Is CTSA p.Ser209fs (c.625_626del) pathogenic?

CTSA p.Ser209fs (c.625626del) is classified Pathogenic/Likely pathogenic in CTSA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-11). Very rare (popmax 0.00268%, afr); Associated with galactosialidosis.

What condition is associated with CTSA p.Ser209fs (c.625_626del)?

CTSA p.Ser209fs (c.625_626del) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Ser209fs (c.625_626del) in the general population?

CTSA p.Ser209fs (c.625_626del) is very rare (popmax 0.00268%, afr) (gnomAD).

How is Galactosialidosis inherited?

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

CTSA p.Ser209fs

c.625_626del · rs1180450281 · VCV2996664

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Conditions

galactosialidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP -0.46, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00268% African / African-American · 2/74,564 alleles

Filtering AF 0.000445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000186% 3/1,613,226 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,282
European (non-Finnish)	8.48e-05%	1,179,839

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.Ser209fs
Coding: c.625_626del
MANE Select: NM_000308
dbSNP: rs1180450281
Type: Microsatellite
Location: chr20:45893241 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 209: 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.Leu18_Leu19del Benign/Likely benign ★★ same condition
CTSA p.Leu19dup Benign/Likely benign ★★ same condition
CTSA p.Pro7fs Pathogenic ★ same condition
CTSA p.Tyr395_Asn396delinsTer Pathogenic ★ same condition
CTSA p.Leu16_Leu19del Uncertain significance ★ same condition
CTSA p.Leu17_Leu19del Uncertain significance ★ same condition
CTSA p.Leu17_Leu19dup Uncertain significance ★ same condition
CTSA p.Leu18_Leu19dup Uncertain significance ★ 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-ser209fs (accessed [today's date]).

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