Is HEXB p.Val39= (c.117G>T) pathogenic?

HEXB p.Val39= (c.117G>T) is classified Likely benign in HEXB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-01). Very rare (popmax 0.000256%, nfe); Associated with Sandhoff disease.

What condition is associated with HEXB p.Val39= (c.117G>T)?

HEXB p.Val39= (c.117G>T) is associated with Sandhoff disease (ClinVar).

How common is HEXB p.Val39= (c.117G>T) in the general population?

HEXB p.Val39= (c.117G>T) is very rare (popmax 0.000256%, nfe) (gnomAD).

How is Sandhoff disease inherited?

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

HEXB p.Val39=

c.117G>T · rs2478686769 · VCV2118134

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

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 0.93	GERP 0.59, phastCons 0.002
Overall
CADD	8.013	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000256% European (non-Finnish) · 3/1,169,886 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000209% 3/1,437,862 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.Val39=
Coding: c.117G>T
MANE Select: NM_000521
dbSNP: rs2478686769
Type: single nucleotide variant
Location: chr5:74685377 (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 p.Val39fs Pathogenic ★★ 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
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

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-val39 (accessed [today's date]).

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