PLEKHG5

Summary

PLEKHG5 (pleckstrin homology and RhoGEF domain containing G5, HGNC:29105) is a protein-coding gene on chromosome 1p36.31, encoding Pleckstrin homology domain-containing family G member 5 (O94827). Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons.

This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 57449 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuromuscular disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,496 total — 52 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 29
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020631

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29105
Approved symbol	PLEKHG5
Name	pleckstrin homology and RhoGEF domain containing G5
Location	1p36.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0720, Syx, GEF720, Tech, ARHGEF45
Ensembl gene	ENSG00000171680
Ensembl biotype	protein_coding
OMIM	611101
Entrez	57449

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 28 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000340850, ENST00000377725, ENST00000377728, ENST00000377732, ENST00000377740, ENST00000377748, ENST00000400913, ENST00000400915, ENST00000487949, ENST00000489097, ENST00000535355, ENST00000537245, ENST00000673471, ENST00000674685, ENST00000674790, ENST00000674803, ENST00000674943, ENST00000675093, ENST00000675123, ENST00000675139, ENST00000675548, ENST00000675655, ENST00000675694, ENST00000675812, ENST00000675976, ENST00000676255, ENST00000676287, ENST00000676362, ENST00000676401, ENST00000856966, ENST00000856967, ENST00000934259, ENST00000934260, ENST00000934261, ENST00000948663, ENST00000948664, ENST00000948665, ENST00000948666, ENST00000948667, ENST00000948668

RefSeq mRNA: 8 — MANE Select: NM_020631 NM_001042663, NM_001042664, NM_001042665, NM_001265592, NM_001265593, NM_001265594, NM_020631, NM_198681

CCDS: CCDS41241, CCDS57967, CCDS57968, CCDS79

Canonical transcript exons

ENST00000377728 — 21 exons

Exon	Start	End
ENSE00001474961	6491637	6491667
ENSE00002879000	6474451	6474587
ENSE00003043127	6475047	6475138
ENSE00003458585	6477529	6477658
ENSE00003477218	6470735	6470884
ENSE00003515189	6467825	6468586
ENSE00003515734	6469335	6469450
ENSE00003528986	6470236	6470355
ENSE00003560717	6471488	6471637
ENSE00003590576	6469544	6469676
ENSE00003596813	6470990	6471100
ENSE00003616103	6467122	6467572
ENSE00003621777	6472527	6472622
ENSE00003627040	6470506	6470643
ENSE00003633976	6475462	6475522
ENSE00003634700	6475931	6476036
ENSE00003634776	6472986	6473174
ENSE00003640283	6471758	6471808
ENSE00003641730	6474013	6474164
ENSE00003646939	6473251	6473454
ENSE00003686482	6469042	6469241

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 98.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5209 / max 241.9075, expressed in 1401 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10051	3.3895	1163
10041	1.1039	463
10046	0.7412	351
10043	0.4212	202
10037	0.3767	189
10050	0.3395	187
10049	0.2473	113
10045	0.2304	101
10044	0.2094	91
10042	0.1416	79

