Is ALS2 p.Lys1292= (c.3876G>A) pathogenic?

ALS2 p.Lys1292= (c.3876G>A) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.025%, amr); Associated with ALS2-related disorder.

How common is ALS2 p.Lys1292= (c.3876G>A) in the general population?

ALS2 p.Lys1292= (c.3876G>A) is ultra-rare (popmax 0.025%, amr) (gnomAD).

ALS2 p.Lys1292=

Q: What condition is associated with ALS2 p.Lys1292= (c.3876G>A)?

ALS2 p.Lys1292= (c.3876G>A) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile, infantile-onset ascending hereditary spastic paralysis (ClinVar).

c.3876G>A · rs200417604 · VCV333590

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

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 -0.39	GERP -1.2, phastCons 0.087
Overall
CADD	5.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/60,014 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00905% 146/1,614,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,001
European (non-Finnish)	0.0104%	9,594
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Finnishnot grpmax-eligible	0.00312%	32,021

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.Lys1292=
Coding: c.3876G>A
MANE Select: NM_020919
dbSNP: rs200417604
Type: single nucleotide variant
Location: chr2:201715800 (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-lys1292 (accessed [today's date]).

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