Is GM2A p.Val153Ala (c.458T>C) pathogenic?

GM2A p.Val153Ala (c.458T>C) is classified Benign in GM2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0804); Common (popmax 14.2%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Tay-Sachs disease AB variant.

What condition is associated with GM2A p.Val153Ala (c.458T>C)?

GM2A p.Val153Ala (c.458T>C) 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.

What do computational predictors say about GM2A p.Val153Ala (c.458T>C)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

GM2A p.Val153Ala

Q: How common is GM2A p.Val153Ala (c.458T>C) in the general population?

GM2A p.Val153Ala (c.458T>C) is common (popmax 14.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.458T>C · rs61740602 · VCV352255

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tay-Sachs disease AB variant

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -2.7
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.75 · regional, not allelic
Overall
CADD	0.233	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

Grpmax group 14.2% Middle Eastern · 858/6,062 alleles

Filtering AF 13.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.1%

Overall 8.81% 142,253/1,613,900 alleles · common exomes 131,347/1,461,786 · genomes 10,906/152,114 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	18.8%	5
Middle Easterngrpmax	14.2%	7
South Asian	12.6%	8
Finnishnot grpmax-eligible	9.28%	11
European (non-Finnish)	9.26%	11
Ashkenazi Jewishnot grpmax-eligible	9.26%	11
Remaining individualsnot grpmax-eligible	9.23%	11
Admixed American	5.79%	17
African / African-American	2.69%	37
East Asian	1.23%	81

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val153Ala
Coding: c.458T>C
MANE Select: NM_000405
dbSNP: rs61740602
Type: single nucleotide variant
Location: chr5:151267327 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.10 · 8 PDB
Residue 153: 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-val153ala (accessed [today's date]).

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