Is CTSA p.Thr451= (c.1353G>A) pathogenic?

CTSA p.Thr451= (c.1353G>A) is classified Benign in CTSA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 5.42%, afr) — too common for a highly-penetrant pathogenic allele; Associated with galactosialidosis.

What condition is associated with CTSA p.Thr451= (c.1353G>A)?

CTSA p.Thr451= (c.1353G>A) is associated with galactosialidosis (ClinVar).

How is Galactosialidosis inherited?

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

CTSA p.Thr451=

Q: How common is CTSA p.Thr451= (c.1353G>A) in the general population?

CTSA p.Thr451= (c.1353G>A) is common (popmax 5.42%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1353G>A · rs25649 · VCV338540

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 5.42%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

galactosialidosis

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 -0.86	GERP -3.9, phastCons 0.003
Overall
CADD	4.151	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.42% African / African-American · 4,065/74,982 alleles

Filtering AF 5.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.23%

Overall 0.308% 4,977/1,613,826 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.42%	18
Remaining individualsnot grpmax-eligible	0.418%	239
Admixed American	0.41%	244
Middle Eastern	0.149%	673
European (non-Finnish)	0.0329%	3,041
South Asian	0.00878%	11,383

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: CTSA
Protein: p.Thr451=
Coding: c.1353G>A
MANE Select: NM_000308
dbSNP: rs25649
Type: single nucleotide variant
Location: chr20:45898103 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 451: a β-strand

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

Disease context

galactosialidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Galactosialidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CTSA p.Thr451Lys Uncertain significance ★ ⚠ same residue
CTSA c.1-2A>G Pathogenic/Likely pathogenic ★★ same condition
CTSA c.358-2A>G Likely pathogenic ★★ same condition
CTSA c.601-2A>G Pathogenic/Likely pathogenic ★★ same condition
CTSA c.692+3A>G Pathogenic ★★ same condition
CTSA c.948+1G>A Likely pathogenic ★★ same condition
CTSA p.Arg375Ter Pathogenic/Likely pathogenic ★★ same condition
CTSA p.Cys256Ter 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/ctsa-p-thr451 (accessed [today's date]).

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