Is HEXA p.Ser9fs (c.25dup) pathogenic?

HEXA p.Ser9fs (c.25dup) is classified Pathogenic in HEXA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-08). Absent from gnomAD; Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Ser9fs (c.25dup)?

HEXA p.Ser9fs (c.25dup) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Ser9fs (c.25dup) in the general population?

HEXA p.Ser9fs (c.25dup) is absent from gnomAD (gnomAD).

How is Tay-Sachs disease inherited?

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

HEXA p.Ser9fs

c.25dup · rs1057517348 · VCV2003511

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Tay-Sachs disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP -0.45, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HEXA
Protein: p.Ser9fs
Coding: c.25dup
MANE Select: NM_000520
dbSNP: rs1057517348
Type: Duplication
Location: chr15:72375947 (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.Ser9Ter Pathogenic ★ same residue
HEXA p.Ser9= Likely benign ★ same residue
HEXA c.459+2dup Likely pathogenic ★★ same condition
HEXA p.Leu183fs Pathogenic ★★ same condition
HEXA p.Leu517fs Pathogenic/Likely pathogenic ★★ same condition
HEXA p.Ser364fs Pathogenic/Likely pathogenic ★★ same condition
HEXA p.Thr21fs Pathogenic/Likely pathogenic ★★ same condition
HEXA p.Tyr427fs 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-ser9fs (accessed [today's date]).

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