HEXA

Chr 15AR

hexosaminidase subunit alpha

Also known as: TSD

NCBI Gene: 3073ENSG00000213614UniProt: P06865

This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

[Hex A pseudodeficiency]MIM #272800
AR
GM2-gangliosidosis, several formsMIM #272800
AR
Tay-Sachs diseaseMIM #272800
AR
586
ClinVar variants
92
Pathogenic / LP
0.00
pLI score
6
Active trials
Clinical Summary— HEXA
🧬
Gene-Disease Validity (ClinGen)
Tay-Sachs disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
92 Pathogenic / Likely Pathogenic· 259 VUS of 586 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available

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.
0.97LOEUF
pLI 0.000
Z-score 1.68
OE 0.68 (0.49–0.97)
Tolerant

Typical tolerance to LoF variation

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.
-0.41Z-score
OE missense 1.07 (0.97–1.18)
297 obs / 277.8 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.0.68 (0.49–0.97)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (0.97–1.18)
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.0.96
0≤1.21.6
LoF obs/exp: 22 / 32.3Missense obs/exp: 297 / 277.8Syn Z: 0.32

ClinVar Variant Classifications

586 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57
Likely Pathogenic35
VUS259
Likely Benign228
Benign1
Conflicting6
57
Pathogenic
35
Likely Pathogenic
259
VUS
228
Likely Benign
1
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
26
3
27
1
57
Likely Pathogenic
13
13
9
0
35
VUS
0
209
31
19
259
Likely Benign
0
5
108
115
228
Benign
0
0
1
0
1
Conflicting
—6
Total39230176135586

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

View in ClinVar →

Protein Context — Lollipop Plot

HEXA · protein map & ClinVar variants

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

Gene2Phenotype Curations

HEXA-related GM2-gangliosidosis

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
HEXOSAMINIDASE A; HEXA
MIM #606869 · *

[Hex A pseudodeficiency]

MIM #272800

Molecular basis of disorder known

Autosomal recessive

GM2-gangliosidosis, several forms

MIM #272800

Molecular basis of disorder known

Autosomal recessive

Tay-Sachs disease

MIM #272800

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HEXA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Repeat expansion diseases.
Paulson H·Handb Clin Neurol
2018Review
Gut microbiota-derived hexa-acylated lipopolysaccharides enhance cancer immunotherapy responses.
Sardar P et al.·Nat Microbiol
2025
Phenotype and management of neurologic intronic repeat disorders (NIRDs).
Finsterer J·Rev Neurol (Paris)
2023Review
Late-onset Tay-Sachs disease.
Barritt AW et al.·Pract Neurol
2017Case report
Inhibiting autophagy before it starts.
Lin Y et al.·Autophagy
2024
Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial.
Eichler F et al.·Nat Med
2025Clinical trial
Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models.
Lucas-Del-Pozo S et al.·Neurobiol Dis
2025Functional
Unravelling the mechanisms causing murepavadin resistance in Pseudomonas aeruginosa: lipopolysaccharide alterations and its consequences.
Hernández-García M et al.·Front Cell Infect Microbiol
2024Functional
A pathogenic alpha synuclein variant exacerbates disease progression in a neuron-specific Gba-KO mouse.
Duffy HBD et al.·Neurobiol Dis
2025Functional
DTaP(5)-IPV-Hib vaccine (Pediacel®).
Frampton JE·Paediatr Drugs
2011
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Complex molecular dynamics of symmetric model discotic liquid crystals: comparison of hexakis(hepta-alkanoyloxy)triphenylene (HOT6) with hexakis(hexa-alkyloxy)triphenylene (HAT6).
Krause C et al.·Soft Matter
2026Functional
Crystal structure of trans-(1,8-dibutyl-1,3,6,8,10,13-hexa-aza-cyclo-tetra-decane-κ4 N 3,N 6,N 10,N 13)bis-(perchlorato-κO)nickel(II) from synchrotron data.
Kim D et al.·Acta Crystallogr E Crystallogr Commun
2026🔓 Open Access
Crystal structure of tetra-kis-(imidazolium) hexa-kis-(imidazole-κN)cobalt(II) bis-(benzene-1,3,5-tri-carboxyl-ate) dihydrate.
Velazquez Garcia JJ et al.·Acta Crystallogr E Crystallogr Commun
2026🔓 Open Access
Pyrimethamine-based targeting of HEXA gene mutations in Tay-Sachs disease: a computational analysis.
Ranjani S et al.·J Biomol Struct Dyn
2026
A Hexa-Band Metamaterial Absorber for S, C, X, and Ku Band Applications.
Sultan MA et al.·Sensors (Basel)
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
GM2 GangliosidosisTay Sachs DiseaseSandhoff Disease

Long-Term Follow-Up of Subjects Treated With AXO-AAV-GM2 for Tay-Sachs or Sandhoff Disease

ACTIVE NOT RECRUITING
NCT06614569Terence FlotteStarted 2024-09-17
AXO-AAV-GM2
Tay-Sachs DiseaseSandhoff DiseaseLate Onset Tay-Sachs Disease

A Natural History Study of the Gangliosidoses

RECRUITING
NCT00668187University of MinnesotaStarted 2010-12
Tay-Sachs Disease GangliosideSandhoff Disease Ganglioside

Translational Potential of ex Vivo Gene Therapy in GM2 Gangliosidosis

NOT YET RECRUITING
NCT07445490Assistance Publique - Hôpitaux de ParisStarted 2026-05
blood sample
LeukodystrophyWhite Matter DiseaseLeukoencephalopathies

The Myelin Disorders Biorepository Project

RECRUITING
NCT03047369Children's Hospital of PhiladelphiaStarted 2016-12-08
Infantile GM2 Gangliosidosis (Disorder)

First-in-Human Study of TSHA-101 Gene Therapy for Treatment of Infantile Onset GM2 Gangliosidosis

ACTIVE NOT RECRUITING
NCT04798235Phase PHASE1, PHASE2Dr. Anupam SehgalStarted 2021-03-12
TSHA-101
Healthy Adults

Adult HMO Supplementation and the Gut Microbiome

NOT YET RECRUITING
NCT06570330Phase NASeeding IncStarted 2024-09
SuperHMONon-GMO corn Maltodextrin, Rapid Absorption

External Resources

Links to major genomics databases and tools