Is HEXB p.Pro74Arg (c.221C>G) pathogenic?

HEXB p.Pro74Arg (c.221C>G) is classified Uncertain significance in HEXB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-09). AlphaMissense: likely benign (0.0853); Very rare (popmax 8.48e-05%, nfe); Associated with Sandhoff disease.

What condition is associated with HEXB p.Pro74Arg (c.221C>G)?

HEXB p.Pro74Arg (c.221C>G) is associated with Sandhoff disease (ClinVar).

How common is HEXB p.Pro74Arg (c.221C>G) in the general population?

HEXB p.Pro74Arg (c.221C>G) is very rare (popmax 8.48e-05%, nfe) (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.Pro74Arg (c.221C>G)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

HEXB p.Pro74Arg

c.221C>G · rs1748843339 · VCV2187539

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sandhoff disease

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.028	GERP -3
Regional constraint	o/e 0.91	unconstrained · MANE · 36 kb · p 0.021 · regional, not allelic
Overall
CADD	11.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,022 alleles

Overall 6.85e-05% 1/1,459,518 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.Pro74Arg
Coding: c.221C>G
MANE Select: NM_000521
dbSNP: rs1748843339
Type: single nucleotide variant
Location: chr5:74685481 (GRCh38)
Gene constraint: LOEUF 1.095 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12 · 8 PDB
Residue 74: 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 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-pro74arg (accessed [today's date]).

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