Is HEXA p.Pro475Ser (c.1423C>T) pathogenic?

HEXA p.Pro475Ser (c.1423C>T) is classified Uncertain significance in HEXA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-21). AlphaMissense: likely pathogenic (0.9369); Very rare (popmax 8.47e-05%, nfe); Associated with Tay-Sachs disease.

What condition is associated with HEXA p.Pro475Ser (c.1423C>T)?

HEXA p.Pro475Ser (c.1423C>T) is associated with Tay-Sachs disease (ClinVar).

How common is HEXA p.Pro475Ser (c.1423C>T) in the general population?

HEXA p.Pro475Ser (c.1423C>T) is very rare (popmax 8.47e-05%, nfe) (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.Pro475Ser (c.1423C>T)?

AlphaMissense predicts likely pathogenic (score 0.9369) — an in-silico prediction, not a clinical call.

HEXA p.Pro475Ser

c.1423C>T · VCV3660130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tay-Sachs disease

Computational evidence

Protein change
AlphaMissense	0.9369	likely pathogenic
REVEL	0.984	strongly pathogenic-leaning
SaProt	LLR -9.37	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 32 kb · p 0.87 · regional, not allelic
Overall
CADD	28.7	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.2e-05% 1/1,614,150 alleles · very rare exomes 1/1,461,790 · genomes 0/152,360 · joint denominator

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.Pro475Ser
Coding: c.1423C>T
MANE Select: NM_000520
Type: single nucleotide variant
Location: chr15:72345549 (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.Pro475Arg Uncertain significance ★★ ⚠ same residue
HEXA p.Pro475= 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-pro475ser (accessed [today's date]).

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