Is HEXB p.Arg100Pro (c.299G>C) pathogenic?

HEXB p.Arg100Pro (c.299G>C) is classified Pathogenic in HEXB (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9831); Absent from gnomAD v4.1; Associated with Sandhoff disease.

What condition is associated with HEXB p.Arg100Pro (c.299G>C)?

HEXB p.Arg100Pro (c.299G>C) is associated with Sandhoff disease (ClinVar).

How common is HEXB p.Arg100Pro (c.299G>C) in the general population?

HEXB p.Arg100Pro (c.299G>C) is absent from gnomAD v4.1 (gnomAD).

How is Sandhoff disease inherited?

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

What do computational predictors say about HEXB p.Arg100Pro (c.299G>C)?

AlphaMissense predicts likely pathogenic (score 0.9831) — an in-silico prediction, not a clinical call.

HEXB p.Arg100Pro

c.299G>C · rs1060499701 · VCV397589

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9831 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sandhoff disease

Computational evidence

Protein change
AlphaMissense	0.9831	likely pathogenic ✓ concordant with ClinVar · top 1% in HEXB
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -18.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.49	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 36 kb · p 0.021 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HEXB
Protein: p.Arg100Pro
Coding: c.299G>C
MANE Select: NM_000521
dbSNP: rs1060499701
Type: single nucleotide variant
Location: chr5:74685559 (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.Arg100= Uncertain significance ★ 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-arg100pro (accessed [today's date]).

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