Is ALS2 p.Gly540Glu (c.1619G>A) pathogenic?

ALS2 p.Gly540Glu (c.1619G>A) is classified Pathogenic in ALS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2011-02-10). AlphaMissense: likely pathogenic (0.999); Very rare (popmax 0.000169%, nfe); Associated with juvenile primary lateral sclerosis.

What condition is associated with ALS2 p.Gly540Glu (c.1619G>A)?

ALS2 p.Gly540Glu (c.1619G>A) is associated with juvenile primary lateral sclerosis (ClinVar).

How common is ALS2 p.Gly540Glu (c.1619G>A) in the general population?

ALS2 p.Gly540Glu (c.1619G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Juvenile primary lateral sclerosis inherited?

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

What do computational predictors say about ALS2 p.Gly540Glu (c.1619G>A)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

ALS2 p.Gly540Glu

c.1619G>A · rs386134178 · VCV42137

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile primary lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic ✓ concordant with ClinVar · top 1% in ALS2
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -17.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	27.5	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 0.000169% European (non-Finnish) · 2/1,179,982 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,830 alleles · very rare

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.Gly540Glu
Coding: c.1619G>A
MANE Select: NM_020919
dbSNP: rs386134178
Type: single nucleotide variant
Location: chr2:201754524 (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

For Juvenile primary lateral sclerosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ALS2 p.Gly540Arg Uncertain significance ★ ⚠ same residue
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg201Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Trp1053Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Tyr411Ter Pathogenic ★★ same condition
ALS2 p.Cys123Arg Uncertain significance ★★ ⚠ same condition
ALS2 p.Lys1045Met Uncertain significance ★★ ⚠ 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-gly540glu (accessed [today's date]).

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