Tay-Sachs disease AB variant

Summary

Tay-Sachs disease AB variant (MONDO:0010099) is a disease caused by GM2A (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GM2A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 201
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002059	Cerebral atrophy	Very frequent (80-99%)
HP:0002180	Neurodegeneration	Very frequent (80-99%)
HP:0002267	Exaggerated startle response	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002478	Progressive spastic quadriplegia	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0008936	Axial hypotonia	Very frequent (80-99%)
HP:0010780	Hyperacusis	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0100852	Abnormal fear/anxiety-related behavior	Very frequent (80-99%)
HP:0000719	Inappropriate behavior	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002371	Loss of speech	Frequent (30-79%)
HP:0002476	Primitive reflex	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0010729	Cherry red spot of the macula	Frequent (30-79%)
HP:0012547	Abnormal involuntary eye movements	Frequent (30-79%)
HP:0030904	Glabellar reflex	Frequent (30-79%)
HP:0002200	Pseudobulbar signs	Occasional (5-29%)
HP:0030081	Punctate periventricular T2 hyperintense foci	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Tay-Sachs disease AB variant
Mondo ID	MONDO:0010099
MeSH	D049290
OMIM	272750
Orphanet	309246
DOID	DOID:4795
NCIT	C133084
SNOMED CT	71253000
UMLS	C0268275
MedGen	78657
GARD	0017406
Is cancer (heuristic)	no

Also known as: hexosaminidase activator deficiency

Data availability: 201 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › lysosomal lipid storage disorder › sphingolipidosis › gangliosidosis › GM2 gangliosidosis › Tay-Sachs disease AB variant

Related subtypes (2): Sandhoff disease, Tay-Sachs disease

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

201 retrieved; paginated sample, class counts are floors:

102 uncertain significance, 50 likely benign, 29 benign, 8 pathogenic, 8 likely pathogenic, 2 benign/likely benign, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
100728	NM_000405.5(GM2A):c.333del (p.Cys112fs)	GM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1699419	NM_000405.5(GM2A):c.209del (p.Gly70fs)	GM2A	Pathogenic	criteria provided, single submitter
390	NM_000405.5(GM2A):c.412T>C (p.Cys138Arg)	GM2A	Pathogenic	no assertion criteria provided
391	NM_000405.5(GM2A):c.506G>C (p.Arg169Pro)	GM2A	Pathogenic	no assertion criteria provided
393	NM_000405.5(GM2A):c.410del (p.His137fs)	GM2A	Pathogenic	no assertion criteria provided
394	NM_000405.5(GM2A):c.160G>T (p.Glu54Ter)	GM2A	Pathogenic	no assertion criteria provided
529236	NC_000005.10:g.(?151253197)(151267660_?)del	GM2A	Pathogenic	criteria provided, single submitter
3889	NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs)	HEXA	Pathogenic	criteria provided, multiple submitters, no conflicts
1305434	NM_000405.5(GM2A):c.367del (p.Glu123fs)	GM2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324484	NM_000405.5(GM2A):c.4C>T (p.Gln2Ter)	GM2A	Likely pathogenic	criteria provided, single submitter
2584380	NM_000405.5(GM2A):c.364G>A (p.Gly122Arg)	GM2A	Likely pathogenic	criteria provided, single submitter
2664353	NM_000405.5(GM2A):c.427-14T>A	GM2A	Likely pathogenic	criteria provided, single submitter
3591900	NM_000405.5(GM2A):c.226_227del (p.Leu76fs)	GM2A	Likely pathogenic	criteria provided, single submitter
375272	NM_000405.5(GM2A):c.244-2A>T	GM2A	Likely pathogenic	no assertion criteria provided
375273	NM_000405.5(GM2A):c.472G>T (p.Glu158Ter)	GM2A	Likely pathogenic	no assertion criteria provided
976256	NM_000405.5(GM2A):c.262_264del (p.Lys88del)	GM2A	Likely pathogenic	criteria provided, single submitter
3933	NM_000520.6(HEXA):c.902T>G (p.Met301Arg)	HEXA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
556416	NM_000520.6(HEXA):c.109T>A (p.Tyr37Asn)	HEXA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029825	NM_000405.5(GM2A):c.308T>C (p.Ile103Thr)	GM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029826	NM_000405.5(GM2A):c.427-13G>A	GM2A	Uncertain significance	criteria provided, single submitter
1036575	NM_000405.5(GM2A):c.575G>T (p.Gly192Val)	GM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1040377	NM_000405.5(GM2A):c.276_277delinsTT (p.Leu93Phe)	GM2A	Uncertain significance	criteria provided, single submitter
1178787	NM_000405.5(GM2A):c.346G>C (p.Asp116His)	GM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1349635	NM_000405.5(GM2A):c.278_279delinsGT (p.Leu93Arg)	GM2A	Uncertain significance	criteria provided, single submitter
1350409	NM_000405.5(GM2A):c.506G>A (p.Arg169His)	GM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1362753	NM_000405.5(GM2A):c.207G>A (p.Met69Ile)	GM2A	Uncertain significance	criteria provided, single submitter
1367470	NM_000405.5(GM2A):c.388C>T (p.Arg130Cys)	GM2A	Uncertain significance	criteria provided, single submitter
1376354	NM_000405.5(GM2A):c.538C>A (p.Arg180Ser)	GM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1388998	NM_000405.5(GM2A):c.85T>C (p.Ser29Pro)	GM2A	Uncertain significance	criteria provided, single submitter
1397542	NM_000405.5(GM2A):c.496G>A (p.Gly166Arg)	GM2A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GM2A	Definitive	Autosomal recessive	Tay-Sachs disease AB variant	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GM2A	Orphanet:309246	GM2 gangliosidosis, AB variant
HEXA	Orphanet:309178	Tay-Sachs disease, infantile form
HEXA	Orphanet:309185	Tay-Sachs disease, juvenile form
HEXA	Orphanet:309192	Tay-Sachs disease, adult form

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GM2A	HGNC:4367	ENSG00000196743	P17900	Ganglioside GM2 activator	gencc,clinvar
HEXA	HGNC:4878	ENSG00000213614	P06865	Beta-hexosaminidase subunit alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GM2A	Ganglioside GM2 activator	The large binding pocket can accommodate several single chain phospholipids and fatty acids, GM2A also exhibits some calcium-independent phospholipase activity.
HEXA	Beta-hexosaminidase subunit alpha	Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GM2A	Other/Unknown	no		ML_dom, GM2-AP, GM2-AP_sf
HEXA	Enzyme (other)	yes	3.2.1.169	GH20_cat, GH_hydrolase_sf, GH20

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mammalian vulva	1
penis	1
placenta	1
gall bladder	1
stromal cell of endometrium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GM2A	284	ubiquitous	marker	mammalian vulva, penis, placenta
HEXA	293	ubiquitous	marker	type B pancreatic cell, gall bladder, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GM2A	1,074
HEXA	999

Intra-cohort edges

A	B	Sources
GM2A	HEXA	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GM2A	P17900	8
HEXA	P06865	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid catabolism	2	292.8×	1e-04	GM2A, HEXA
Defective HEXA causes GM2G1 (Hyaluronan metabolism)	1	5710.0×	0.001	HEXA
Keratan sulfate degradation	1	356.9×	0.008	HEXA
Hyaluronan degradation	1	356.9×	0.008	HEXA
CS/DS degradation	1	271.9×	0.009	HEXA
Glycosphingolipid metabolism	1	150.3×	0.013	GM2A
Sphingolipid metabolism	1	84.0×	0.020	GM2A
Metabolism of lipids	1	15.8×	0.094	GM2A
Innate Immune System	1	12.8×	0.102	GM2A
Neutrophil degranulation	1	11.5×	0.102	GM2A
Immune System	1	6.5×	0.162	GM2A
Metabolism	1	5.8×	0.165	GM2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ganglioside catabolic process	2	1872.4×	5e-06	GM2A, HEXA
lipid storage	2	543.6×	3e-05	GM2A, HEXA
neuromuscular process controlling balance	2	330.4×	6e-05	GM2A, HEXA
dermatan sulfate proteoglycan catabolic process	1	2106.5×	0.002	HEXA
glycosaminoglycan metabolic process	1	1203.7×	0.003	HEXA
oligosaccharide catabolic process	1	766.0×	0.003	GM2A
glycosphingolipid catabolic process	1	766.0×	0.003	GM2A
cell morphogenesis involved in neuron differentiation	1	766.0×	0.003	HEXA
neuromuscular process controlling posture	1	526.6×	0.004	HEXA
hyaluronan catabolic process	1	495.6×	0.004	HEXA
glycosaminoglycan biosynthetic process	1	421.3×	0.004	HEXA
N-glycan processing	1	366.4×	0.005	HEXA
adult walking behavior	1	247.8×	0.006	HEXA
lysosome organization	1	153.2×	0.009	HEXA
lipid transport	1	131.7×	0.010	GM2A
myelination	1	125.8×	0.010	HEXA
learning or memory	1	120.4×	0.010	GM2A
carbohydrate metabolic process	1	68.0×	0.016	HEXA
skeletal system development	1	62.9×	0.017	HEXA
sensory perception of sound	1	50.5×	0.020	HEXA

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
HEXA	PYRIMETHAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HEXA	1	4
GM2A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRIMETHAMINE	4	HEXA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HEXA	58	Binding:58

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HEXA	3.2.1.169	protein O-GlcNAcase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PYRIMETHAMINE	4	HEXA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HEXA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GM2A

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GM2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.