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.94	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.59	gold quality
cerebellar hemisphere	UBERON:0002245	98.39	gold quality
cerebellar cortex	UBERON:0002129	98.28	gold quality
skin of abdomen	UBERON:0001416	97.39	gold quality
skin of leg	UBERON:0001511	97.27	gold quality
cerebellum	UBERON:0002037	96.52	gold quality
adenohypophysis	UBERON:0002196	96.00	gold quality
upper arm skin	UBERON:0004263	95.61	silver quality
apex of heart	UBERON:0002098	95.51	gold quality
spleen	UBERON:0002106	94.86	gold quality
zone of skin	UBERON:0000014	94.66	gold quality
lower esophagus mucosa	UBERON:0035834	94.39	gold quality
pituitary gland	UBERON:0000007	94.28	gold quality
right frontal lobe	UBERON:0002810	93.95	gold quality
esophagus mucosa	UBERON:0002469	92.87	gold quality
tibial nerve	UBERON:0001323	92.28	gold quality
ganglionic eminence	UBERON:0004023	90.84	gold quality
anterior cingulate cortex	UBERON:0009835	90.19	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.14	gold quality
right uterine tube	UBERON:0001302	89.73	gold quality
prefrontal cortex	UBERON:0000451	89.42	gold quality
right adrenal gland cortex	UBERON:0035827	89.04	gold quality
esophagus	UBERON:0001043	89.01	gold quality
frontal cortex	UBERON:0001870	88.20	gold quality
gall bladder	UBERON:0002110	88.17	gold quality
heart left ventricle	UBERON:0002084	88.11	gold quality
neocortex	UBERON:0001950	88.08	gold quality
right adrenal gland	UBERON:0001233	87.95	gold quality
ectocervix	UBERON:0012249	87.95	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting PLEKHG5, 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-4267	99.96	66.53	2368
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-6876-3P	98.97	65.69	765
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-626	98.89	66.21	762
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-4305	97.94	68.63	533
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-132-5P	96.61	65.79	115
HSA-MIR-6735-3P	96.10	63.81	600

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• We identified a homozygous missense mutation (c.1940 T–>C [p.647 Phe–>Ser]) of the Pleckstrin homology domain-containing, family G member 5 gene, PLEKHG5, in families with lower motor neuron disease. (PMID:17564964)
• a novel means of regulating junctional Syx localization and function by phosphorylation-induced 14-3-3 binding and further support the importance of Syx function in maintaining stable cell-cell contacts. (PMID:23335514)
• Results indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes Charcot-Marie-Tooth disease or lower motor neuron disease affecting the function of neurons and glial cells. (PMID:23777631)
• This study identifies compound heterozygous PLEKHG5 mutations as the cause of recessive intermediate Charcot-Marie-Tooth disease. (PMID:23844677)
• Recruitment of Syx to the cell membrane, the selective activation of Dia1 signaling, coupled with the suppression of ROCK and actin reorganization, plays a key role in establishing cell polarity during directed cell migration. (PMID:24126053)
• PLEKHG5 promoted glioma cell migration and invasion.The expression patterns of PLEKHG5 are related to the glioma patients’ survival. (PMID:31309383)
• Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies. (PMID:33220101)
• PLEKHG5 regulates autophagy, survival and MGMT expression in U251-MG glioblastoma cells. (PMID:33318498)
• Characterization and computational simulation of human Syx, a RhoGEF implicated in glioblastoma. (PMID:35639414)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	plekhg5a	ENSDARG00000025902
danio_rerio	plekhg5b	ENSDARG00000101752
mus_musculus	Plekhg5	ENSMUSG00000039713
rattus_norvegicus	Plekhg5	ENSRNOG00000022694
caenorhabditis_elegans		WBGENE00006476

Paralogs (1): PLEKHG7 (ENSG00000187510)

Protein

Protein identifiers

Pleckstrin homology domain-containing family G member 5 — O94827 (reviewed: O94827)

Alternative names: Guanine nucleotide exchange factor 720

All UniProt accessions (12): A0A5F9ZHW8, A0A6Q8PF22, A0A6Q8PG76, A0A6Q8PGZ5, A0A6Q8PHD3, A0A6Q8PHJ1, A0A6Q8PHR5, O94827, A0A6Q8PHS0, A0A7I2PMD6, A0A804EMX3, Q5SY18

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons. Involved in the control of neuronal cell differentiation. Plays a role in angiogenesis through regulation of endothelial cells chemotaxis. Also affects the migration, adhesion, and matrix/bone degradation in macrophages and osteoclasts.

Subunit / interactions. Interacts with GIPC1/synectin and RHOA.

Subcellular location. Cytoplasm. Perinuclear region. Cell membrane. Cell junction. Cell projection. Lamellipodium.

Tissue specificity. Predominantly expressed in the peripheral nervous system and brain. Highest expression is observed in heart, lung, kidney, testis and moderate expression is present in spleen, pancreas, skeletal muscle, ovary and liver. Weakly expressed in glioblastoma (GBM) cell lines.

