Is HEXA p.Arg504Leu (c.1511G>T) pathogenic?

HEXA p.Arg504Leu (c.1511G>T) is classified Pathogenic/Likely pathogenic in HEXA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-28). AlphaMissense: likely pathogenic (0.9766); Very rare (popmax 0.0011%, sas); Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Arg504Leu (c.1511G>T)?

HEXA p.Arg504Leu (c.1511G>T) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Arg504Leu (c.1511G>T) in the general population?

HEXA p.Arg504Leu (c.1511G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Tay-Sachs disease inherited?

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

What do computational predictors say about HEXA p.Arg504Leu (c.1511G>T)?

AlphaMissense predicts likely pathogenic (score 0.9766) — an in-silico prediction, not a clinical call.

HEXA p.Arg504Leu

c.1511G>T · rs121907955 · VCV555956

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9766 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tay-Sachs disease

Computational evidence

Protein change
AlphaMissense	0.9766	likely pathogenic ✓ concordant with ClinVar · top 6% in HEXA
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 32 kb · p 0.87 · regional, not allelic
Overall
CADD	28.2	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 0.0011% South Asian · 1/91,084 alleles

Overall 6.2e-05% 1/1,614,170 alleles · very rare exomes 1/1,461,832 · genomes 0/152,338 · joint denominator

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: HEXA
Protein: p.Arg504Leu
Coding: c.1511G>T
MANE Select: NM_000520
dbSNP: rs121907955
Type: single nucleotide variant
Location: chr15:72345461 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB
Residue 504: an α-helix; a UniProt-annotated variant site (in gm2g1; infantile); a UniProt-annotated variant site (in gm2g1; juvenile; fails to associate with the beta-subunit to form the enzymatically active heterodimer)

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

Disease context

Tay-Sachs disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Tay-Sachs disease (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Specific population)

Similar variants

HEXA p.Arg504Cys Pathogenic/Likely pathogenic ★★ same residue
HEXA p.Arg504His Pathogenic/Likely pathogenic ★★ same residue
HEXA p.Arg504fs Pathogenic ★★ same residue
HEXA c.1073+1G>A Pathogenic/Likely pathogenic ★★ same condition
HEXA c.1330+1G>A Pathogenic ★★ same condition
HEXA c.1330+2T>C Pathogenic ★★ same condition
HEXA c.1421+1G>C Pathogenic ★★ same condition
HEXA c.1421+1G>T 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/hexa-p-arg504leu (accessed [today's date]).

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