Is HEXA p.Val372= (c.1116G>A) pathogenic?

HEXA p.Val372= (c.1116G>A) is classified Likely benign in HEXA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-10). Ultra-rare (popmax 0.0164%, mid); Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Val372= (c.1116G>A)?

HEXA p.Val372= (c.1116G>A) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Val372= (c.1116G>A) in the general population?

HEXA p.Val372= (c.1116G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Tay-Sachs disease inherited?

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

HEXA p.Val372=

c.1116G>A · rs753609749 · VCV1571377

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 0.39	GERP -0.71, phastCons 0.99
Overall
CADD	11.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000434% 7/1,614,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00333%	30,005
Finnishnot grpmax-eligible	0.00156%	64,044
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	590,019

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.Val372=
Coding: c.1116G>A
MANE Select: NM_000520
dbSNP: rs753609749
Type: single nucleotide variant
Location: chr15:72347716 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB
Residue 372: 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 p.Val372Leu Uncertain significance ★★ ⚠ same residue
HEXA p.Val372Met Uncertain significance ★★ ⚠ same residue
HEXA p.Val372fs Pathogenic/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

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-val372 (accessed [today's date]).

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