# NM_000308.4(CTSA):c.495G>A (p.Pro165=)

https://sugi.bio/variant/ctsa-p-pro165

## Summary

**CTSA p.Pro165= (c.495G>A)** is classified **Likely benign** in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). Very rare (popmax 0.005%, amr); Associated with galactosialidosis.

**At a glance:** Likely benign · review: Single submitter · rsID rs1350708938 · 1 submitter · 1 linked condition · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the CTSA gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Pro165= |
| Coding change (HGVS c.) | c.495G>A |
| MANE Select transcript | [NM_000308](https://www.ncbi.nlm.nih.gov/nuccore/NM_000308) |
| dbSNP | [rs1350708938](https://www.ncbi.nlm.nih.gov/snp/rs1350708938/) |
| Variant type | single nucleotide variant |
| Location | chr20:45892775-45892775 (GRCh38) |
| ClinVar | [VCV1661296](https://www.ncbi.nlm.nih.gov/clinvar/variation/1661296/) |

**All HGVS expressions:** `NC_000020.10:g.44521414G>A`, `NC_000020.11:g.45892775G>A`, `NG_008291.1:g.6824G>A`, `NG_033108.1:g.3513C>T`, `NM_000308.4:c.495G>A`, `NM_001127695.3:c.495G>A`, `NM_001167594.3:c.444G>A`, `NR_133656.2:n.540G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.67) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.946, GERP -3.3 — fast-evolving / accelerated position
- CADD: **PHRED 21.6**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.67**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.67**, donor gain **0.00**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.02. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/60,008 in the highest group · 20/1,614,108 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 20,003 |
| African / African-American | 0.004% | 24,999 |
| East Asian | 0.00223% | 44,878 |
| South Asian | 0.0022% | 45,542 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,510 |
| European (non-Finnish) | 0.000847% | 118,004 |

*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 **165** lies in an α-helix; 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-11 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CTSA variant pages (same residue, condition, or type): [CTSA p.Pro165Leu](/variant/ctsa-p-pro165leu), [CTSA c.1-2A>G](/variant/ctsa-c-1-minus-2a-g), [CTSA c.358-2A>G](/variant/ctsa-c-358-minus-2a-g), [CTSA c.601-2A>G](/variant/ctsa-c-601-minus-2a-g), [CTSA c.692+3A>G](/variant/ctsa-c-692-plus-3a-g), [CTSA c.948+1G>A](/variant/ctsa-c-948-plus-1g-a), [CTSA p.Arg375Ter](/variant/ctsa-p-arg375ter), [CTSA p.Cys256Ter](/variant/ctsa-p-cys256ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1661296). 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.*