Is CTSA p.Pro280Leu (c.839C>T) pathogenic?

CTSA p.Pro280Leu (c.839C>T) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.1821); Very rare (popmax 0.00223%, eas); Associated with galactosialidosis.

What condition is associated with CTSA p.Pro280Leu (c.839C>T)?

CTSA p.Pro280Leu (c.839C>T) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Pro280Leu (c.839C>T) in the general population?

CTSA p.Pro280Leu (c.839C>T) is very rare (popmax 0.00223%, eas) (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.Pro280Leu (c.839C>T)?

AlphaMissense predicts likely benign (score 0.1821) — an in-silico prediction, not a clinical call.

CTSA p.Pro280Leu

c.839C>T · rs778824488 · VCV338534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

galactosialidosis

Computational evidence

Protein change
AlphaMissense	0.1821	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -10.53	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -0.15, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	22.0	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 0.00223% East Asian · 1/44,884 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000479% 7/1,461,876 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Admixed American	0.00167%	60,020
South Asian	0.0011%	91,086
European (non-Finnish)	0.000339%	295,003

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.Pro280Leu
Coding: c.839C>T
MANE Select: NM_000308
dbSNP: rs778824488
Type: single nucleotide variant
Location: chr20:45894711 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 280: a disulfide bond

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.Pro280= Likely benign ★ 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-pro280leu (accessed [today's date]).

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