Disease relevance. Neuronopathy, distal hereditary motor, autosomal recessive 4 (HMNR4) [MIM:611067] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMNR4 is characterized by childhood onset, generalized muscle weakness and atrophy with denervation and normal sensation. Bulbar symptoms and pyramidal signs are absent. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, recessive intermediate C (CMTRIC) [MIM:615376] 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. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
O94827-5	1	yes
O94827-3	2
O94827-4	3
O94827-7	4

RefSeq proteins (8): NP_001036128, NP_001036129, NP_001036130, NP_001252521, NP_001252522, NP_001252523, NP_065682, NP_941374 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR040181	PKHG5/7	Family

Pfam: PF00621

UniProt features (35 total): compositionally biased region 9, region of interest 7, modified residue 5, splice variant 4, sequence conflict 4, sequence variant 3, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94827-F1	64.94	0.32

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 (5): 729, 734, 851, 876, 881

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle

MSigDB gene sets: 175 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_CELL_CHEMOTAXIS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, WHITE_NEUROBLASTOMA_WITH_1P36.3_DELETION, MAYBURD_RESPONSE_TO_L663536_UP, GOBP_TAXIS, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOCC_CELL_CELL_JUNCTION, GOBP_POSITIVE_REGULATION_OF_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (5): Rho protein signal transduction (GO:0007266), endothelial cell chemotaxis (GO:0035767), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), endothelial cell migration (GO:0043542), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (2): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (11): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), lamellipodium (GO:0030027), endocytic vesicle (GO:0030139), axon (GO:0030424), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
RHO GTPase cycle	3
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
small GTPase-mediated signal transduction	2
cytoplasm	2
endothelial cell migration	1
cell chemotaxis	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
cell migration	1
regulation of intracellular signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
anchoring junction	1
cell leading edge	1
plasma membrane bounded cell projection	1
cytoplasmic vesicle	1
neuron projection	1
cell junction	1

Protein interactions and networks

STRING

916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLEKHG5	PLEK2	Q9NYT0	681
PLEKHG5	PLEK	P08567	678
PLEKHG5	MCF2	P10911	609
PLEKHG5	IGHMBP2	P38935	588
PLEKHG5	VAMP2	P19065	586
PLEKHG5	SAPCD1	Q5SSQ6	560
PLEKHG5	RND3	P52199	555
PLEKHG5	RHOA	P06749	525
PLEKHG5	TGM7	Q96PF1	507
PLEKHG5	RAB26	Q9ULW5	497
PLEKHG5	DHTKD1	Q96HY7	469
PLEKHG5	STX1A	Q16623	446
PLEKHG5	EZR	P15311	435
PLEKHG5	SH3TC2	Q8TF17	419
PLEKHG5	DNAJB2	P25686	417

IntAct

13 interactions, top by confidence:

A	B	Type	Score
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
MPDZ	SMCHD1	psi-mi:“MI:0914”(association)	0.590
GNG2	GNB5	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
RND3	PLEKHG5	psi-mi:“MI:0914”(association)	0.350
PLEKHG5	YWHAE	psi-mi:“MI:0914”(association)	0.350
	PLEKHG5	psi-mi:“MI:0915”(physical association)	0.000
PLEKHG5		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): BTRC (Affinity Capture-MS), FBXW11 (Affinity Capture-MS), YWHAE (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), YWHAG (Affinity Capture-MS), PDP1 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAQ (Affinity Capture-MS), USP7 (Affinity Capture-MS), VDAC3 (Co-fractionation), TOMM40 (Co-fractionation), VDAC2 (Co-fractionation), PLEKHG5 (Affinity Capture-RNA), PLEKHG5 (Two-hybrid)

ESM2 similar proteins: A1L3C1, A2AWP8, A2RRU4, A6QM06, A6QNS9, E1BBQ2, F1LQY6, G3V9M2, O43189, O94827, P29372, P29590, P41155, P97260, Q01113, Q02833, Q04841, Q0P5I0, Q12770, Q13387, Q13505, Q29RM4, Q32L49, Q3V1H9, Q5MNU5, Q5R5M3, Q66T02, Q69Z89, Q6GQT6, Q6IPT2, Q6RFZ7, Q6ZN54, Q70EL4, Q7Z6G3, Q8BQB4, Q8C4U2, Q8N1F8, Q8N554, Q8WWW0, Q8WXF8

Diamond homologs: O94827, Q3KR16, Q66T02, Q6RFZ7, Q8R0J1, Q92888, Q9Z1I6, O75962, Q1LUA6, O15085, Q12802, Q5R6F2, Q5ZLX4, Q61210, Q6P9R4, Q6ZSZ5, Q8R4H2, Q9ES67, Q9N0A8, Q9NR81, Q9NZN5, A1IGU4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLEKHG5	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 13 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
Activation of BAD and translocation to mitochondria	5	346.1×	6e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	305.4×	6e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	305.4×	6e-11
Activation of BH3-only proteins	5	225.7×	3e-10
RHO GTPases activate PKNs	5	144.2×	3e-09
Intrinsic Pathway for Apoptosis	5	133.1×	3e-09
SARS-CoV-1-host interactions	5	79.9×	4e-08
Apoptosis	5	76.3×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	5	43.6×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1496 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	25
Uncertain significance	582
Likely benign	655
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069212	NM_020631.6(PLEKHG5):c.909C>A (p.Tyr303Ter)	Pathogenic
1146824	NM_020631.6(PLEKHG5):c.2162_2163insTGAGCAGGAGGAGGAAGAGGAGGAGGAGGAGGAG (p.Glu721fs)	Pathogenic
1416561	NM_020631.6(PLEKHG5):c.386del (p.Leu129fs)	Pathogenic
1424950	NM_020631.6(PLEKHG5):c.1457_1482del (p.Gln486fs)	Pathogenic
1453868	NM_020631.6(PLEKHG5):c.2074_2075del (p.Gln692fs)	Pathogenic
1796001	NM_020631.6(PLEKHG5):c.2788C>T (p.Arg930Ter)	Pathogenic
1999132	NM_020631.6(PLEKHG5):c.1128T>A (p.Cys376Ter)	Pathogenic
2033307	NM_020631.6(PLEKHG5):c.363C>A (p.Tyr121Ter)	Pathogenic
2035800	NM_020631.6(PLEKHG5):c.365_378del (p.Leu122fs)	Pathogenic
2065924	NM_020631.6(PLEKHG5):c.2540del (p.Pro847fs)	Pathogenic
2135331	NM_020631.6(PLEKHG5):c.1258del (p.Asp420fs)	Pathogenic
2921807	NM_020631.6(PLEKHG5):c.2665del (p.Ala889fs)	Pathogenic
2925088	NM_020631.6(PLEKHG5):c.2158G>T (p.Glu720Ter)	Pathogenic
2932016	NM_020631.6(PLEKHG5):c.2945del (p.Lys982fs)	Pathogenic
2937250	NM_020631.6(PLEKHG5):c.2471del (p.Pro824fs)	Pathogenic
2940146	NM_020631.6(PLEKHG5):c.1728dup (p.Ala577fs)	Pathogenic
2940176	NM_020631.6(PLEKHG5):c.2880_2881del (p.Pro961fs)	Pathogenic
2944038	NM_020631.6(PLEKHG5):c.1644C>G (p.Tyr548Ter)	Pathogenic
2944622	NM_020631.6(PLEKHG5):c.2242C>T (p.Gln748Ter)	Pathogenic
2945617	NM_020631.6(PLEKHG5):c.2132del (p.Gln711fs)	Pathogenic
2946537	NM_020631.6(PLEKHG5):c.38dup (p.Gln14fs)	Pathogenic
2947725	NM_020631.6(PLEKHG5):c.1396del (p.Ala466fs)	Pathogenic
2947865	NM_020631.6(PLEKHG5):c.2150_2154del (p.Glu717fs)	Pathogenic
2948081	NM_020631.6(PLEKHG5):c.2489_2490del (p.Phe830fs)	Pathogenic
2950547	NM_020631.6(PLEKHG5):c.187A>T (p.Lys63Ter)	Pathogenic
2950908	NM_020631.6(PLEKHG5):c.2628dup (p.Lys877Ter)	Pathogenic
2952449	NM_020631.6(PLEKHG5):c.1736dup (p.Glu580fs)	Pathogenic
2953611	NM_020631.6(PLEKHG5):c.2231del (p.Ser744fs)	Pathogenic
2954313	NM_020631.6(PLEKHG5):c.2146G>T (p.Glu716Ter)	Pathogenic
3063343	GRCh37/hg19 1p36.32-36.23(chr1:4536962-7934520)x1	Pathogenic

