Is HEXA p.Val253= (c.759G>A) pathogenic?

HEXA p.Val253= (c.759G>A) is classified Benign/Likely benign in HEXA (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-04-01). Rare (popmax 0.629%, mid); Associated with Inborn genetic diseases.

What condition is associated with HEXA p.Val253= (c.759G>A)?

HEXA p.Val253= (c.759G>A) is associated with Inborn genetic diseases, Tay-Sachs disease (ClinVar).

How common is HEXA p.Val253= (c.759G>A) in the general population?

HEXA p.Val253= (c.759G>A) is rare (popmax 0.629%, mid) (gnomAD).

HEXA p.Val253=

c.759G>A · rs117513345 · VCV256352

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.629%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.16	GERP -1.8, phastCons 0.034
Overall
CADD	14.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.629% Middle Eastern · 38/6,040 alleles

Filtering AF 0.565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.561%

Overall 0.498% 8,043/1,614,144 alleles · rare exomes 7,423/1,461,826 · genomes 620/152,318 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
Middle Easterngrpmax	0.629%	159
Finnishnot grpmax-eligible	0.612%	163
European (non-Finnish)	0.577%	173
Remaining individualsnot grpmax-eligible	0.427%	234
Ashkenazi Jewishnot grpmax-eligible	0.402%	249
Admixed American	0.282%	355
South Asian	0.206%	484
African / African-American	0.0733%	1,364
East Asian	0.00223%	44,884

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val253=
Coding: c.759G>A
MANE Select: NM_000520
dbSNP: rs117513345
Type: single nucleotide variant
Location: chr15:72350564 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB
Residue 253: a β-strand

Full HEXA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tay-Sachs disease

Similar variants

HEXA p.Val253Leu Uncertain significance ★ ⚠ 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
HEXA c.253+1G>A 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-val253 (accessed [today's date]).

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