Is ALS2 p.Ser1267fs (c.3799dup) pathogenic?

ALS2 p.Ser1267fs (c.3799dup) is classified Pathogenic in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-15). Absent from gnomAD; Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Ser1267fs (c.3799dup)?

ALS2 p.Ser1267fs (c.3799dup) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Ser1267fs (c.3799dup) in the general population?

ALS2 p.Ser1267fs (c.3799dup) is absent from gnomAD (gnomAD).

ALS2 p.Ser1267fs

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.3799dup · rs2469734144 · VCV2856462

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 24 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 0.6, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ALS2
Protein: p.Ser1267fs
Coding: c.3799dup
MANE Select: NM_020919
dbSNP: rs2469734144
Type: Duplication
Location: chr2:201718113 (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.Val1525fs Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ile1517fs Pathogenic ★ same condition
ALS2 p.Thr512fs Pathogenic ★ same condition
ALS2 c.1738-6dup Benign ★ same condition
ALS2 c.176-10dup Benign ★ same condition
ALS2 c.176-8dup Likely benign ★ same condition
ALS2 c.2912+10dup Likely benign ★ same condition
ALS2 c.1640+1G>A 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-ser1267fs (accessed [today's date]).

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