Is ALS2 p.Glu347fs (c.1039_1042del) pathogenic?

ALS2 p.Glu347fs (c.10391042del) is classified Likely pathogenic in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-13). Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Glu347fs (c.1039_1042del)?

ALS2 p.Glu347fs (c.1039_1042del) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

ALS2 p.Glu347fs

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.1039_1042del · VCV4849695

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.17	GERP -0.51

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: ALS2
Protein: p.Glu347fs
Coding: c.1039_1042del
MANE Select: NM_020919
Type: Deletion
Location: chr2:201760952 (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.Glu347= Likely benign ★ same residue
ALS2 p.Glu246fs Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Leu352fs Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Leu623fs Pathogenic ★★ same condition
ALS2 p.Val1287_Pro1288del Uncertain significance ★★ same condition
ALS2 c.1472-20del Benign/Likely benign ★★ same condition
ALS2 c.3625-16_3625-15del Benign/Likely benign ★★ same condition
ALS2 c.1113+1del 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-glu347fs (accessed [today's date]).

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