Is GM2A p.Ter194= (c.582A>G) pathogenic?

GM2A p.Ter194= (c.582A>G) is classified Benign in GM2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 46.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Tay-Sachs disease AB variant.

What condition is associated with GM2A p.Ter194= (c.582A>G)?

GM2A p.Ter194= (c.582A>G) 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.Ter194=

Q: How common is GM2A p.Ter194= (c.582A>G) in the general population?

GM2A p.Ter194= (c.582A>G) is common (popmax 46.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.582A>G · rs1048723 · VCV167152

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Common

common (popmax 46.9%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

Tay-Sachs disease AB variant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -2.4, phastCons 0.66
Overall
CADD	5.604	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

Grpmax group 46.9% Admixed American · 28,111/59,978 alleles

Filtering AF 46.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 46.2%

Overall 27.4% 441,932/1,613,664 alleles · common exomes 404,436/1,461,542 · genomes 37,496/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	46.9%	2
Ashkenazi Jewishnot grpmax-eligible	33.4%	3
Middle Eastern	33%	3
South Asian	33%	3
East Asian	27.7%	4
Remaining individualsnot grpmax-eligible	27.6%	4
European (non-Finnish)	26.8%	4
Finnishnot grpmax-eligible	24.6%	4
Amishnot grpmax-eligible	21.6%	5
African / African-American	13.2%	8

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.Ter194=
Coding: c.582A>G
MANE Select: NM_000405
dbSNP: rs1048723
Type: single nucleotide variant
Location: chr5:151267451 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.10 · 8 PDB

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-ter194 (accessed [today's date]).

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