Is HEXA p.Phe155fs (c.465del) pathogenic?

HEXA p.Phe155fs (c.465del) is classified Pathogenic/Likely pathogenic in HEXA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00134%, afr); Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Phe155fs (c.465del)?

HEXA p.Phe155fs (c.465del) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Phe155fs (c.465del) in the general population?

HEXA p.Phe155fs (c.465del) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Tay-Sachs disease inherited?

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

HEXA p.Phe155fs

c.465del · rs1057516850 · VCV370895

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

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 5 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.89	GERP -3.1, phastCons 0.99

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,628 alleles

Filtering AF 0.000296% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000214%

Overall 0.000564% 9/1,596,022 alleles · very rare exomes 9/1,443,820 · genomes 0/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,628
European (non-Finnish)	0.000687%	145,495

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.Phe155fs
Coding: c.465del
MANE Select: NM_000520
dbSNP: rs1057516850
Type: Deletion
Location: chr15:72353173 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB
Residue 155: a β-strand

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 c.1525_1526+27del Pathogenic/Likely pathogenic ★★ same condition
HEXA c.237_253+7del Pathogenic ★★ same condition
HEXA p.Ala479fs Pathogenic/Likely pathogenic ★★ same condition
HEXA p.Arg504fs Pathogenic ★★ same condition
HEXA p.Asp395fs Pathogenic/Likely pathogenic ★★ same condition
HEXA p.Gln390fs Pathogenic/Likely pathogenic ★★ same condition
HEXA p.Glu375fs Pathogenic/Likely pathogenic ★★ same condition
HEXA p.Gly250fs 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-phe155fs (accessed [today's date]).

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