Is ALS2 p.Pro1148del (c.3442_3444del) pathogenic?

ALS2 p.Pro1148del (c.34423444del) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-24). Very rare (popmax 8.48e-05%, nfe); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Pro1148del (c.3442_3444del)?

ALS2 p.Pro1148del (c.3442_3444del) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Pro1148del (c.3442_3444del) in the general population?

ALS2 p.Pro1148del (c.3442_3444del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

ALS2 p.Pro1148del

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.3442_3444del · rs2106001109 · VCV1374199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, 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 7.9	GERP 1.8, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,828 alleles

Overall 6.84e-05% 1/1,461,640 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.Pro1148del
Coding: c.3442_3444del
MANE Select: NM_020919
dbSNP: rs2106001109
Type: Deletion
Location: chr2:201724363 (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.Pro1148Ser Uncertain significance ★★ ⚠ same residue
ALS2 p.Pro1148Leu Uncertain significance ★ ⚠ 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

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-pro1148del (accessed [today's date]).

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