HEXB

Chr 5AR

hexosaminidase subunit beta

Also known as: ENC-1AS, HEL-248, HEL-S-111

NCBI Gene: 3074 ENSG00000049860 OMIM: 606873

Hexosaminidase B encodes the beta subunit of lysosomal beta-hexosaminidase, which degrades GM2 ganglioside and other molecules containing terminal N-acetyl hexosamines. Mutations cause Sandhoff disease (GM2-gangliosidosis type II) with infantile, juvenile, and adult forms through autosomal recessive inheritance. The pathogenic mechanism involves accumulation of GM2 ganglioside in neurons leading to neurodegeneration.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.921 OMIM phenotype

Clinical Summary— HEXB

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Gene-Disease Validity (ClinGen)

Sandhoff disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

238 unique Pathogenic / Likely Pathogenic· 239 VUS of 956 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HEXB

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.93

OE 0.63 (0.44–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.65Z-score

OE missense 0.89 (0.81–0.99)

260 obs / 291.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.44–0.92)

0≤0.351.4

Missense OE?0.89 (0.81–0.99)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 20 / 31.7Missense obs/exp: 260 / 291.1Syn Z: -0.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHEXB-related GM2-gangliosidosisLOFAR

This gene — mechanism propensity

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

0.7131th %ile

GOF

0.6444th %ile

LOF

0.2191th %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

956 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic102

Likely Pathogenic136

VUS239

Likely Benign393

Benign42

Conflicting30

102

Pathogenic

136

Likely Pathogenic

239

VUS

393

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	80	5	17	0	102
Likely Pathogenic	99	26	10	1	136
VUS	5	196	28	10	239
Likely Benign	1	7	175	210	393
Benign	0	4	38	0	42
Conflicting	—				30
Total	185	238	268	221	942

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap HEXB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →