Is ALS2 p.Thr526= (c.1578A>G) pathogenic?

ALS2 p.Thr526= (c.1578A>G) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-16). Rare (popmax 0.841%, mid); Associated with infantile-onset ascending hereditary spastic paralysis.

How common is ALS2 p.Thr526= (c.1578A>G) in the general population?

ALS2 p.Thr526= (c.1578A>G) is rare (popmax 0.841%, mid) (gnomAD).

ALS2 p.Thr526=

Q: What condition is associated with ALS2 p.Thr526= (c.1578A>G)?

ALS2 p.Thr526= (c.1578A>G) is associated with infantile-onset ascending hereditary spastic paralysis, hereditary spastic paraplegia (ClinVar).

Q: How is Infantile-onset ascending hereditary spastic paralysis inherited?

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

c.1578A>G · rs147284131 · VCV417160

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.841%, mid)

Conditions

infantile-onset ascending hereditary spastic paralysis

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 -0.025	GERP 0.67, phastCons 0.89
Overall
CADD	10.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.841% Middle Eastern · 51/6,062 alleles

Filtering AF 0.657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.592%

Overall 0.0275% 444/1,614,170 alleles · rare exomes 418/1,461,864 · genomes 26/152,306 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.841%	119
Remaining individualsnot grpmax-eligible	0.056%	1,786
Admixed American	0.0483%	2,070
European (non-Finnish)	0.0257%	3,894
African / African-American	0.0147%	6,822
South Asian	0.0132%	7,590
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Finnishnot grpmax-eligible	0.00312%	32,024

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.Thr526=
Coding: c.1578A>G
MANE Select: NM_020919
dbSNP: rs147284131
Type: single nucleotide variant
Location: chr2:201754565 (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

infantile-onset ascending hereditary spastic paralysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

For Infantile-onset ascending hereditary spastic paralysis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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 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
ALS2 p.Arg1510Ter Pathogenic/Likely 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-thr526 (accessed [today's date]).

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