SpliceAI

3546 predictions. Top by Δscore:

Variant	Effect	Δscore
1:6468587:C:CC	acceptor_gain	1.0000
1:6469040:A:AC	donor_gain	1.0000
1:6469041:C:CC	donor_gain	1.0000
1:6469237:TGGTT:T	acceptor_gain	1.0000
1:6469238:GGTT:G	acceptor_gain	1.0000
1:6469239:GTT:G	acceptor_gain	1.0000
1:6469240:TT:T	acceptor_gain	1.0000
1:6469241:TCTG:T	acceptor_loss	1.0000
1:6469242:C:CC	acceptor_gain	1.0000
1:6469242:CT:C	acceptor_loss	1.0000
1:6469249:CAAGG:C	acceptor_gain	1.0000
1:6469250:A:T	acceptor_gain	1.0000
1:6469253:G:C	acceptor_gain	1.0000
1:6469254:T:C	acceptor_gain	1.0000
1:6469254:T:TC	acceptor_gain	1.0000
1:6469330:CTCA:C	donor_loss	1.0000
1:6469331:TCACC:T	donor_loss	1.0000
1:6469332:CA:C	donor_loss	1.0000
1:6469333:A:AG	donor_loss	1.0000
1:6469449:CC:C	acceptor_gain	1.0000
1:6469450:CC:C	acceptor_gain	1.0000
1:6469539:CTTAC:C	donor_loss	1.0000
1:6469540:TTAC:T	donor_loss	1.0000
1:6469541:TAC:T	donor_loss	1.0000
1:6469542:A:AC	donor_gain	1.0000
1:6469542:A:AT	donor_loss	1.0000
1:6469542:AC:A	donor_gain	1.0000
1:6469543:C:CA	donor_gain	1.0000
1:6469543:CC:C	donor_gain	1.0000
1:6469543:CCA:C	donor_gain	1.0000

AlphaMissense

6539 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:6469645:A:G	L611P	0.998
1:6470793:A:G	L495P	0.998
1:6470793:A:T	L495H	0.998
1:6470796:A:G	L494P	0.998
1:6470805:T:C	Y491C	0.998
1:6470806:A:G	Y491H	0.998
1:6470807:C:A	K490N	0.998
1:6470807:C:G	K490N	0.998
1:6472576:A:G	L344P	0.998
1:6473012:A:G	W320R	0.998
1:6473012:A:T	W320R	0.998
1:6469361:A:G	W675R	0.997
1:6469361:A:T	W675R	0.997
1:6469600:A:T	V626D	0.997
1:6469639:A:G	L613S	0.997
1:6470806:A:C	Y491D	0.997
1:6470814:A:T	L488H	0.997
1:6471494:G:C	F425L	0.997
1:6471494:G:T	F425L	0.997
1:6471496:A:G	F425L	0.997
1:6471783:A:G	L369P	0.997
1:6472564:T:A	E348V	0.997
1:6474456:A:T	V145D	0.997
1:6475119:A:G	F77S	0.997
1:6469411:G:T	A658D	0.996
1:6470793:A:C	L495R	0.996
1:6470799:A:G	L493P	0.996
1:6470809:T:C	K490E	0.996
1:6470826:G:T	P484H	0.996
1:6471070:A:C	Y438D	0.996

