# NM_020919.4(ALS2):c.396G>A (p.Pro132=)

https://sugi.bio/variant/als2-p-pro132

## Summary

**ALS2 p.Pro132= (c.396G>A)** is classified **Conflicting classifications of pathogenicity** in ALS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-11). Ultra-rare (popmax 0.0307%, afr); Associated with amyotrophic lateral sclerosis type 2, juvenile.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs374978798 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0307%, afr)

## For patients & families {#patients}

This is a change in the ALS2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to amyotrophic lateral sclerosis type 2, juvenile.

*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) | Childhood |
| Prevalence | <1 / 1 000 000 (Europe) |
| Diagnostic panels | ALS2 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Juvenile amyotrophic lateral sclerosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Muscle weakness — Very frequent (99-80%)
- Lower limb spasticity — Very frequent (99-80%)
- Skeletal muscle atrophy — Very frequent (99-80%)
- Distal amyotrophy — Very frequent (99-80%)
- Upper limb spasticity — Very frequent (99-80%)
- Amyotrophic lateral sclerosis — Very frequent (99-80%)
- Spastic diplegia — Frequent (79-30%)
- Hypertonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015137/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.Pro132= |
| Coding change (HGVS c.) | c.396G>A |
| MANE Select transcript | [NM_020919](https://www.ncbi.nlm.nih.gov/nuccore/NM_020919) |
| dbSNP | [rs374978798](https://www.ncbi.nlm.nih.gov/snp/rs374978798/) |
| Variant type | single nucleotide variant |
| Location | chr2:201761598-201761598 (GRCh38) |
| ClinVar | [VCV700826](https://www.ncbi.nlm.nih.gov/clinvar/variation/700826/) |

**All HGVS expressions:** `LRG_654:g.24575G>A`, `LRG_654t1:c.396G>A`, `NC_000002.11:g.202626321C>T`, `NC_000002.12:g.201761598C>T`, `NG_008775.1:g.24575G>A`, `NM_001135745.2:c.396G>A`, `NM_020919.4:c.396G>A`

## 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 -3.358, GERP -3.73 — fast-evolving / accelerated position
- CADD: **PHRED 6.816**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0307%** (afr) · FAF95 0.0209% · FAF99 0.0178% · 23/75,038 in the highest group · 46/1,614,186 alleles overall — ultra-rare (popmax 0.0307%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0307% | 3,263 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,418 |
| Admixed American | 0.00666% | 15,004 |
| South Asian | 0.00549% | 18,218 |
| European (non-Finnish) | 0.000678% | 147,505 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-05-11.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely benign).

**Submission history:** 4 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-11 |

## Associated conditions {#conditions}

[amyotrophic lateral sclerosis type 2, juvenile](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-2-juvenile/), [infantile-onset ascending hereditary spastic paralysis](https://sugi.bio/atlas/disease/infantile-onset-ascending-hereditary-spastic-paralysis/).

**Reported phenotype names (ClinVar):** Amyotrophic lateral sclerosis type 2, juvenile, ALS2-related disorder, Infantile-onset ascending hereditary spastic paralysis, Inborn genetic diseases, ALS, JUVENILE, Amyotrophic lateral sclerosis type 2, ALS2-related condition, ALS2-related disorders, ALS2-Related Spectrum Disorders, Infantile-Onset Ascending Hereditary Spastic Paralysis (IAHSP).

## Similar variants {#similar}

Related ALS2 variant pages (same residue, condition, or type): [ALS2 p.Pro132Leu](/variant/als2-p-pro132leu), [ALS2 c.1640+1G>A](/variant/als2-c-1640-plus-1g-a), [ALS2 c.2580+2T>C](/variant/als2-c-2580-plus-2t-c), [ALS2 c.3703-2A>G](/variant/als2-c-3703-minus-2a-g), [ALS2 c.4626+1G>A](/variant/als2-c-4626-plus-1g-a), [ALS2 p.Ala573Glu](/variant/als2-p-ala573glu), [ALS2 p.Arg1139Ter](/variant/als2-p-arg1139ter), [ALS2 p.Arg1421Ter](/variant/als2-p-arg1421ter).

### 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 700826). 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.*