Is ALS2 p.Ala120del (c.356CTG[1]) pathogenic?

ALS2 p.Ala120del (c.356CTG[1]) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-19). Very rare (popmax 0.000254%, nfe); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Ala120del (c.356CTG[1])?

ALS2 p.Ala120del (c.356CTG[1]) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Ala120del (c.356CTG[1]) in the general population?

ALS2 p.Ala120del (c.356CTG[1]) is very rare (popmax 0.000254%, nfe) (gnomAD).

ALS2 p.Ala120del

Q: How is Infantile-onset ascending hereditary spastic paralysis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.356CTG[1] · rs1693774824 · VCV2099500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Overall
CADD	19.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,046 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,066 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALS2
Protein: p.Ala120del
Coding: c.356CTG[1]
MANE Select: NM_020919
dbSNP: rs1693774824
Type: Microsatellite
Location: chr2:201761633 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69

Full ALS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

infantile-onset ascending hereditary spastic paralysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile-onset ascending hereditary spastic paralysis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALS2 p.Ala120Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
ALS2 p.Leu56del Uncertain significance ★ same condition
ALS2 c.1114-15GT[2] Likely benign ★ same condition
ALS2 c.2171-25CAT[3] Likely benign ★ same condition
ALS2 c.3702+17_3702+20del Likely benign ★ same condition
ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.2580+2T>C Pathogenic ★★ same condition
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/als2-p-ala120del (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown