ALS2

alsin Rho guanine nucleotide exchange factor ALS2, the group of Dbl family Rho GEFs|VPS9 domain containing

Basic information

Region (hg38): 2:201700267-201782112

Previous symbols: [ "ALS2CR6" ]

Links

ENSG00000003393

∙ NCBI:57679 ∙ OMIM:606352 ∙ HGNC:443 ∙ Uniprot:Q96Q42 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

juvenile primary lateral sclerosis (Strong), mode of inheritance: AR
infantile-onset ascending hereditary spastic paralysis (Strong), mode of inheritance: AR
amyotrophic lateral sclerosis type 2, juvenile (Strong), mode of inheritance: AR
juvenile primary lateral sclerosis (Supportive), mode of inheritance: AR
infantile-onset ascending hereditary spastic paralysis (Supportive), mode of inheritance: AR
juvenile amyotrophic lateral sclerosis (Supportive), mode of inheritance: AR
juvenile primary lateral sclerosis (Strong), mode of inheritance: AR
infantile-onset ascending hereditary spastic paralysis (Strong), mode of inheritance: AR
ALS2-related motor neuron disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paralysis, infantile onset ascending; Primary lateral sclerosis, juvenile; Amyotrophic lateral sclerosis 2	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	2328408; 7920663; 8745388; 11586298; 11586297; 12145748; 12509863; 16718699; 18523452; 18810511; 19122027

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALS2 gene.

Infantile-onset_ascending_hereditary_spastic_paralysis (752 variants)
not_provided (212 variants)
Inborn_genetic_diseases (126 variants)
Amyotrophic_lateral_sclerosis_type_2,_juvenile (103 variants)
ALS2-related_disorder (80 variants)
Hereditary_spastic_paraplegia (39 variants)
not_specified (33 variants)
Juvenile_primary_lateral_sclerosis (22 variants)
ALS2-related_motor_neuron_disease (8 variants)
Amyotrophic_lateral_sclerosis (4 variants)
Tip-toe_gait (3 variants)
Amyotrophic_Lateral_Sclerosis,_Recessive (3 variants)
Peripheral_axonal_neuropathy (2 variants)
Abnormal_central_motor_function (2 variants)
Juvenile_amyotrophic_lateral_sclerosis (1 variants)
Hypokinesia (1 variants)
Spasticity (1 variants)
Global_developmental_delay (1 variants)
Abnormal_cerebral_white_matter_morphology (1 variants)
Microcephaly (1 variants)
Hypertyrosinemia (1 variants)
Limb_dystonia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALS2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000020919.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			20 clinvar	185 clinvar	7 clinvar	212
missense	4 clinvar	12 clinvar	393 clinvar	28 clinvar		437
nonsense	26 clinvar	12 clinvar	2 clinvar			40
start loss						0
frameshift	24 clinvar	12 clinvar	2 clinvar			38
splice donor/acceptor (+/-2bp)	11 clinvar	20 clinvar	1 clinvar			32
Total	65	56	418	213	7

Highest pathogenic variant AF is 0.00003323266

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALS2	protein_coding	protein_coding	ENST00000264276	33	80636

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.72e-12	1.00	124625	0	177	124802	0.000709

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.90	713	870	0.819	0.0000459	10787
Missense in Polyphen		142	245.32	0.57885		3020
Synonymous	0.485	317	328	0.966	0.0000181	3249
Loss of Function	5.42	36	92.2	0.390	0.00000510	1069

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00127	0.00126
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000390	0.000389
Finnish	0.00126	0.00125
European (Non-Finnish)	0.000885	0.000883
Middle Eastern	0.000390	0.000389
South Asian	0.000425	0.000360
Other	0.000662	0.000660

dbNSFP

Source: dbNSFP

Function: FUNCTION: May act as a GTPase regulator. Controls survival and growth of spinal motoneurons (By similarity). {ECO:0000250}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 2 (ALS2) [MIM:205100]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:11586298}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Juvenile primary lateral sclerosis (JPLS) [MIM:606353]: A neurodegenerative disorder which is closely related to but clinically distinct from amyotrophic lateral sclerosis. It is a progressive paralytic disorder which results from dysfunction of the upper motor neurons while the lower neurons are unaffected. {ECO:0000269|PubMed:11586297}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Infantile-onset ascending spastic paralysis (IAHSP) [MIM:607225]: Characterized by progressive spasticity and weakness of limbs. {ECO:0000269|PubMed:12145748}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human);Amyotrophic lateral sclerosis (ALS);Vesicle-mediated transport;Membrane Trafficking;Rab regulation of trafficking;RAB GEFs exchange GTP for GDP on RABs (Consensus)

Intolerance Scores

loftool: 0.318
rvis_EVS: -1.46
rvis_percentile_EVS: 3.89

Haploinsufficiency Scores

pHI: 0.240
hipred: Y
hipred_score: 0.706
ghis: 0.592

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.873

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

Gene name: Als2
Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; muscle phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);

Zebrafish Information Network

Gene name: als2b
Affected structure: motor neuron
Phenotype tag: abnormal
Phenotype quality: decreased amount

Gene ontology

Biological process: behavioral fear response;in utero embryonic development;receptor recycling;response to oxidative stress;endosome organization;axonogenesis;neuromuscular junction development;locomotory behavior;protein localization;cell death;endosomal transport;Rac protein signal transduction;positive regulation of Rac protein signal transduction;regulation of Rho protein signal transduction;synaptic transmission, glutamatergic;positive regulation of GTPase activity;positive regulation of protein kinase activity;neuron projection morphogenesis;regulation of endosome size;positive regulation of protein serine/threonine kinase activity
Cellular component: ruffle;early endosome;centrosome;cytosol;postsynaptic density;membrane;lamellipodium;dendrite;growth cone;vesicle;protein-containing complex;neuronal cell body;dendritic spine;intracellular membrane-bounded organelle
Molecular function: guanyl-nucleotide exchange factor activity;protein binding;Rab guanyl-nucleotide exchange factor activity;Rab GTPase binding;Rac guanyl-nucleotide exchange factor activity;protein homodimerization activity;protein serine/threonine kinase activator activity