GM2A

Chr 5AR

ganglioside GM2 activator

Also known as: GM2-AP, GM2AP, SAP-3

NCBI Gene: 2760ENSG00000196743UniProt: P17900

This gene encodes a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme beta-hexosaminidase A. Beta-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene result in GM2-gangliosidosis type AB or the AB variant of Tay-Sachs disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

Primary Disease Associations & Inheritance

GM2-gangliosidosis, AB variantMIM #272750
AR
251
ClinVar variants
28
Pathogenic / LP
0.03
pLI score
0
Active trials
Clinical Summary— GM2A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 119 VUS of 251 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.28LOEUF
pLI 0.031
Z-score 1.14
OE 0.50 (0.23–1.28)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.30Z-score
OE missense 1.08 (0.93–1.26)
116 obs / 107.3 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.50 (0.23–1.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (0.93–1.26)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.21
0≤1.21.6
LoF obs/exp: 3 / 6.0Missense obs/exp: 116 / 107.3Syn Z: -1.10

ClinVar Variant Classifications

251 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic9
VUS119
Likely Benign60
Benign38
19
Pathogenic
9
Likely Pathogenic
119
VUS
60
Likely Benign
38
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
14
0
19
Likely Pathogenic
4
1
4
0
9
VUS
1
67
49
2
119
Likely Benign
0
6
24
30
60
Benign
0
4
32
2
38
Total88012334245

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GM2A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GM2A-related GM2-gangliosidosis, type AB

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
GM2 ACTIVATOR; GM2A
MIM #613109 · *

GM2-gangliosidosis, AB variant

MIM #272750

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Two patients from Turkey with a novel variant in the GM2A gene and review of the literature.
İnci A et al.·J Pediatr Endocrinol Metab
2021Review
The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A gene loci.
Cordeiro P et al.·Genet Med
2000Review
Integrated multiplex ligation dependent probe amplification (MLPA) assays for the detection of alterations in the HEXB, GM2A and SMARCAL1 genes to support the diagnosis of Morbus Sandhoff, M. Tay-Sachs variant AB and Schimke immuno-osseous dysplasia in humans.
Sobek AK et al.·Mol Cell Probes
2013
Clinical and biochemical abnormalities in a feline model of GM2 activator deficiency.
Beecy SJ et al.·Mol Genet Metab
2025Functional
Evaluation of the Landscape of Pharmacodynamic Biomarkers in GM1 and GM2 Gangliosidosis.
Stern S et al.·Clin Transl Sci
2025Review
GM2 gangliosidosis AB variant: first case of late onset and review of the literature.
Ganne B et al.·Neurol Sci
2022Review
Biochemical consequences of mutations causing the GM2 gangliosidoses.
Mahuran DJ·Biochim Biophys Acta
1999Review
Efficacy of Adeno-Associated Virus Serotype 9-Mediated Gene Therapy for AB-Variant GM2 Gangliosidosis.
Vyas M et al.·Int J Mol Sci
2023
Label-free quantitative proteomics reveals the Steap3-Gm2a axis inhibiting the phagosomal escape of Listeria monocytogenes.
Yuan J et al.·Microbes Infect
2022
The mouse gene encoding the GM2 activator protein (Gm2a): cDNA sequence, expression, and chromosome mapping.
Yamanaka S et al.·Genomics
1994Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools