Is HEXB p.Ser446= (c.1338T>A) pathogenic?

HEXB p.Ser446= (c.1338T>A) is classified Uncertain significance in HEXB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). Very rare (popmax 0.00446%, eas); Associated with Sandhoff disease.

What condition is associated with HEXB p.Ser446= (c.1338T>A)?

HEXB p.Ser446= (c.1338T>A) is associated with Sandhoff disease (ClinVar).

How common is HEXB p.Ser446= (c.1338T>A) in the general population?

HEXB p.Ser446= (c.1338T>A) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Sandhoff disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

HEXB p.Ser446=

c.1338T>A · VCV4277402

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Sandhoff disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.06	moderately benign-leaning
Splicing
SpliceAI	Δ0.79	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 0.63	GERP -1.2, phastCons 1
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000744% 12/1,613,928 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,620
East Asiangrpmax	0.00446%	22,438
South Asian	0.00329%	30,363
Admixed American	0.00167%	60,002
African / African-American	0.00133%	74,928
European (non-Finnish)	8.48e-05%	1,179,915

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HEXB
Protein: p.Ser446=
Coding: c.1338T>A
MANE Select: NM_000521
Type: single nucleotide variant
Location: chr5:74718892 (GRCh38)
Gene constraint: LOEUF 1.095 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12 · 8 PDB

Full HEXB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Sandhoff disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sandhoff disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Portugal)

Similar variants

HEXB c.1082+2T>C Likely pathogenic ★★ same condition
HEXB c.1082+5G>A Pathogenic/Likely pathogenic ★★ same condition
HEXB c.1243-2A>G Pathogenic/Likely pathogenic ★★ same condition
HEXB c.1417+5G>A Pathogenic/Likely pathogenic ★★ same condition
HEXB c.1508+1G>A Likely pathogenic ★★ same condition
HEXB c.1509-26G>A Pathogenic/Likely pathogenic ★★ same condition
HEXB c.300-1G>A Likely pathogenic ★★ same condition
HEXB c.445+1G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hexb-p-ser446 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown