ALS2

Chr 2AR

alsin Rho guanine nucleotide exchange factor ALS2

Also known as: ALS2CR6, ALSJ, IAHSP, PLSJ

NCBI Gene: 57679ENSG00000003393UniProt: Q96Q42

The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 2, juvenileMIM #205100
AR
Primary lateral sclerosis, juvenileMIM #606353
AR
Spastic paralysis, infantile onset ascendingMIM #607225
AR
Amyotrophic lateral sclerosis 2, juvenileMIM #205100
AR
UniProtJuvenile primary lateral sclerosis
UniProtInfantile-onset ascending spastic paralysis
461
ClinVar variants
48
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ALS2
🧬
Gene-Disease Validity (ClinGen)
ALS2-related motor neuron disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
48 Pathogenic / Likely Pathogenic· 166 VUS of 461 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.52LOEUF
pLI 0.000
Z-score 5.42
OE 0.39 (0.30–0.52)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.90Z-score
OE missense 0.82 (0.77–0.87)
713 obs / 870.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.39 (0.30–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.77–0.87)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 36 / 92.2Missense obs/exp: 713 / 870.5Syn Z: 0.48

ClinVar Variant Classifications

461 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic14
VUS166
Likely Benign226
Benign18
Conflicting3
34
Pathogenic
14
Likely Pathogenic
166
VUS
226
Likely Benign
18
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
2
22
0
34
Likely Pathogenic
12
1
1
0
14
VUS
1
152
11
2
166
Likely Benign
0
4
108
114
226
Benign
0
0
13
5
18
Conflicting
—3
Total23159155121461

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ALS2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ALS2-related disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Amyotrophic lateral sclerosis 2, juvenile

MIM #205100

Molecular basis of disorder known

Autosomal recessive

Primary lateral sclerosis, juvenile

MIM #606353

Molecular basis of disorder known

Autosomal recessive

Spastic paralysis, infantile onset ascending

MIM #607225

Molecular basis of disorder known

Autosomal recessive

Amyotrophic lateral sclerosis 2, juvenile

MIM #205100

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ALS2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.
Shi Y et al.·Nat Med
2018
Phenotype and Genotype of Children with ALS2 gene-Related Disorder.
Yoganathan S et al.·Neuropediatrics
2025
Juvenile Amyotrophic Lateral Sclerosis: A Review.
Lehky T et al.·Genes (Basel)
2021Review
Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function.
Sato K et al.·J Biol Chem
2018
Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study.
Mitsi E et al.·Sci Rep
2024
Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS.
Zaki MS et al.·Clin Genet
2023Cohort
A Retrospective Review of 18 Patients With Childhood-Onset Hereditary Spastic Paraplegia, Nine With Novel Variants.
Kilic MA et al.·Pediatr Neurol
2024Review
The expanding clinical and genetic spectrum of alsin-related disorders: the first cohort of Brazilian patients.
Alves De Siqueira Carvalho A et al.·Amyotroph Lateral Scler Frontotemporal Degener
2022Review
ALS2-related disorders in Spanish children.
Nogueira E et al.·Neurol Sci
2021
Dystonia: an update on phenomenology, classification, pathogenesis and treatment.
Balint B et al.·Curr Opin Neurol
2014Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools