Is ALS2 p.Leu623fs (c.1867_1868del) pathogenic?

ALS2 p.Leu623fs (c.18671868del) is classified Pathogenic in ALS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-18). Very rare (popmax 0.00534%, afr); Associated with amyotrophic lateral sclerosis type 2, juvenile.

What condition is associated with ALS2 p.Leu623fs (c.1867_1868del)?

ALS2 p.Leu623fs (c.1867_1868del) is associated with amyotrophic lateral sclerosis type 2, juvenile, juvenile primary lateral sclerosis, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Leu623fs (c.1867_1868del) in the general population?

ALS2 p.Leu623fs (c.1867_1868del) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Juvenile amyotrophic lateral sclerosis inherited?

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

ALS2 p.Leu623fs

c.1867_1868del · rs386134181 · VCV4406

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

amyotrophic lateral sclerosis type 2, juvenile

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 9 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP 0.85, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,924 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,731
European (non-Finnish)	0.000169%	590,023

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.Leu623fs
Coding: c.1867_1868del
MANE Select: NM_020919
dbSNP: rs386134181
Type: Deletion
Location: chr2:201746696 (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

amyotrophic lateral sclerosis type 2, juvenile — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: juvenile primary lateral sclerosis infantile-onset ascending hereditary spastic paralysis

For Juvenile amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ALS2 p.Glu246fs Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Leu352fs Pathogenic/Likely 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
ALS2 c.4838+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-leu623fs (accessed [today's date]).

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