Is HEXA p.Val60Phe (c.178G>T) pathogenic?

HEXA p.Val60Phe (c.178G>T) is classified Uncertain significance in HEXA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.4163); Absent from gnomAD v4.1; Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Val60Phe (c.178G>T)?

HEXA p.Val60Phe (c.178G>T) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Val60Phe (c.178G>T) in the general population?

HEXA p.Val60Phe (c.178G>T) 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.

What do computational predictors say about HEXA p.Val60Phe (c.178G>T)?

AlphaMissense predicts ambiguous (score 0.4163) — an in-silico prediction, not a clinical call.

HEXA p.Val60Phe

c.178G>T · rs2542581637 · VCV1720246

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4163 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Tay-Sachs disease

Computational evidence

Protein change
AlphaMissense	0.4163	ambiguous
REVEL	0.651	pathogenic-leaning
SaProt	LLR -11.90	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 32 kb · p 0.87 · regional, not allelic
Overall
CADD	23.6	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

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.Val60Phe
Coding: c.178G>T
MANE Select: NM_000520
dbSNP: rs2542581637
Type: single nucleotide variant
Location: chr15:72375795 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB
Residue 60: a disulfide bond; an α-helix

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.Val60Ala Uncertain significance ★ ⚠ same residue
HEXA p.Val60fs Likely 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-val60phe (accessed [today's date]).

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