Is GM2A p.Ile59Val (c.175A>G) pathogenic?

GM2A p.Ile59Val (c.175A>G) is classified Benign in GM2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0585); Common (popmax 76.8%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Tay-Sachs disease AB variant.

What condition is associated with GM2A p.Ile59Val (c.175A>G)?

GM2A p.Ile59Val (c.175A>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.

What do computational predictors say about GM2A p.Ile59Val (c.175A>G)?

AlphaMissense predicts likely benign (score 0.0585) — an in-silico prediction, not a clinical call.

GM2A p.Ile59Val

Q: How common is GM2A p.Ile59Val (c.175A>G) in the general population?

GM2A p.Ile59Val (c.175A>G) is common (popmax 76.8%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.175A>G · rs153477 · VCV167150

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0585 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 76.8%, sas) — 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	0.0585	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -5.30	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 0.12	GERP -2.8
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.75 · regional, not allelic
Overall
CADD	0.075	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 76.8% South Asian · 69,883/90,996 alleles

Filtering AF 76.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 76.1%

Overall 63.4% 1,020,737/1,609,530 alleles · common exomes 925,008/1,457,456 · genomes 95,729/152,074 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	76.8%	1
Middle Eastern	75.4%	1
Admixed American	75.3%	1
Amishnot grpmax-eligible	73.8%	1
Ashkenazi Jewishnot grpmax-eligible	68.9%	1
East Asian	65.7%	2
Remaining individualsnot grpmax-eligible	64.8%	2
European (non-Finnish)	61.8%	2
Finnishnot grpmax-eligible	61.8%	2
African / African-American	58.9%	2

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.Ile59Val
Coding: c.175A>G
MANE Select: NM_000405
dbSNP: rs153477
Type: single nucleotide variant
Location: chr5:151259848 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.10 · 8 PDB
Residue 59: a UniProt-annotated variant site (in); 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.Ile59= Likely benign ★★ 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
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-ile59val (accessed [today's date]).

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