Is ALS2 p.Arg547= (c.1641G>A) pathogenic?

ALS2 p.Arg547= (c.1641G>A) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-22). Ultra-rare (popmax 0.0829%, nfe); Associated with ALS2-related disorder.

How common is ALS2 p.Arg547= (c.1641G>A) in the general population?

ALS2 p.Arg547= (c.1641G>A) is ultra-rare (popmax 0.0829%, nfe) (gnomAD).

ALS2 p.Arg547=

Q: What condition is associated with ALS2 p.Arg547= (c.1641G>A)?

ALS2 p.Arg547= (c.1641G>A) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile, infantile-onset ascending hereditary spastic paralysis (ClinVar).

c.1641G>A · rs34122078 · VCV465181

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0829%, nfe)

Conditions

ALS2-related disorder

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 0.82	GERP -0.073, phastCons 1
Overall
CADD	16.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0829% European (non-Finnish) · 978/1,179,578 alleles

Filtering AF 0.0786% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0769%

Overall 0.0645% 1,040/1,613,462 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0829%	1,206
African / African-American	0.0534%	1,872
Remaining individualsnot grpmax-eligible	0.0256%	3,903
Admixed American	0.00667%	14,993
Finnishnot grpmax-eligible	0.00312%	32,005

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.Arg547=
Coding: c.1641G>A
MANE Select: NM_020919
dbSNP: rs34122078
Type: single nucleotide variant
Location: chr2:201753242 (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

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

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-arg547 (accessed [today's date]).

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