Is HEXB p.Arg100= (c.300A>C) pathogenic?

HEXB p.Arg100= (c.300A>C) is classified Uncertain significance in HEXB (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-02). Very rare (popmax 0.00167%, amr); Associated with Sandhoff disease.

What condition is associated with HEXB p.Arg100= (c.300A>C)?

HEXB p.Arg100= (c.300A>C) is associated with Sandhoff disease (ClinVar).

How common is HEXB p.Arg100= (c.300A>C) in the general population?

HEXB p.Arg100= (c.300A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Sandhoff disease inherited?

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

HEXB p.Arg100=

c.300A>C · rs1303786596 · VCV1061546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Sandhoff disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83	GERP -2
Overall
CADD	5.732	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Overall 6.85e-05% 1/1,459,644 alleles · very rare

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.Arg100=
Coding: c.300A>C
MANE Select: NM_000521
dbSNP: rs1303786596
Type: single nucleotide variant
Location: chr5:74689328 (GRCh38)
Gene constraint: LOEUF 1.095 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12 · 8 PDB
Residue 100: 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.Arg100Ter Pathogenic ★★ same residue
HEXB p.Arg100Leu Likely pathogenic ★ same residue
HEXB p.Arg100Pro Pathogenic same residue
HEXB p.Arg100fs Pathogenic ★★ same residue
HEXB p.Arg100Gln Uncertain significance ★ ⚠ same residue
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

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-arg100 (accessed [today's date]).

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