Is GM2A p.Ile58fs (c.172dup) pathogenic?

GM2A p.Ile58fs (c.172dup) is classified Likely pathogenic in GM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-23). Associated with Tay-Sachs disease AB variant.

What condition is associated with GM2A p.Ile58fs (c.172dup)?

GM2A p.Ile58fs (c.172dup) is associated with Tay-Sachs disease AB variant (ClinVar).

How is GM2 gangliosidosis, AB variant inherited?

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

GM2A p.Ile58fs

c.172dup · VCV4850392

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Tay-Sachs disease AB variant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.69	GERP 0.41

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

Variant & gene context

Gene: GM2A
Protein: p.Ile58fs
Coding: c.172dup
MANE Select: NM_000405
Type: Duplication
Location: chr5:151259844 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.10 · 8 PDB
Residue 58: a β-strand

Full GM2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Tay-Sachs disease AB variant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For GM2 gangliosidosis, AB variant (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

GM2A p.Ile58Phe Uncertain significance ★★ same residue
GM2A p.Ile58Thr Uncertain significance ★ ⚠ same residue
GM2A p.Ile58Val Uncertain significance ★ ⚠ same residue
GM2A c.243+13dup Benign ★ same condition
GM2A c.244-6dup Benign ★ same condition
GM2A p.Cys112fs Pathogenic ★★ same condition
GM2A p.Glu123fs Likely pathogenic ★★ same condition
GM2A c.*356C>A Uncertain significance ★★ 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/gm2a-p-ile58fs (accessed [today's date]).

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