Is HEXA p.Ser417= (c.1251T>G) pathogenic?

HEXA p.Ser417= (c.1251T>G) is classified Likely benign in HEXA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). Absent from gnomAD v4.1; Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Ser417= (c.1251T>G)?

HEXA p.Ser417= (c.1251T>G) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Ser417= (c.1251T>G) in the general population?

HEXA p.Ser417= (c.1251T>G) is absent from gnomAD v4.1 (gnomAD).

How is Tay-Sachs disease inherited?

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

HEXA p.Ser417=

c.1251T>G · rs2542514314 · VCV2096119

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Tay-Sachs 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 -0.17	GERP -3.9, phastCons 0.003
Overall
CADD	1.22	PHRED · no single calibrated threshold — expert panels disagree

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: HEXA
Protein: p.Ser417=
Coding: c.1251T>G
MANE Select: NM_000520
dbSNP: rs2542514314
Type: single nucleotide variant
Location: chr15:72346606 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB

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.Ser417Cys Uncertain significance ★ ⚠ same residue
HEXA p.Ser417fs 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
HEXA c.1526+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-ser417 (accessed [today's date]).

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