Is ALS2 p.Thr185fs (c.553del) pathogenic?

ALS2 p.Thr185fs (c.553del) is classified Pathogenic in ALS2 (ClinVar, Single submitter, 3 submitters; last evaluated 2020-01-16). Absent from gnomAD; Associated with juvenile primary lateral sclerosis.

What condition is associated with ALS2 p.Thr185fs (c.553del)?

ALS2 p.Thr185fs (c.553del) is associated with juvenile primary lateral sclerosis, amyotrophic lateral sclerosis type 2, juvenile (ClinVar).

How common is ALS2 p.Thr185fs (c.553del) in the general population?

ALS2 p.Thr185fs (c.553del) is absent from gnomAD (gnomAD).

How is Juvenile primary lateral sclerosis inherited?

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

ALS2 p.Thr185fs

c.553del · rs386134174 · VCV4414

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

juvenile primary lateral sclerosis

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 6.7	GERP 0.8, 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.Thr185fs
Coding: c.553del
MANE Select: NM_020919
dbSNP: rs386134174
Type: Deletion
Location: chr2:201761441 (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

juvenile primary lateral sclerosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 2, juvenile

For Juvenile primary lateral sclerosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ALS2 p.Leu623fs Pathogenic ★★ same condition
ALS2 p.Asp1298fs Likely pathogenic ★ same condition
ALS2 p.Gln1355fs Likely pathogenic ★ same condition
ALS2 p.Ile441fs Likely pathogenic ★ same condition
ALS2 p.Ala47fs Pathogenic same condition
ALS2 c.2580+2T>C Pathogenic ★★ same condition
ALS2 c.4626+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala573Glu 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-thr185fs (accessed [today's date]).

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