Is GM2A p.Arg169Pro (c.506G>C) pathogenic?

GM2A p.Arg169Pro (c.506G>C) is classified Pathogenic in GM2A (ClinVar, No assertion criteria, 1 submitter; last evaluated 1993-11-01). AlphaMissense: likely pathogenic (0.9857); Absent from gnomAD v4.1; Associated with Tay-Sachs disease AB variant.

What condition is associated with GM2A p.Arg169Pro (c.506G>C)?

GM2A p.Arg169Pro (c.506G>C) is associated with Tay-Sachs disease AB variant (ClinVar).

How common is GM2A p.Arg169Pro (c.506G>C) in the general population?

GM2A p.Arg169Pro (c.506G>C) is absent from gnomAD v4.1 (gnomAD).

How is GM2 gangliosidosis, AB variant inherited?

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

What do computational predictors say about GM2A p.Arg169Pro (c.506G>C)?

AlphaMissense predicts likely pathogenic (score 0.9857) — an in-silico prediction, not a clinical call.

GM2A p.Arg169Pro

c.506G>C · rs104893892 · VCV391

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9857 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tay-Sachs disease AB variant

Computational evidence

Protein change
AlphaMissense	0.9857	likely pathogenic ✓ concordant with ClinVar · top 1% in GM2A
REVEL	0.727	pathogenic-leaning
SaProt	LLR -15.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.75 · regional, not allelic
Overall
CADD	25.1	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.Arg169Pro
Coding: c.506G>C
MANE Select: NM_000405
dbSNP: rs104893892
Type: single nucleotide variant
Location: chr5:151267375 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.10 · 8 PDB
Residue 169: a UniProt-annotated variant site (in gm2gab); 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.Arg169His Uncertain significance ★★ ⚠ same residue
GM2A p.Arg169Ser Uncertain significance ★★ ⚠ same residue
GM2A p.Arg169Cys Uncertain significance ★ 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.Arg180His Uncertain significance ★★ ⚠ same condition
GM2A p.Arg180Ser 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-arg169pro (accessed [today's date]).

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