# NM_000308.4(CTSA):c.1096G>A (p.Val366Ile)

https://sugi.bio/variant/ctsa-p-val366ile

## Summary

**CTSA p.Val366Ile (c.1096G>A)** is classified **Uncertain significance** in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely benign (0.1307); Very rare (popmax 0.00223%, eas); Associated with galactosialidosis.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs369583698 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CTSA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Val366Ile |
| Coding change (HGVS c.) | c.1096G>A |
| MANE Select transcript | [NM_000308](https://www.ncbi.nlm.nih.gov/nuccore/NM_000308) |
| dbSNP | [rs369583698](https://www.ncbi.nlm.nih.gov/snp/rs369583698/) |
| Variant type | single nucleotide variant |
| Location | chr20:45896972-45896972 (GRCh38) |
| ClinVar | [VCV1914516](https://www.ncbi.nlm.nih.gov/clinvar/variation/1914516/) |

**All HGVS expressions:** `NC_000020.10:g.44525611G>A`, `NC_000020.11:g.45896972G>A`, `NG_008291.1:g.11021G>A`, `NG_012115.2:g.20176C>T`, `NM_000308.4:c.1096G>A`, `NM_001127695.3:c.1096G>A`, `NM_001167594.3:c.1045G>A`, `NR_133656.2:n.1148G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1307)
- REVEL 0.492 (indeterminate)
- SaProt LLR -7.413 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 11.899, GERP 1.95, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.0**. 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.*
- Regional missense constraint: **o/e 0.85** across the covering region of the MANE Select transcript (45,894,015–45,898,447), spanning 4,432 bp. Chi-square p 0.0086. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.43 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/44,884 in the highest group · 5/1,613,994 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| East Asian (grpmax) | 0.00223% | 44,884 |
| European (non-Finnish) | 0.00017% | 589,964 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **366** lies in an α-helix.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-12.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-12 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CTSA variant pages (same residue, condition, or type): [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), [CTSA p.Cys281Ter](/variant/ctsa-p-cys281ter).

### 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 1914516). 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.*