Is ALS2 c.3512+8A>G pathogenic?

ALS2 c.3512+8A>G is classified Likely benign in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-17). Absent from gnomAD v4.1; Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 c.3512+8A>G?

ALS2 c.3512+8A>G is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 c.3512+8A>G in the general population?

ALS2 c.3512+8A>G is absent from gnomAD v4.1 (gnomAD).

ALS2 c.3512+8A>G

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

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

rs2469762470 · VCV2044790

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.16	GERP -0.59, phastCons 0.32
Non-coding constraint	Z 1.14	1 kb window · o/e 0.91 · regional · uncalibrated
Overall
CADD	8.487	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALS2
Coding: c.3512+8A>G
MANE Select: NM_020919
dbSNP: rs2469762470
Type: single nucleotide variant
Location: chr2:201724287 (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

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-c-3512-plus-8a-g (accessed [today's date]).

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