Is GM2A p.Ile58Phe (c.172A>T) pathogenic?

GM2A p.Ile58Phe (c.172A>T) is classified Uncertain significance in GM2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.4587); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with GM2A p.Ile58Phe (c.172A>T)?

GM2A p.Ile58Phe (c.172A>T) is associated with Inborn genetic diseases, Tay-Sachs disease AB variant (ClinVar).

How common is GM2A p.Ile58Phe (c.172A>T) in the general population?

GM2A p.Ile58Phe (c.172A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GM2A p.Ile58Phe (c.172A>T)?

AlphaMissense predicts ambiguous (score 0.4587) — an in-silico prediction, not a clinical call.

GM2A p.Ile58Phe

c.172A>T · rs755382727 · VCV2089550

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4587 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4587	ambiguous
REVEL	0.514	indeterminate
SaProt	LLR -8.85	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.46	GERP 0.29, phastCons 0.001
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.75 · regional, not allelic
Overall
CADD	17.63	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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: GM2A
Protein: p.Ile58Phe
Coding: c.172A>T
MANE Select: NM_000405
dbSNP: rs755382727
Type: single nucleotide variant
Location: chr5:151259845 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tay-Sachs disease AB variant

Similar variants

GM2A p.Ile58Thr Uncertain significance ★ ⚠ same residue
GM2A p.Ile58Val Uncertain significance ★ ⚠ same residue
GM2A p.Ile58fs Likely pathogenic ★ same residue
GM2A c.*356C>A Uncertain significance ★★ same condition
GM2A c.*724G>C Uncertain significance ★★ same condition
GM2A p.Ala188Gly Uncertain significance ★★ ⚠ same condition
GM2A p.Arg169His Uncertain significance ★★ ⚠ same condition
GM2A p.Arg169Ser 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-ile58phe (accessed [today's date]).

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