Is GM2A p.Ser172= (c.516C>T) pathogenic?

GM2A p.Ser172= (c.516C>T) is classified Likely benign in GM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-05). Ultra-rare (popmax 0.0317%, amr); Associated with Tay-Sachs disease AB variant.

What condition is associated with GM2A p.Ser172= (c.516C>T)?

GM2A p.Ser172= (c.516C>T) is associated with Tay-Sachs disease AB variant (ClinVar).

How common is GM2A p.Ser172= (c.516C>T) in the general population?

GM2A p.Ser172= (c.516C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

How is GM2 gangliosidosis, AB variant inherited?

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

GM2A p.Ser172=

c.516C>T · rs754452771 · VCV1540710

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Conditions

Tay-Sachs disease AB variant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2	GERP -1.6
Overall
CADD	5.287	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/59,998 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00285% 46/1,614,044 alleles · ultra-rare exomes 43/1,461,876 · genomes 3/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
South Asian	0.0154%	6,505
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Finnishnot grpmax-eligible	0.00156%	64,042
European (non-Finnish)	0.000847%	118,003

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GM2A
Protein: p.Ser172=
Coding: c.516C>T
MANE Select: NM_000405
dbSNP: rs754452771
Type: single nucleotide variant
Location: chr5:151267385 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.10 · 8 PDB
Residue 172: 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 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
GM2A p.Arg180His Uncertain significance ★★ ⚠ same condition
GM2A p.Arg180Ser Uncertain significance ★★ ⚠ same condition
GM2A p.Asp116His 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-ser172 (accessed [today's date]).

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