ARHGEF28

Summary

ARHGEF28 (Rho guanine nucleotide exchange factor 28, HGNC:30322) is a protein-coding gene on chromosome 5q13.2, encoding Rho guanine nucleotide exchange factor 28 (Q8N1W1). Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors.

This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 64283 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis (Moderate, GenCC)
• GWAS associations: 20
• Clinical variants (ClinVar): 512 total
• MANE Select transcript: NM_001177693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30322
Approved symbol	ARHGEF28
Name	Rho guanine nucleotide exchange factor 28
Location	5q13.2
Locus type	gene with protein product
Status	Approved
Aliases	RGNEF, p190RhoGEF, RIP2
Ensembl gene	ENSG00000214944
Ensembl biotype	protein_coding
OMIM	612790
Entrez	64283

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000296794, ENST00000296799, ENST00000426542, ENST00000437974, ENST00000503341, ENST00000504003, ENST00000506334, ENST00000509848, ENST00000510131, ENST00000510312, ENST00000512883, ENST00000513042, ENST00000513841, ENST00000545377, ENST00000872894, ENST00000872895, ENST00000872896, ENST00000872897, ENST00000948319

RefSeq mRNA: 5 — MANE Select: NM_001177693 NM_001080479, NM_001177693, NM_001244364, NM_001388076, NM_001388078

CCDS: CCDS47231, CCDS54870, CCDS58957, CCDS93734

Canonical transcript exons

ENST00000513042 — 36 exons

Exon	Start	End
ENSE00001031211	73776516	73776696
ENSE00001031236	73897962	73898093
ENSE00001031238	73901184	73901284
ENSE00001083678	73909412	73909897
ENSE00001083680	73904222	73904260
ENSE00001083683	73904358	73904405
ENSE00001128075	73911275	73911575
ENSE00001287981	73848976	73849087
ENSE00001292330	73870069	73870209
ENSE00001298580	73857656	73857779
ENSE00001310195	73868100	73868227
ENSE00001310294	73852650	73852692
ENSE00001311696	73867876	73868020
ENSE00001313953	73872999	73873246
ENSE00001319949	73858087	73858219
ENSE00001426813	73684841	73684884
ENSE00001723410	73882472	73882594
ENSE00002028392	73626196	73626322
ENSE00002212806	73832338	73832459
ENSE00002233674	73752909	73753202
ENSE00002272138	73773855	73774038
ENSE00002277937	73780676	73780745
ENSE00002277991	73795331	73795391
ENSE00002301496	73749837	73749984
ENSE00002319120	73794402	73794454
ENSE00003476693	73893197	73893288
ENSE00003490742	73894393	73894575
ENSE00003511034	73885850	73886104
ENSE00003556712	73883767	73883884
ENSE00003569047	73892052	73892230
ENSE00003623104	73887603	73887679
ENSE00003633695	73840480	73840760
ENSE00003639108	73846268	73846475
ENSE00003667648	73865965	73866013
ENSE00003686377	73864817	73864872
ENSE00003917431	73940844	73941990

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 92.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.3193 / max 109.5974, expressed in 1053 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57047	3.1856	961
57056	0.8799	221
57055	0.0876	35
57054	0.0610	21
57057	0.0326	12
57050	0.0276	10
57053	0.0182	7
57051	0.0149	7
57052	0.0119	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	92.17	gold quality
right adrenal gland	UBERON:0001233	91.73	gold quality
right adrenal gland cortex	UBERON:0035827	91.65	gold quality
metanephros cortex	UBERON:0010533	91.18	gold quality
left ovary	UBERON:0002119	90.64	gold quality
left adrenal gland	UBERON:0001234	90.37	gold quality
epithelium of nasopharynx	UBERON:0001951	90.12	gold quality
left adrenal gland cortex	UBERON:0035825	89.93	gold quality
epithelium of bronchus	UBERON:0002031	89.80	gold quality
body of pancreas	UBERON:0001150	89.79	gold quality
tibial nerve	UBERON:0001323	89.78	gold quality
bronchial epithelial cell	CL:0002328	89.77	gold quality
right uterine tube	UBERON:0001302	89.72	gold quality
minor salivary gland	UBERON:0001830	89.49	gold quality
adrenal cortex	UBERON:0001235	89.47	gold quality
bronchus	UBERON:0002185	89.39	gold quality
adrenal gland	UBERON:0002369	89.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.11	gold quality
mouth mucosa	UBERON:0003729	88.85	gold quality
saliva-secreting gland	UBERON:0001044	88.76	gold quality
gingival epithelium	UBERON:0001949	88.67	gold quality
adult mammalian kidney	UBERON:0000082	88.65	gold quality
skin of abdomen	UBERON:0001416	88.53	gold quality
right ovary	UBERON:0002118	88.39	gold quality
ovary	UBERON:0000992	88.11	gold quality
palpebral conjunctiva	UBERON:0001812	87.81	gold quality
kidney	UBERON:0002113	87.74	gold quality
body of stomach	UBERON:0001161	87.51	gold quality
calcaneal tendon	UBERON:0003701	87.50	gold quality
adrenal tissue	UBERON:0018303	87.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting ARHGEF28, 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-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-188-3P	100.00	68.76	1240
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-6833-5P	99.50	68.93	1161

Literature-anchored findings (GeneRIF, showing 13)

• RGNEF is a human homologue of p190RhoGEF, and its RNA is expressed in both brain and spinal cord (PMID:19488899)
• Studies identify Rgnef as a novel regulator of colon carcinoma motility and invasion, and they show that a Rgnef-FAK linkage promotes colon carcinoma progression in vivo. (PMID:21224360)
• This study demonistrated that RGNEF-immunoreactive neuronal cytoplasmic inclusions (NCIs) can co-localize with TDP-43, FUS/TLS and p62 within spinal motor neurons. (PMID:22941224)
• Study identified a heterozygous mutation in amyotrophic lateral sclerosis patients that is predicted to generate a premature truncated ARHGEF28 gene product. There were extensive regions of homozygosity in the ARHGEF28 gene in two familial ALS patients. (PMID:23286752)
• This study showed that ARHGEF28 gene exon 6/intron 6 junction mutations in Chinese amyotrophic lateral sclerosis cohort. (PMID:24712971)
• results show that Rgnef functions as an effector of Galpha13 signaling and that this linkage may mediate FAK activation in DLD-1 colon carcinoma cells (PMID:25922072)
• Data show interaction between activated Rac family small GTPase 1 (Rac1) and Rho guanine nucleotide exchange factor 28 (p190RhoGEF), suggeseting a potential mechanism for cross-talk regulation where Rac can directly effect stimulation of small GTP binding protein RhoA (RhoA). (PMID:29196061)
• a 23-amino acid region containing a bipartite nuclear localization signal (NLS) within the Pleckstrin Homology (PH) domain of RGNEF, which when deleted or mutated abolishes the nuclear localization of this protein. (PMID:30482479)
• Rare, low-frequency and common coding variants of ARHGEF28 gene and their association with sporadic amyotrophic lateral sclerosis. (PMID:31060816)
• A new role for Rgnef in ovarian cancer to facilitate NF-kappaB-mediated gene expression protecting cells from oxidative stress. (PMID:31308489)
• Circular RNA circRGNEF promotes bladder cancer progression via miR-548/KIF2C axis regulation. (PMID:32305958)
• Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network. (PMID:32764283)
• Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, in Mouse Macrophages Negatively Affects M1 Polarization and Inflammatory Responses. (PMID:35422804)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef28a	ENSDARG00000060415
mus_musculus	Arhgef28	ENSMUSG00000021662
rattus_norvegicus	Arhgef28	ENSRNOG00000016544
drosophila_melanogaster	cyst	FBGN0032796
caenorhabditis_elegans	prhg-1	WBGENE00022391

Paralogs (8): PLEKHG6 (ENSG00000008323), ARHGEF1 (ENSG00000076928), ARHGEF18 (ENSG00000104880), ARHGEF2 (ENSG00000116584), ARHGEF11 (ENSG00000132694), ARHGEF3 (ENSG00000163947), NET1 (ENSG00000173848), ARHGEF12 (ENSG00000196914)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 28 — Q8N1W1 (reviewed: Q8N1W1)

Alternative names: 190 kDa guanine nucleotide exchange factor, Rho guanine nucleotide exchange factor

All UniProt accessions (3): D6RAP0, D6RGZ3, Q8N1W1

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors. Functions in axonal branching, synapse formation and dendritic morphogenesis. Also functions in focal adhesion formation, cell motility and B-lymphocytes activation. May regulate NEFL expression and aggregation and play a role in apoptosis.

Subunit / interactions. Homooligomer; forms cytoplasmic aggregates. Forms a complex with MAPK8 and MAPK8IP1. Interacts with RHOA. Interacts with microtubules. Interacts with YWHAE and YWHAH. Interacts with PTK2/FAK1. Interacts with NEFL. Interacts with CTNND2; prevents interaction with RHOA.

Subcellular location. Cytoplasm. Cell membrane.

Post-translational modifications. Phosphorylated on tyrosine upon stimulation of cells by laminin.

Isoforms (6)

UniProt ID	Names	Canonical?
Q8N1W1-1	1	yes
Q8N1W1-2	2
Q8N1W1-3	3
Q8N1W1-4	4
Q8N1W1-5	5
Q8N1W1-6	6

RefSeq proteins (5): NP_001073948, NP_001171164, NP_001231293, NP_001375005, NP_001375007 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001849	PH_domain	Domain
IPR002219	PKC_DAG/PE	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR037819	ARHGEF28_PH	Domain
IPR041020	PH_16	Domain
IPR046349	C1-like_sf	Homologous_superfamily
IPR051632	Rho_GEF	Family

Pfam: PF00130, PF00621, PF17838

UniProt features (64 total): region of interest 12, strand 10, compositionally biased region 9, sequence variant 8, splice variant 7, sequence conflict 5, modified residue 4, helix 4, domain 2, chain 1, coiled-coil region 1, zinc finger region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6BC0	X-RAY DIFFRACTION	2.2
6BC1	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N1W1-F1	62.42	0.23

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 (4): 313, 478, 624, 1538

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-422475	Axon guidance
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 162 (showing top): GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEUROGENESIS, DELYS_THYROID_CANCER_DN, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_DIFFERENTIATION, GOBP_EPHRIN_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_DEVELOPMENT, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, WANG_PROSTATE_CANCER_ANDROGEN_INDEPENDENT, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_AXONOGENESIS, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY

GO Biological Process (7): cell morphogenesis (GO:0000902), central nervous system neuron axonogenesis (GO:0021955), regulation of Rho protein signal transduction (GO:0035023), ephrin receptor signaling pathway (GO:0048013), regulation of small GTPase mediated signal transduction (GO:0051056), neurofilament cytoskeleton organization (GO:0060052), cell differentiation (GO:0030154)

GO Molecular Function (5): RNA binding (GO:0003723), guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
RHO GTPase cycle	3
EPH-Ephrin signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Axon guidance	1
Nervous system development	1
Signaling by Rho GTPases	1
Developmental Biology	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
anatomical structure morphogenesis	1
axonogenesis	1
central nervous system neuron development	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
cell surface receptor protein tyrosine kinase signaling pathway	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
intermediate filament cytoskeleton organization	1
cellular developmental process	1
nucleic acid binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
transition metal ion binding	1
binding	1
cation binding	1
cytoplasm	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

994 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF28	NEFM	P07197	774
ARHGEF28	RHOA	P06749	742
ARHGEF28	NEFL	P07196	715
ARHGEF28	MCF2	P10911	701
ARHGEF28	SOD1	P00441	656
ARHGEF28	PXN	P49023	638
ARHGEF28	PLEK2	Q9NYT0	611
ARHGEF28	PLEK	P08567	605
ARHGEF28	CTNND2	Q9UQB3	600
ARHGEF28	CDC42	P21181	600
ARHGEF28	CTNNAL1	Q9UBT7	559
ARHGEF28	AKT1	P31749	549
ARHGEF28	ARHGAP35	Q9NRY4	530
ARHGEF28	TLN2	Q9Y4G6	525
ARHGEF28	TLN1	Q9Y490	518

IntAct

35 interactions, top by confidence:

A	B	Type	Score
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
VEGFB	LAMB2	psi-mi:“MI:0914”(association)	0.530
POC1A	TXNDC9	psi-mi:“MI:0914”(association)	0.480
ARHGEF28	MYH9	psi-mi:“MI:0915”(physical association)	0.400
	ARHGEF28	psi-mi:“MI:0915”(physical association)	0.370
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
LYN	TOM1L1	psi-mi:“MI:0914”(association)	0.350
C6orf141	ITPRID2	psi-mi:“MI:0914”(association)	0.350
CFAP184	UTRN	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CRYBB3	VWA8	psi-mi:“MI:0914”(association)	0.350
DYNLT4	NPR1	psi-mi:“MI:0914”(association)	0.350
GZMH	PCDH7	psi-mi:“MI:0914”(association)	0.350
KLK15	GLA	psi-mi:“MI:0914”(association)	0.350
RPL28	LEFTY2	psi-mi:“MI:0914”(association)	0.350
TUBB	VWA8	psi-mi:“MI:0914”(association)	0.350
UPK2	IFT56	psi-mi:“MI:0914”(association)	0.350
	TTC8	psi-mi:“MI:0914”(association)	0.350
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAZ	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (34): ARHGEF28 (Affinity Capture-MS), ARHGEF28 (Affinity Capture-RNA), ARHGEF28 (Affinity Capture-RNA), ARHGEF28 (Two-hybrid), CTAG1A (Two-hybrid), ARHGEF28 (Proximity Label-MS), ARHGEF18 (Affinity Capture-Western), ARHGEF9 (Affinity Capture-Western), ARHGEF28 (FRET), ARHGEF28 (Negative Genetic), ARHGEF28 (Affinity Capture-Western), ARHGEF28 (Affinity Capture-Western), ARHGEF28 (Biochemical Activity), ARHGEF28 (Affinity Capture-MS), ARHGEF28 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8F1M4, A0A8M9QN10, A0JMQ9, A6NIR3, A8DZE6, A8WH69, B2KF05, F1QCY8, O43147, O43900, O54880, P0C6P5, P59729, P97433, Q13009, Q18PD9, Q2NKQ1, Q32L09, Q3U5C7, Q58D79, Q5EB20, Q5PQS0, Q5U464, Q60592, Q6IVY4, Q6P0Q8, Q6ZQF7, Q6ZUJ8, Q71QF9, Q768S4, Q7T2V3, Q7TNN8, Q7TSI1, Q7ZVP1, Q803A0, Q80U12, Q80VL3, Q80Y24, Q8BPQ7, Q8BRB7

Diamond homologs: B2DCZ9, E9Q394, F1M3G7, P0C6P5, P97433, Q12802, Q5FVC2, Q60875, Q6P9R4, Q6ZSZ5, Q865S3, Q8N1W1, Q92974, Q9NZN5, Q61210, Q92888, Q9Z1I6, Q8R4H2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ARHGEF28	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
GNA13	“up-regulates activity”	ARHGEF28	binding
GNAQ	“up-regulates activity”	ARHGEF28	binding
PTK2	“up-regulates activity”	ARHGEF28	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 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	7	183.8×	3e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	162.2×	5e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	162.2×	5e-13
Activation of BH3-only proteins	7	119.8×	4e-12
RHO GTPases activate PKNs	8	87.5×	1e-12
Intrinsic Pathway for Apoptosis	7	70.7×	2e-10
FOXO-mediated transcription	5	57.9×	3e-07
Translocation of SLC2A4 (GLUT4) to the plasma membrane	9	47.9×	5e-12

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	48.2×	1e-05
intracellular protein localization	7	19.3×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	269
Likely benign	88
Benign	106

Top pathogenic / likely-pathogenic (0)

SpliceAI

7457 predictions. Top by Δscore:

Variant	Effect	Δscore
5:73684839:A:AG	acceptor_gain	1.0000
5:73684840:G:GG	acceptor_gain	1.0000
5:73684882:TACGT:T	donor_loss	1.0000
5:73684883:ACGT:A	donor_loss	1.0000
5:73684884:CGTAA:C	donor_loss	1.0000
5:73684885:G:GG	donor_gain	1.0000
5:73684885:GTA:G	donor_loss	1.0000
5:73749835:A:AG	acceptor_gain	1.0000
5:73749835:AG:A	acceptor_gain	1.0000
5:73749836:G:GG	acceptor_gain	1.0000
5:73749836:GG:G	acceptor_gain	1.0000
5:73749836:GGGGC:G	acceptor_gain	1.0000
5:73749981:CCAGG:C	donor_loss	1.0000
5:73749982:CAGGT:C	donor_loss	1.0000
5:73749983:AGG:A	donor_loss	1.0000
5:73749984:GG:G	donor_loss	1.0000
5:73749985:G:GC	donor_loss	1.0000
5:73749986:T:G	donor_loss	1.0000
5:73773852:CAG:C	acceptor_loss	1.0000
5:73773853:A:AG	acceptor_gain	1.0000
5:73773853:A:G	acceptor_loss	1.0000
5:73773854:G:GA	acceptor_gain	1.0000
5:73773854:GT:G	acceptor_gain	1.0000
5:73773854:GTA:G	acceptor_gain	1.0000
5:73773854:GTAT:G	acceptor_gain	1.0000
5:73773854:GTATC:G	acceptor_gain	1.0000
5:73774032:TCACA:T	donor_gain	1.0000
5:73774037:AA:A	donor_gain	1.0000
5:73774038:AG:A	donor_loss	1.0000
5:73774039:G:GG	donor_gain	1.0000

AlphaMissense

11233 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:73892124:T:C	F1154L	1.000
5:73892125:T:C	F1154S	1.000
5:73892125:T:G	F1154C	1.000
5:73892126:T:A	F1154L	1.000
5:73892126:T:G	F1154L	1.000
5:73892128:T:C	L1155P	1.000
5:73892131:T:A	I1156N	1.000
5:73892131:T:C	I1156T	1.000
5:73870134:T:A	W831R	0.999
5:73870134:T:C	W831R	0.999
5:73873002:T:C	L857P	0.999
5:73886081:A:T	K1096I	0.999
5:73886082:A:C	K1096N	0.999
5:73886082:A:T	K1096N	0.999
5:73886095:C:A	R1101S	0.999
5:73886096:G:C	R1101P	0.999
5:73886102:A:T	K1103I	0.999
5:73886103:A:C	K1103N	0.999
5:73886103:A:T	K1103N	0.999
5:73892086:T:C	L1141P	0.999
5:73892096:A:C	R1144S	0.999
5:73892096:A:T	R1144S	0.999
5:73892104:C:A	A1147D	0.999
5:73892124:T:A	F1154I	0.999
5:73892124:T:G	F1154V	0.999
5:73892128:T:A	L1155Q	0.999
5:73892131:T:G	I1156S	0.999
5:73892158:T:C	M1165T	0.999
5:73892158:T:G	M1165R	0.999
5:73892190:C:A	R1176S	0.999

dbSNP variants (sampled 300 via entrez): RS1000009562 (5:73832741 A>G), RS1000018819 (5:73686685 T>A), RS1000023424 (5:73931771 T>G), RS1000049442 (5:73761482 T>C), RS1000050847 (5:73788936 G>A), RS1000052220 (5:73918036 C>T), RS1000054854 (5:73847731 C>G), RS1000075208 (5:73891464 G>A), RS1000081574 (5:73651822 A>C), RS1000097397 (5:73625929 G>C), RS1000108326 (5:73672633 A>G), RS1000112025 (5:73803542 G>A), RS1000113288 (5:73885257 T>C), RS1000120354 (5:73925984 A>G), RS1000133429 (5:73938330 A>T)

Disease associations

OMIM: gene MIM:612790 | disease phenotypes: MIM:156000

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Limited	SD

Mondo (2): Meniere disease (MONDO:0007972), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (1): NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001049_10	D-dimer levels	1.000000e-06
GCST001762_813	Obesity-related traits	7.000000e-06
GCST003989_32	Chin dimples	5.000000e-12
GCST004567_127	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	4.000000e-09
GCST004567_43	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	4.000000e-09
GCST004576_94	Waist-to-hip ratio adjusted for body mass index	6.000000e-09
GCST004576_95	Waist-to-hip ratio adjusted for body mass index	1.000000e-08
GCST004578_127	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-06
GCST004578_131	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-06
GCST006611_73	HDL cholesterol	3.000000e-09
GCST011385_2	Vaginal microbiome composition (Shannon diversity index)	4.000000e-06
GCST012335_35	Hodgkin’s lymphoma	1.000000e-10
GCST012442_33	Age-related hearing impairment	5.000000e-12
GCST012442_34	Age-related hearing impairment	3.000000e-23
GCST90002385_286	High light scatter reticulocyte count	2.000000e-10
GCST90002386_31	High light scatter reticulocyte percentage of red cells	3.000000e-09
GCST90002397_41	Mean spheric corpuscular volume	8.000000e-14
GCST90002405_66	Reticulocyte count	8.000000e-12
GCST90002406_175	Reticulocyte fraction of red cells	2.000000e-10
GCST90007000_1	Gut microbiota relative abundance (unclassified genus belonging to family Ruminococcaceae)	2.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004507	D dimer measurement
EFO:0004458	C-reactive protein measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008002	physical activity measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0011013	vaginal microbiome measurement
EFO:0007986	reticulocyte count
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D008575	Meniere Disease	C09.218.568.217.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs929740	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects methylation, decreases methylation	3
Calcitriol	increases expression	2
Formaldehyde	decreases expression	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases 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
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases reaction, increases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Mercury	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension