GM2A

Chr 5

ganglioside GM2 activator

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

NCBI Gene: 2760 ENSG00000196743 UniProt: P17900

This gene encodes a glycolipid transport protein that acts as a cofactor for lysosomal beta-hexosaminidase A, extracting GM2 ganglioside molecules from membranes and presenting them for degradation. Mutations cause GM2-gangliosidosis AB variant (also called AB variant of Tay-Sachs disease), an autosomal recessive lysosomal storage disorder affecting the nervous system. The gene is not highly constrained against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.28

Clinical Summary— GM2A

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Gene-Disease Validity (ClinGen)

Tay-Sachs disease AB variant · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 118 VUS of 238 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GM2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.30Z-score

OE missense 1.08 (0.93–1.26)

116 obs / 107.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.50 (0.23–1.28)

0≤0.351.4

Missense OE?1.08 (0.93–1.26)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 3 / 6.0Missense obs/exp: 116 / 107.3Syn Z: -1.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGM2A-related GM2-gangliosidosis, type ABLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6840th %ile

GOF

0.4678th %ile

LOF

0.2580th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

238 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic10

VUS118

Likely Benign58

Benign38

Pathogenic

Likely Pathogenic

118

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	2	1	0	8
Likely Pathogenic	7	2	1	0	10
VUS	1	67	48	2	118
Likely Benign	0	5	23	30	58
Benign	0	4	32	2	38
Total	13	80	105	34	232

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap GM2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →