Is CTSA p.Cys331fs (c.991del) pathogenic?

CTSA p.Cys331fs (c.991del) is classified Pathogenic in CTSA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0133%, amr); Associated with galactosialidosis.

What condition is associated with CTSA p.Cys331fs (c.991del)?

CTSA p.Cys331fs (c.991del) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Cys331fs (c.991del) in the general population?

CTSA p.Cys331fs (c.991del) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is Galactosialidosis inherited?

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

CTSA p.Cys331fs

c.991del · rs745743780 · VCV1073864

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

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 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.083	GERP -0.65, phastCons 0.52
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 0.0133% Admixed American · 8/59,990 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000805% 13/1,614,038 alleles · ultra-rare exomes 10/1,461,856 · genomes 3/152,182 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.000169%	590,012

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.Cys331fs
Coding: c.991del
MANE Select: NM_000308
dbSNP: rs745743780
Type: Deletion
Location: chr20:45895036 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 331: 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 c.445-18_447del Likely pathogenic ★★ same condition
CTSA p.Ala336fs Pathogenic/Likely pathogenic ★★ same condition
CTSA p.Arg48fs Pathogenic ★★ same condition
CTSA p.Glu166fs Pathogenic/Likely pathogenic ★★ same condition
CTSA p.Gly322_Asp323insTer Pathogenic/Likely pathogenic ★★ same condition
CTSA p.Leu126fs Pathogenic/Likely pathogenic ★★ same condition
CTSA p.Leu38fs Pathogenic/Likely pathogenic ★★ same condition
CTSA p.Tyr278fs 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-cys331fs (accessed [today's date]).

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