Is HEXA p.Ser3= (c.9C>T) pathogenic?

HEXA p.Ser3= (c.9C>T) is classified Benign/Likely benign in HEXA (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 13.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Ser3= (c.9C>T)?

HEXA p.Ser3= (c.9C>T) is associated with Tay-Sachs disease (ClinVar).

How is Tay-Sachs disease inherited?

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

HEXA p.Ser3=

Q: How common is HEXA p.Ser3= (c.9C>T) in the general population?

HEXA p.Ser3= (c.9C>T) is common (popmax 13.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.9C>T · rs1800428 · VCV93193

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 13.6%, eas) — too common for a highly-penetrant pathogenic allele

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 1.7	GERP 0.54, phastCons 0.006
Overall
CADD	10.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.6% East Asian · 6,119/44,864 alleles

Filtering AF 13.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.2%

Overall 4.24% 68,358/1,613,708 alleles · common exomes 63,351/1,461,388 · genomes 5,007/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	13.6%	7
Amishnot grpmax-eligible	11.1%	9
South Asian	4.69%	21
European (non-Finnish)	4.33%	23
Middle Eastern	4.03%	25
Remaining individualsnot grpmax-eligible	3.93%	25
Admixed American	2.6%	38
Finnishnot grpmax-eligible	2.36%	42
Ashkenazi Jewishnot grpmax-eligible	1.73%	58
African / African-American	0.711%	141

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.Ser3=
Coding: c.9C>T
MANE Select: NM_000520
dbSNP: rs1800428
Type: single nucleotide variant
Location: chr15:72375964 (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.Ser3Gly Uncertain significance ★ ⚠ same residue
HEXA p.Ser3Ile Uncertain significance ★ ⚠ same residue
HEXA p.Ser3Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ser3 (accessed [today's date]).

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