Is HEXB p.Pro504Ser (c.1510C>T) pathogenic?

HEXB p.Pro504Ser (c.1510C>T) is classified Pathogenic/Likely pathogenic in HEXB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-12). AlphaMissense: likely pathogenic (0.9185); Ultra-rare (popmax 0.0167%, amr); Associated with HEXB-related disorders.

What condition is associated with HEXB p.Pro504Ser (c.1510C>T)?

HEXB p.Pro504Ser (c.1510C>T) is associated with HEXB-related disorders, Sandhoff disease (ClinVar).

How common is HEXB p.Pro504Ser (c.1510C>T) in the general population?

HEXB p.Pro504Ser (c.1510C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about HEXB p.Pro504Ser (c.1510C>T)?

AlphaMissense predicts likely pathogenic (score 0.9185) — an in-silico prediction, not a clinical call.

HEXB p.Pro504Ser

c.1510C>T · rs121907985 · VCV3884

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9185 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HEXB-related disorders

Computational evidence

Protein change
AlphaMissense	0.9185	likely pathogenic ✓ concordant with ClinVar · top 10% in HEXB
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -10.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 36 kb · p 0.021 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0167% Admixed American · 10/59,982 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00285% 46/1,613,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,998
Remaining individualsnot grpmax-eligible	0.0032%	31,235
European (non-Finnish)	0.0028%	35,749
African / African-American	0.00134%	74,894

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.Pro504Ser
Coding: c.1510C>T
MANE Select: NM_000521
dbSNP: rs121907985
Type: single nucleotide variant
Location: chr5:74720644 (GRCh38)
Gene constraint: LOEUF 1.095 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12 · 8 PDB
Residue 504: a UniProt-annotated variant site (in gm2g2; decreases the isozyme a transport out of the endoplasmic reticulum. lowers its heat stability. affects the ability of isozyme a to hydrolyze gm2 ganglioside)

Full HEXB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

HEXB-related disorders

Also linked: Sandhoff disease

Similar variants

HEXB p.Pro504= Likely benign ★ 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-pro504ser (accessed [today's date]).

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