# NM_020919.4(ALS2):c.267T>C (p.Val89=)

https://sugi.bio/variant/als2-p-val89

## Summary

**ALS2 p.Val89= (c.267T>C)** is classified **Likely benign** in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-02). Ultra-rare (popmax 0.0681%, sas); Associated with infantile-onset ascending hereditary spastic paralysis.

**At a glance:** Likely benign · review: Single submitter · rsID rs571219883 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0681%, sas)

## For patients & families {#patients}

This is a change in the ALS2 gene that is classified as likely benign — not considered 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.Val89= |
| Coding change (HGVS c.) | c.267T>C |
| MANE Select transcript | [NM_020919](https://www.ncbi.nlm.nih.gov/nuccore/NM_020919) |
| dbSNP | [rs571219883](https://www.ncbi.nlm.nih.gov/snp/rs571219883/) |
| Variant type | single nucleotide variant |
| Location | chr2:201761727-201761727 (GRCh38) |
| ClinVar | [VCV1095002](https://www.ncbi.nlm.nih.gov/clinvar/variation/1095002/) |

**All HGVS expressions:** `LRG_654:g.24446T>C`, `LRG_654t1:c.267T>C`, `NC_000002.11:g.202626450A>G`, `NC_000002.12:g.201761727A>G`, `NG_008775.1:g.24446T>C`, `NM_001135745.2:c.267T>C`, `NM_020919.4:c.267T>C`

## 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 0.586, GERP -0.559, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 6.727**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.23 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0681%** (sas) · FAF95 0.0544% · FAF99 0.0495% · 62/91,084 in the highest group · 70/1,614,178 alleles overall — ultra-rare (popmax 0.0681%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0681% | 1,469 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,502 |
| European (non-Finnish) | 0.000254% | 393,345 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

## 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, Autosomal Recessive Juvenile Amyotrophic Lateral Sclerosis, Infantile-Onset Ascending Hereditary Spastic Paralysis (IAHSP).

## Similar variants {#similar}

Related ALS2 variant pages (same residue, condition, or type): [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 p.Ala573Glu](/variant/als2-p-ala573glu), [ALS2 p.Arg1139Ter](/variant/als2-p-arg1139ter), [ALS2 p.Arg1421Ter](/variant/als2-p-arg1421ter), [ALS2 p.Arg1461Ter](/variant/als2-p-arg1461ter), [ALS2 p.Arg1510Ter](/variant/als2-p-arg1510ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1095002). 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.*