Is CTSA p.Ala448Thr (c.1342G>A) pathogenic?

CTSA p.Ala448Thr (c.1342G>A) is classified Uncertain significance in CTSA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-08-23). AlphaMissense: likely benign (0.0948); Rare (popmax 0.165%, mid); Associated with galactosialidosis.

What condition is associated with CTSA p.Ala448Thr (c.1342G>A)?

CTSA p.Ala448Thr (c.1342G>A) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Ala448Thr (c.1342G>A) in the general population?

CTSA p.Ala448Thr (c.1342G>A) is rare (popmax 0.165%, mid) (gnomAD).

How is Galactosialidosis inherited?

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

What do computational predictors say about CTSA p.Ala448Thr (c.1342G>A)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

CTSA p.Ala448Thr

c.1342G>A · rs144407534 · VCV896026

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

galactosialidosis

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -3.9, phastCons 0.031
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	6.351	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 0.165% Middle Eastern · 10/6,062 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0364% 588/1,614,064 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
Admixed American	0.08%	1,251
Remaining individualsnot grpmax-eligible	0.056%	1,786
European (non-Finnish)	0.0408%	2,453
South Asian	0.00769%	13,012
African / African-American	0.00667%	15,003
East Asian	0.00223%	44,860
Finnishnot grpmax-eligible	0.00156%	64,034

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.Ala448Thr
Coding: c.1342G>A
MANE Select: NM_000308
dbSNP: rs144407534
Type: single nucleotide variant
Location: chr20:45898092 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 448: 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.Ala448Val 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-ala448thr (accessed [today's date]).

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