Is ALS2 p.Leu1339= (c.4015C>T) pathogenic?

ALS2 p.Leu1339= (c.4015C>T) is classified Benign in ALS2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 99%, eas) — too common for a highly-penetrant pathogenic allele; Associated with amyotrophic lateral sclerosis type 2, juvenile.

What condition is associated with ALS2 p.Leu1339= (c.4015C>T)?

ALS2 p.Leu1339= (c.4015C>T) is associated with amyotrophic lateral sclerosis type 2, juvenile, juvenile primary lateral sclerosis, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How is Juvenile amyotrophic lateral sclerosis inherited?

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

ALS2 p.Leu1339=

Q: How common is ALS2 p.Leu1339= (c.4015C>T) in the general population?

ALS2 p.Leu1339= (c.4015C>T) is common (popmax 99%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4015C>T · rs3219168 · VCV261377

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 99%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

amyotrophic lateral sclerosis type 2, juvenile

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -3.7
Overall
CADD	0.276	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99% East Asian · 44,263/44,716 alleles

Filtering AF 98.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 97.9%

Overall 92.2% 1,472,688/1,597,622 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	99%	1
Amishnot grpmax-eligible	98.1%	1
South Asian	95.8%	1
Finnishnot grpmax-eligible	95.5%	1
European (non-Finnish)	92.3%	1
Remaining individualsnot grpmax-eligible	92%	1
Ashkenazi Jewishnot grpmax-eligible	91.5%	1
Middle Eastern	90.3%	1
Admixed American	88.8%	1
African / African-American	82%	1

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.Leu1339=
Coding: c.4015C>T
MANE Select: NM_020919
dbSNP: rs3219168
Type: single nucleotide variant
Location: chr2:201711098 (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 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.2580+2T>C Pathogenic ★★ same condition
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.4626+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala573Glu Likely pathogenic ★★ same condition
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1461Ter 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-leu1339 (accessed [today's date]).

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