# NM_020919.4(ALS2):c.1039_1042del (p.Glu347fs)

https://sugi.bio/variant/als2-p-glu347fs

## Summary

**ALS2 p.Glu347fs (c.1039_1042del)** is classified **Likely pathogenic** in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-13). Associated with infantile-onset ascending hereditary spastic paralysis.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the ALS2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to infantile-onset ascending hereditary spastic paralysis.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | ALS2 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Infantile-onset ascending hereditary spastic paralysis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Spasticity — Very frequent (99-80%)
- Spastic paraplegia — Very frequent (99-80%)
- Dysarthria — Very frequent (99-80%)
- Hyperreflexia — Very frequent (99-80%)
- Anarthria — Very frequent (99-80%)
- Tetraplegia — Very frequent (99-80%)
- Spastic tetraplegia — Very frequent (99-80%)
- Impaired mastication — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004914/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALS2](https://sugi.bio/atlas/gene/ALS2/) |
| Protein change (HGVS p.) | p.Glu347fs |
| Coding change (HGVS c.) | c.1039_1042del |
| MANE Select transcript | [NM_020919](https://www.ncbi.nlm.nih.gov/nuccore/NM_020919) |
| Variant type | Deletion |
| Location | chr2:201760952-201760955 (GRCh38) |
| ClinVar | [VCV4849695](https://www.ncbi.nlm.nih.gov/clinvar/variation/4849695/) |

**All HGVS expressions:** `LRG_654:g.25218_25221del`, `LRG_654t1:c.1039_1042del`, `NC_000002.11:g.202625678_202625681del`, `NC_000002.12:g.201760955_201760958del`, `NG_008775.1:g.25218_25221del`, `NM_001135745.2:c.1039_1042del`, `NM_001410975.1:c.1039_1042del`, `NM_020919.4:c.1039_1042del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.17, GERP -0.512 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.649, pLI 2.816e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 34**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ALS2** population constraint: LOEUF 0.649, pLI 2.816e-17, missense-Z 2.9747; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ALS2-related motor neuron disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.69, 40% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ALS2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ALS2's established molecular role includes guanyl-nucleotide exchange factor activity.


### Pathways affected {#pathways}

ALS2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** guanyl-nucleotide exchange factor activity, GTPase activator activity, small GTPase binding, identical protein binding, protein homodimerization activity, protein serine/threonine kinase activator activity.

**Biological process:** lysosomal transport, positive regulation of GTPase activity, positive regulation of protein kinase activity, neuron projection morphogenesis, regulation of endosome size, protein homooligomerization.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-13.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-02-13 |

## Associated conditions {#conditions}

[infantile-onset ascending hereditary spastic paralysis](https://sugi.bio/atlas/disease/infantile-onset-ascending-hereditary-spastic-paralysis/).

**Reported phenotype names (ClinVar):** Infantile-onset ascending hereditary spastic paralysis, Infantile-Onset Ascending Hereditary Spastic Paralysis (IAHSP), Autosomal Recessive Juvenile Amyotrophic Lateral Sclerosis.

## Similar variants {#similar}

Related ALS2 variant pages (same residue, condition, or type): [ALS2 p.Glu347=](/variant/als2-p-glu347), [ALS2 p.Glu246fs](/variant/als2-p-glu246fs), [ALS2 p.Leu352fs](/variant/als2-p-leu352fs), [ALS2 p.Leu623fs](/variant/als2-p-leu623fs), [ALS2 p.Val1287_Pro1288del](/variant/als2-p-val1287-pro1288del), [ALS2 c.1472-20del](/variant/als2-c-1472-minus-20del), [ALS2 c.3625-16_3625-15del](/variant/als2-c-3625-minus-16-3625-minus-15del), [ALS2 c.1113+1del](/variant/als2-c-1113-plus-1del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4849695). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*