# NM_000308.4(CTSA):c.991del (p.Cys331fs)

https://sugi.bio/variant/ctsa-p-cys331fs

## Summary

**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.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs745743780 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0133%, amr)

## For patients & families {#patients}

This is a change in the CTSA gene that is considered disease-causing, submitted by 2 submitters, and is linked to galactosialidosis.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CTSA is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Galactosialidosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Coarse facial features — Very frequent (99-80%)
- Hearing impairment — Very frequent (99-80%)
- Abnormality of the vertebral column — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Skeletal dysplasia — Very frequent (99-80%)
- Abnormal vertebral morphology — Very frequent (99-80%)
- Corneal opacity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003953/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTSA](https://sugi.bio/atlas/gene/CTSA/) |
| Protein change (HGVS p.) | p.Cys331fs |
| Coding change (HGVS c.) | c.991del |
| MANE Select transcript | [NM_000308](https://www.ncbi.nlm.nih.gov/nuccore/NM_000308) |
| dbSNP | [rs745743780](https://www.ncbi.nlm.nih.gov/snp/rs745743780/) |
| Variant type | Deletion |
| Location | chr20:45895036-45895036 (GRCh38) |
| ClinVar | [VCV1073864](https://www.ncbi.nlm.nih.gov/clinvar/variation/1073864/) |

**All HGVS expressions:** `NC_000020.10:g.44523675del`, `NC_000020.11:g.45895036del`, `NG_008291.1:g.9085del`, `NG_033108.1:g.1252del`, `NM_000308.4:c.991del`, `NM_001127695.3:c.991del`, `NM_001167594.3:c.940del`, `NR_133656.2:n.1043del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.083, GERP -0.651, phastCons 0.52 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.851, pLI 1.4137e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 15**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0133%** (amr) · FAF95 0.00662% · FAF99 0.00483% · 8/59,990 in the highest group · 13/1,614,038 alleles overall — ultra-rare (popmax 0.0133%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0133% | 7,499 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| European (non-Finnish) | 0.000169% | 590,012 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CTSA** population constraint: LOEUF 0.851, pLI 1.4137e-09, missense-Z 1.6492. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **galactosialidosis** — Definitive (AR)

## Protein context {#protein}

Residue **331** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 94.59, 87% of residues very-high.

**12 experimental structure(s)** (PDB): [1IVY](https://www.rcsb.org/structure/1IVY), [3BP4](https://www.rcsb.org/structure/3BP4), [3BP7](https://www.rcsb.org/structure/3BP7), [3BXN](https://www.rcsb.org/structure/3BXN), [4AZ0](https://www.rcsb.org/structure/4AZ0), [4AZ3](https://www.rcsb.org/structure/4AZ3).

## What this gene does {#gene-function}

*Describes the biological roles of CTSA (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CTSA's established molecular role includes carboxypeptidase activity. In Reactome, CTSA is annotated in disease pathway(s) including **Defective NEU1 causes sialidosis**.

**Disease mechanism (Reactome):** CTSA loss or alteration is curated in [Defective NEU1 causes sialidosis](https://reactome.org/content/detail/R-HSA-4341670).

### Pathways affected {#pathways}

CTSA participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective NEU1 causes sialidosis](https://reactome.org/content/detail/R-HSA-4341670) | curated |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Processing of antigen in germinal center B cells](https://reactome.org/content/detail/R-HSA-9979719) | curated |
| [Sialic acid metabolism](https://reactome.org/content/detail/R-HSA-4085001) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** carboxypeptidase activity, serine-type carboxypeptidase activity.

**Biological process:** proteolysis, regulation of protein stability, negative regulation of chaperone-mediated autophagy.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-08.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-11 |
| OLLIN Analises Genomicas, OLLIN | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-08 |

## Associated conditions {#conditions}

[galactosialidosis](https://sugi.bio/atlas/disease/galactosialidosis/).

**Reported phenotype names (ClinVar):** Combined deficiency of sialidase AND beta galactosidase, NEURAMINIDASE DEFICIENCY WITH BETA-GALACTOSIDASE DEFICIENCY, NEURAMINIDASE/BETA-GALACTOSIDASE EXPRESSION, PPCA DEFICIENCY, PROTECTIVE PROTEIN/CATHEPSIN A DEFICIENCY, Galactosialidosis, CATHEPSIN A DEFICIENCY, GOLDBERG SYNDROME.

## Similar variants {#similar}

Related CTSA variant pages (same residue, condition, or type): [CTSA c.445-18_447del](/variant/ctsa-c-445-minus-18-447del), [CTSA p.Ala336fs](/variant/ctsa-p-ala336fs), [CTSA p.Arg48fs](/variant/ctsa-p-arg48fs), [CTSA p.Glu166fs](/variant/ctsa-p-glu166fs), [CTSA p.Gly322_Asp323insTer](/variant/ctsa-p-gly322-asp323inster), [CTSA p.Leu126fs](/variant/ctsa-p-leu126fs), [CTSA p.Leu38fs](/variant/ctsa-p-leu38fs), [CTSA p.Tyr278fs](/variant/ctsa-p-tyr278fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1073864). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*