Is ALS2 p.Trp38Ter (c.114G>A) pathogenic?

ALS2 p.Trp38Ter (c.114G>A) is classified Pathogenic in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-30). Absent from gnomAD v4.1; Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Trp38Ter (c.114G>A)?

ALS2 p.Trp38Ter (c.114G>A) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Trp38Ter (c.114G>A) in the general population?

ALS2 p.Trp38Ter (c.114G>A) is absent from gnomAD v4.1 (gnomAD).

ALS2 p.Trp38Ter

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.114G>A · rs2469943073 · VCV2796368

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

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.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 34
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.92, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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
Protein: p.Trp38Ter
Coding: c.114G>A
MANE Select: NM_020919
dbSNP: rs2469943073
Type: single nucleotide variant
Location: chr2:201767290 (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-p-trp38ter (accessed [today's date]).

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