Is HEXB p.Ser331fs (c.992_993insAGTATGTA) pathogenic?

HEXB p.Ser331fs (c.992993insAGTATGTA) is classified Pathogenic in HEXB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). Absent from gnomAD; Associated with Sandhoff disease.

What condition is associated with HEXB p.Ser331fs (c.992_993insAGTATGTA)?

HEXB p.Ser331fs (c.992_993insAGTATGTA) is associated with Sandhoff disease (ClinVar).

How common is HEXB p.Ser331fs (c.992_993insAGTATGTA) in the general population?

HEXB p.Ser331fs (c.992_993insAGTATGTA) is absent from gnomAD (gnomAD).

How is Sandhoff disease inherited?

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

HEXB p.Ser331fs

c.992_993insAGTATGTA · rs2112175171 · VCV1459374

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Sandhoff disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.71	GERP -5.4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HEXB
Protein: p.Ser331fs
Coding: c.992_993insAGTATGTA
MANE Select: NM_000521
dbSNP: rs2112175171
Type: Insertion
Location: chr5:74715600 (GRCh38)
Gene constraint: LOEUF 1.095 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12 · 8 PDB
Residue 331: a disulfide bond; an α-helix

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 p.Ser331= Likely benign ★ same residue
HEXB p.Tyr387delinsPhePhePhePhePhePheXaaXaaXaaXaaPhePhePheSerPheTyrPheIlePheTer Pathogenic ★ same condition
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.1418-12_1418del Likely pathogenic ★★ same condition
HEXB c.1508+1G>A Likely 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-ser331fs (accessed [today's date]).

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