GNB3 (ENSG00000111664), GNB2 (ENSG00000172354)

Protein

Protein identifiers

Guanine nucleotide-binding protein subunit beta-4 — Q9HAV0 (reviewed: Q9HAV0)

Alternative names: Transducin beta chain 4

All UniProt accessions (8): Q9HAV0, A0A6Q8PFE0, A0A6Q8PFV8, A0A6Q8PFW8, A0A6Q8PG88, A0A7I2S2S9, C9JD14, H7C5J5

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.

Subunit / interactions. G proteins are composed of 3 units, alpha, beta and gamma.

Tissue specificity. Strongly expressed in lung and placenta, whereas it is weakly expressed in brain and heart. Abundantly expressed in the axons and Schwann cells of peripheral nerves.

Disease relevance. Charcot-Marie-Tooth disease, dominant intermediate F (CMTDIF) [MIM:615185] A 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. CMTDIF is characterized by onset around adolescence of slowly progressive distal muscle atrophy and weakness affecting the upper and lower limbs and resulting in steppage gait. There is distal sensory impairment with decreased reflexes. Nerve conduction velocities are variable, ranging from the demyelinating to the axonal range. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the WD repeat G protein beta family.

RefSeq proteins (1): NP_067642* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001632	WD40_G-protein_beta-like	Domain
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016346	G-protein_beta_1-5	Family
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF25391

UniProt features (14 total): repeat 7, modified residue 3, sequence variant 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAV0-F1	97.14	0.97

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 (3): 2, 266, 2

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
R-HSA-1296041	Activation of G protein gated Potassium channels
R-HSA-163359	Glucagon signaling in metabolic regulation
R-HSA-202040	G-protein activation
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-392170	ADP signalling through P2Y purinoceptor 12
R-HSA-392451	G beta:gamma signalling through PI3Kgamma
R-HSA-392851	Prostacyclin signalling through prostacyclin receptor
R-HSA-400042	Adrenaline,noradrenaline inhibits insulin secretion
R-HSA-4086398	Ca2+ pathway
R-HSA-416476	G alpha (q) signalling events
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-418217	G beta:gamma signalling through PLC beta
R-HSA-418555	G alpha (s) signalling events
R-HSA-418592	ADP signalling through P2Y purinoceptor 1
R-HSA-418594	G alpha (i) signalling events
R-HSA-418597	G alpha (z) signalling events
R-HSA-420092	Glucagon-type ligand receptors
R-HSA-428930	Thromboxane signalling through TP receptor
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-456926	Thrombin signalling through proteinase activated receptors (PARs)
R-HSA-500657	Presynaptic function of Kainate receptors
R-HSA-6814122	Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding
R-HSA-8964315	G beta:gamma signalling through BTK
R-HSA-8964616	G beta:gamma signalling through CDC42
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-997272	Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits

MSigDB gene sets: 426 (showing top): ATF_B, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, REACTOME_ADRENALINE_NORADRENALINE_INHIBITS_INSULIN_SECRETION, GOCC_VACUOLAR_MEMBRANE, REACTOME_POTASSIUM_CHANNELS, REACTOME_INWARDLY_RECTIFYING_K_CHANNELS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, MEF2_02, REACTOME_GLUCAGON_SIGNALING_IN_METABOLIC_REGULATION, GGGTGGRR_PAX4_03, chr3q26, GOBP_NEURAL_NUCLEUS_DEVELOPMENT, FOSTER_TOLERANT_MACROPHAGE_UP, ATF1_Q6

GO Biological Process (3): G protein-coupled receptor signaling pathway (GO:0007186), substantia nigra development (GO:0021762), signal transduction (GO:0007165)

GO Molecular Function (3): signaling receptor complex adaptor activity (GO:0030159), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (6): cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829), heterotrimeric G-protein complex (GO:0005834), synapse (GO:0045202), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
GPCR downstream signalling	5
Signal amplification	3
Regulation of insulin secretion	2
G-protein beta:gamma signalling	2
G protein gated Potassium channels	1
Integration of energy metabolism	1
Opioid Signalling	1
Platelet homeostasis	1
Beta-catenin independent WNT signaling	1
Class B/2 (Secretin family receptors)	1
Aquaporin-mediated transport	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
G protein-coupled receptor activity	1
signal transduction	1
midbrain development	1
neural nucleus development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signaling receptor binding	1
signaling adaptor activity	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1
extrinsic component of cytoplasmic side of plasma membrane	1
plasma membrane protein complex	1
GTPase complex	1
cell junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

3021 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNB4	PLCB2	Q00722	836
GNB4	GNG4	P50150	834
GNB4	GNG13	Q9P2W3	832
GNB4	GNGT2	O14610	813
GNB4	GNGT1	P63211	808
GNB4	GNAO1	P09471	762
GNB4	GNG2	P59768	736
GNB4	GRIK2	Q13002	729
GNB4	GNG11	P50152	692
GNB4	GNG12	Q9UBI6	683
GNB4	GNG10	P50151	669
GNB4	GNG7	O60262	629
GNB4	GNG5	P30670	596
GNB4	SUCLG2	Q96I99	559
GNB4	LIN7B	Q9HAP6	549

IntAct

140 interactions, top by confidence:

A	B	Type	Score
GNGT1	Ntsr1	psi-mi:“MI:0914”(association)	0.750
GNB4	GNAI1	psi-mi:“MI:0915”(physical association)	0.670
GNG3	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG4	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG5	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG7	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG8	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG10	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
GNG8	GNB5	psi-mi:“MI:0914”(association)	0.640
GNG2	GNAS	psi-mi:“MI:0914”(association)	0.620
GNG5	GNB5	psi-mi:“MI:0914”(association)	0.620
GNG2	GNAI1	psi-mi:“MI:0914”(association)	0.610
Haus4	HAUS5	psi-mi:“MI:0915”(physical association)	0.560
GNB4	CASP6	psi-mi:“MI:0915”(physical association)	0.560
GNB4	LAMP2	psi-mi:“MI:0915”(physical association)	0.560
GNB4	SH3GLB1	psi-mi:“MI:0915”(physical association)	0.560
MTNR1A	PGRMC1	psi-mi:“MI:0914”(association)	0.530
MTNR1B	IRS4	psi-mi:“MI:0914”(association)	0.530

BioGRID (182): GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), GNB4 (Affinity Capture-MS)

ESM2 similar proteins: A0A223GEB2, G1SJB4, G4MQX3, O18640, O24076, O24456, O35353, O42248, O42249, P16520, P17343, P23232, P25387, P26308, P29387, P38011, P46800, P49026, P49027, P52287, P54311, P62871, P63243, P63244, P63245, P63246, P63247, P68040, P69103, P69104, P79147, P83774, P93340, Q01369, Q08706, Q10281, Q20636, Q21215, Q25189, Q39336

Diamond homologs: A0A223GEB2, A1CJY4, A1D7I5, A1L271, A2QEV8, A4R3M4, A4RDD7, A6H603, A7THX0, A8ILK1, B0XYC8, B3MJV8, B4HWV6, B4Q9T6, B6QC56, B8AP31, B8M0Q1, E3LB80, G0SC29, O14435, O14775, O35353, O45040, P11017, P16520, P17343, P18851, P23232, P26308, P29387, P29829, P36408, P49177, P49178, P52287, P54311, P54313, P61480, P62871, P62872

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 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
Prostacyclin signalling through prostacyclin receptor	15	110.0×	8e-28
ADP signalling through P2Y purinoceptor 12	18	109.0×	6e-33
G beta:gamma signalling through BTK	14	108.3×	7e-26
G beta:gamma signalling through PLC beta	14	97.5×	6e-25
G beta:gamma signalling through CDC42	14	97.5×	6e-25
Presynaptic function of Kainate receptors	14	92.8×	2e-24
Thromboxane signalling through TP receptor	15	87.0×	1e-25
Adrenaline,noradrenaline inhibits insulin secretion	17	81.6×	7e-28

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	21	7.8×	1e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	145
Likely benign	123
Benign	29

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
41941	NM_021629.4(GNB4):c.265A>G (p.Lys89Glu)	Pathogenic
488522	NM_021629.4(GNB4):c.229G>A (p.Gly77Arg)	Pathogenic
41940	NM_021629.4(GNB4):c.158G>A (p.Gly53Asp)	Likely pathogenic
617599	NM_021629.4(GNB4):c.659A>G (p.Gln220Arg)	Likely pathogenic
834350	NM_021629.4(GNB4):c.227A>G (p.Asp76Gly)	Likely pathogenic

SpliceAI

1844 predictions. Top by Δscore:

Variant	Effect	Δscore
3:179413405:CACT:C	donor_loss	1.0000
3:179413406:ACTT:A	donor_loss	1.0000
3:179413407:CTTA:C	donor_loss	1.0000
3:179413408:TTACA:T	donor_loss	1.0000
3:179413409:T:TC	donor_loss	1.0000
3:179413409:TAC:T	donor_gain	1.0000
3:179413410:A:AC	donor_gain	1.0000
3:179413410:A:C	donor_loss	1.0000
3:179413410:ACA:A	donor_gain	1.0000
3:179413411:C:CC	donor_gain	1.0000
3:179413411:C:CG	donor_loss	1.0000
3:179413411:CA:C	donor_gain	1.0000
3:179413411:CAC:C	donor_gain	1.0000
3:179413411:CACT:C	donor_gain	1.0000
3:179413411:CACTG:C	donor_gain	1.0000
3:179413609:AAGCA:A	acceptor_gain	1.0000
3:179413610:AGCA:A	acceptor_gain	1.0000
3:179413611:GCA:G	acceptor_gain	1.0000
3:179413612:CA:C	acceptor_gain	1.0000
3:179413612:CAC:C	acceptor_gain	1.0000
3:179413614:C:CC	acceptor_gain	1.0000
3:179413616:G:C	acceptor_gain	1.0000
3:179413620:T:TC	acceptor_gain	1.0000
3:179414990:C:CT	acceptor_gain	1.0000
3:179426138:TTTTA:T	donor_loss	1.0000
3:179426139:TTTA:T	donor_loss	1.0000
3:179426140:TTAC:T	donor_loss	1.0000
3:179426141:TAC:T	donor_loss	1.0000
3:179426143:CCT:C	donor_loss	1.0000
3:179426240:CAG:C	acceptor_gain	1.0000

AlphaMissense

2240 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:179401221:A:G	W339R	1.000
3:179401221:A:T	W339R	1.000
3:179401229:A:G	L336P	1.000
3:179401238:T:A	D333V	1.000
3:179401238:T:G	D333A	1.000
3:179401239:C:A	D333Y	1.000
3:179401239:C:G	D333H	1.000
3:179401240:C:A	W332C	1.000
3:179401240:C:G	W332C	1.000
3:179401241:C:A	W332L	1.000
3:179401241:C:G	W332S	1.000
3:179401242:A:G	W332R	1.000
3:179401242:A:T	W332R	1.000
3:179401244:G:A	S331F	1.000
3:179401244:G:T	S331Y	1.000
3:179401245:A:G	S331P	1.000
3:179401247:C:T	G330D	1.000
3:179401248:C:G	G330R	1.000
3:179401250:G:A	T329I	1.000
3:179401250:G:C	T329R	1.000
3:179401250:G:T	T329K	1.000
3:179401285:G:C	C317W	1.000
3:179401288:G:C	S316R	1.000
3:179401288:G:T	S316R	1.000
3:179401290:T:G	S316R	1.000
3:179401292:A:T	V315E	1.000
3:179401295:C:G	R314P	1.000
3:179401296:G:A	R314C	1.000
3:179401296:G:T	R314S	1.000
3:179405215:C:A	W297C	1.000

dbSNP variants (sampled 300 via entrez): RS1000040223 (3:179495047 C>T), RS1000046019 (3:179478109 A>G), RS1000079171 (3:179398705 C>T), RS1000103392 (3:179484937 T>TA), RS1000113286 (3:179495357 G>A), RS1000118217 (3:179444510 T>C), RS1000142452 (3:179460075 C>G), RS1000154676 (3:179526974 G>A), RS1000161313 (3:179399151 A>C), RS1000164873 (3:179463246 C>G,T), RS1000170385 (3:179444751 A>G), RS1000174109 (3:179460445 A>G), RS1000275557 (3:179481633 C>T), RS1000306611 (3:179481924 A>T), RS1000327060 (3:179404828 C>T)

Disease associations

OMIM: gene MIM:610863 | disease phenotypes: MIM:615185, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease dominant intermediate F	Strong	Autosomal dominant
Charcot-Marie-Tooth disease	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Moderate	AD

Mondo (2): Charcot-Marie-Tooth disease dominant intermediate F (MONDO:0014074), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (2): Autosomal dominant intermediate Charcot-Marie-Tooth disease type F (Orphanet:352670), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001265	Hyporeflexia
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0002495	Impaired vibratory sensation
HP:0002936	Distal sensory impairment
HP:0003376	Steppage gait
HP:0003383	Onion bulb formation
HP:0003438	Absent Achilles reflex
HP:0003450	Axonal regeneration
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0006844	Absent patellar reflexes
HP:0007149	Distal upper limb amyotrophy
HP:0007328	Impaired pain sensation
HP:0008944	Distal lower limb amyotrophy
HP:0008959	Distal upper limb muscle weakness
HP:0009053	Distal lower limb muscle weakness
HP:0011096	Peripheral demyelination
HP:0011462	Young adult onset

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001969_15	Heart rate	2.000000e-14
GCST003818_83	Resting heart rate	2.000000e-24
GCST005789_9	Resting heart rate	3.000000e-06
GCST006061_82	Atrial fibrillation	3.000000e-09
GCST006061_83	Atrial fibrillation	4.000000e-09
GCST006414_82	Atrial fibrillation	5.000000e-09

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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	3
bisphenol A	increases expression, increases methylation, decreases expression	2
Copper	affects binding, increases expression, decreases expression	2
Estradiol	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
abrine	decreases expression	1
asparanin A	decreases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Glyphosate	decreases expression	1
Barium	decreases reaction, increases transport, affects binding	1
Caffeine	decreases phosphorylation	1
Chelating Agents	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	increases expression	1
Dihydrotestosterone	increases expression	1
Tamoxifen	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1T2	Abcam HeLa GNB4 KO	Cancer cell line	Female
CVCL_D9FM	Ubigene HEK293 GNB4 KO	Transformed cell line	Female
CVCL_E0DZ	Ubigene HeLa GNB4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

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