ALS2

Chr 2

alsin Rho guanine nucleotide exchange factor ALS2

Also known as: ALS2CR6, ALSJ, IAHSP, PLSJ

NCBI Gene: 57679 ENSG00000003393 UniProt: Q96Q42

The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5, localizing to early endosomal compartments where it modulates endosomal dynamics. Mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis, juvenile primary lateral sclerosis, and infantile-onset ascending spastic paralysis. The pathogenic mechanism involves disruption of endosomal trafficking through impaired RAB5 activation.

GeneReviews ResearchSummary from RefSeq, OMIM

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAmyotrophic lateral sclerosis 2

UniProtJuvenile primary lateral sclerosis

UniProtInfantile-onset ascending spastic paralysis

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · ALS2-related motor neuron disease · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

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LOEUF

LOF

Mechanism· G2P

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GeneReview available — ALS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (2)

gnomad: Error: gnomAD API error: 400

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in ALS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 43

1,966 rare PASS variants

Rare truncating (LoF)

1 in 760

263 rare PASS variants

Rare synonymous (reference)

1 in 77

797 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ALS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 53	1 in 770
South Asian	~43k	1 in 32	1 in 900
Remaining (unassigned)	~30k	1 in 36	1 in 830
European (Finnish)	~27k	1 in 120	1 in 3,300
Admixed American	~22k	1 in 37	1 in 2,300
African / African American	~21k	1 in 29	1 in 700
East Asian	~20k	1 in 32	1 in 260
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 37	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 27 of 33 coding exons well covered in gnomAD exomes; exons 2, 12, 17, 20, 26, 30 marginal. Genomes: all 33.? see exons ↓