Is ALS2 p.Gly477fs (c.1425_1428del) pathogenic?

ALS2 p.Gly477fs (c.14251428del) is classified Pathogenic in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-22). Very rare (popmax 0.00133%, afr); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Gly477fs (c.1425_1428del)?

ALS2 p.Gly477fs (c.1425_1428del) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Gly477fs (c.1425_1428del) in the general population?

ALS2 p.Gly477fs (c.1425_1428del) is very rare (popmax 0.00133%, afr) (gnomAD).

ALS2 p.Gly477fs

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.1425_1428del · rs878855058 · VCV241308

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 5 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,028 alleles

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

Overall 0.000274% 4/1,461,782 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,028
European (non-Finnish)	0.000254%	393,334

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.Gly477fs
Coding: c.1425_1428del
MANE Select: NM_020919
dbSNP: rs878855058
Type: Deletion
Location: chr2:201757445 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 477: the 'disordered' region

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.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
ALS2 c.3517delG 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-gly477fs (accessed [today's date]).

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