Is HEXA p.Pro397Ser (c.1189C>T) pathogenic?

HEXA p.Pro397Ser (c.1189C>T) is classified Uncertain significance in HEXA (ClinVar, Single submitter, 2 submitters; last evaluated 2022-07-11). AlphaMissense: likely benign (0.0933); Ultra-rare (popmax 0.0121%, sas); Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Pro397Ser (c.1189C>T)?

HEXA p.Pro397Ser (c.1189C>T) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Pro397Ser (c.1189C>T) in the general population?

HEXA p.Pro397Ser (c.1189C>T) is ultra-rare (popmax 0.0121%, sas) (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.Pro397Ser (c.1189C>T)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

HEXA p.Pro397Ser

c.1189C>T · rs778878211 · VCV555043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tay-Sachs disease

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.502	indeterminate
SaProt	LLR -4.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 32 kb · p 0.87 · regional, not allelic
Overall
CADD	19.81	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,074 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000929% 15/1,614,120 alleles · ultra-rare exomes 15/1,461,832 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
European (non-Finnish)	0.000339%	295,006

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.Pro397Ser
Coding: c.1189C>T
MANE Select: NM_000520
dbSNP: rs778878211
Type: single nucleotide variant
Location: chr15:72346668 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB
Residue 397: 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.Pro397Thr Uncertain significance ★ ⚠ same residue
HEXA p.Pro397= Likely benign ★ 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-pro397ser (accessed [today's date]).

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