Is ALS2 p.Glu159Lys (c.475G>A) pathogenic?

ALS2 p.Glu159Lys (c.475G>A) is classified Benign/Likely benign in ALS2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1424); Common (popmax 5.16%, amr) — too common for a highly-penetrant pathogenic allele; Associated with ALS2-related disorder.

What condition is associated with ALS2 p.Glu159Lys (c.475G>A)?

ALS2 p.Glu159Lys (c.475G>A) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile, juvenile primary lateral sclerosis (ClinVar).

What do computational predictors say about ALS2 p.Glu159Lys (c.475G>A)?

AlphaMissense predicts likely benign (score 0.1424) — an in-silico prediction, not a clinical call.

ALS2 p.Glu159Lys

Q: How common is ALS2 p.Glu159Lys (c.475G>A) in the general population?

ALS2 p.Glu159Lys (c.475G>A) is common (popmax 5.16%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.475G>A · rs3219155 · VCV241312

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1424 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.16%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1424	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -4.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.16% Admixed American · 3,099/60,016 alleles

Filtering AF 5.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.95%

Overall 0.231% 3,723/1,613,970 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.16%	19
Ashkenazi Jewishnot grpmax-eligible	0.611%	164
Remaining individualsnot grpmax-eligible	0.272%	368
East Asian	0.232%	431
African / African-American	0.0893%	1,120
South Asian	0.0318%	3,141
European (non-Finnish)	0.00619%	16,162

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.Glu159Lys
Coding: c.475G>A
MANE Select: NM_020919
dbSNP: rs3219155
Type: single nucleotide variant
Location: chr2:201761519 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 159: a UniProt-annotated variant site (in)

Full ALS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: amyotrophic lateral sclerosis type 2, juvenile juvenile primary lateral sclerosis infantile-onset ascending hereditary spastic paralysis hereditary spastic paraplegia

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-glu159lys (accessed [today's date]).

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