Is HEXA p.Pro439= (c.1317C>G) pathogenic?

HEXA p.Pro439= (c.1317C>G) is classified Likely benign in HEXA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0162%, nfe); Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Pro439= (c.1317C>G)?

HEXA p.Pro439= (c.1317C>G) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Pro439= (c.1317C>G) in the general population?

HEXA p.Pro439= (c.1317C>G) is ultra-rare (popmax 0.0162%, nfe) (gnomAD).

How is Tay-Sachs disease inherited?

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

HEXA p.Pro439=

c.1317C>G · rs1003506073 · VCV1592351

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0162%, nfe)

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 -1.3, phastCons 1
Overall
CADD	12.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0162% European (non-Finnish) · 191/1,179,894 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0121% 195/1,613,834 alleles · ultra-rare exomes 188/1,461,670 · genomes 7/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0162%	6,177
Remaining individualsnot grpmax-eligible	0.0064%	15,621

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.Pro439=
Coding: c.1317C>G
MANE Select: NM_000520
dbSNP: rs1003506073
Type: single nucleotide variant
Location: chr15:72346540 (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.Pro439Thr 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-pro439 (accessed [today's date]).

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