dbSNP variants (sampled 300 via entrez): RS1000013961 (1:6490981 G>T), RS1000220200 (1:6485601 T>C,G), RS1000272403 (1:6475530 G>A,T), RS1000289825 (1:6510887 G>A), RS1000447821 (1:6500444 C>G), RS1000452337 (1:6506177 C>T), RS1000480635 (1:6495351 C>A,G,T), RS1000507679 (1:6509721 C>A,T), RS1000525919 (1:6495600 G>A), RS1000580353 (1:6475696 G>A), RS1000672637 (1:6505340 G>C), RS1000690015 (1:6488248 C>T), RS1000715970 (1:6487519 A>C), RS1000738846 (1:6506346 A>G), RS1000775772 (1:6468530 G>A)

Disease associations

OMIM: gene MIM:611101 | disease phenotypes: MIM:611067, MIM:615376, MIM:182970, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronopathy, distal hereditary motor, autosomal recessive 4	Strong	Autosomal recessive
Charcot-Marie-Tooth disease recessive intermediate C	Strong	Autosomal recessive
hereditary peripheral neuropathy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuromuscular disease	Definitive	AR

Mondo (10): neuronopathy, distal hereditary motor, autosomal recessive 4 (MONDO:0012608), Charcot-Marie-Tooth disease recessive intermediate C (MONDO:0014154), hereditary motor neuron disease (MONDO:0024257), peripheral neuropathy (MONDO:0005244), atrophy of testis (MONDO:0001415), distal hereditary motor neuropathy (MONDO:0018894), spinal muscular atrophy, facioscapulohumeral type (MONDO:0008452), hereditary spastic paraplegia (MONDO:0019064), juvenile amyotrophic lateral sclerosis (MONDO:0017593), hereditary peripheral neuropathy (MONDO:0020127)

Orphanet (6): Autosomal recessive lower motor neuron disease with childhood onset (Orphanet:206580), Autosomal recessive intermediate Charcot-Marie-Tooth disease type C (Orphanet:369867), Genetic motor neuron disease (Orphanet:98505), Distal hereditary motor neuropathy (Orphanet:53739), Hereditary spastic paraplegia (Orphanet:685), Juvenile amyotrophic lateral sclerosis (Orphanet:300605)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001765	Hammertoe
HP:0002366	Abnormal lower motor neuron morphology
HP:0002460	Distal muscle weakness
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002936	Distal sensory impairment
HP:0003307	Hyperlordosis
HP:0003376	Steppage gait
HP:0003387	Decreased number of large peripheral myelinated nerve fibers
HP:0003431	Decreased motor nerve conduction velocity
HP:0003445	EMG: neuropathic changes
HP:0003474	Somatic sensory dysfunction
HP:0003551	Difficulty climbing stairs
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003678	Rapidly progressive
HP:0003693	Distal amyotrophy
HP:0003697	Scapuloperoneal amyotrophy
HP:0003701	Proximal muscle weakness
HP:0007269	Spinal muscular atrophy
HP:0008180	Mildly elevated creatine kinase
HP:0009473	Joint contracture of the hand
HP:0011463	Childhood onset

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000363_5	QT interval	1.000000e-16
GCST005531_26	Multiple sclerosis	5.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
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
C567023	Spinal Muscular Atrophy, Distal, Autosomal Recessive, 4 (supp.)
C566674	Spinal Muscular Atrophy, Facioscapulohumeral Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Benzo(a)pyrene	affects methylation	2
Ozone	increases abundance, affects cotreatment, decreases expression, increases oxidation	2
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bufotalin	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
beta-lapachone	decreases expression, increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
cupric chloride	increases expression	1
muconaldehyde	decreases expression	1
CGP 52608	increases reaction, affects binding	1
calfactant	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	affects response to substance	1
Acetaminophen	decreases expression	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation	1
Vehicle Emissions	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Cannabinoids	affects methylation, increases abundance	1

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.