# NM_001334.3(CTSO):c.862C>T (p.Arg288Trp)

https://sugi.bio/variant/ctso-p-arg288trp

## Summary

**CTSO p.Arg288Trp (c.862C>T)** is classified **Uncertain significance** in CTSO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: ambiguous (0.3423); Very rare (popmax 0.00835%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs773065737 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00835%, amr)

## For patients & families {#patients}

This is a change in the CTSO gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTSO](https://sugi.bio/atlas/gene/CTSO/) |
| Protein change (HGVS p.) | p.Arg288Trp |
| Coding change (HGVS c.) | c.862C>T |
| MANE Select transcript | [NM_000396](https://www.ncbi.nlm.nih.gov/nuccore/NM_000396) (variant reported on NM_001334) |
| dbSNP | [rs773065737](https://www.ncbi.nlm.nih.gov/snp/rs773065737/) |
| Variant type | single nucleotide variant |
| Location | chr4:155928405-155928405 (GRCh38) |
| ClinVar | [VCV2261111](https://www.ncbi.nlm.nih.gov/clinvar/variation/2261111/) |

**All HGVS expressions:** `NC_000004.11:g.156849557G>A`, `NC_000004.12:g.155928405G>A`, `NM_001334.3:c.862C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3423) — no call either way
- REVEL 0.378 (indeterminate)
- SaProt LLR -13.193 (damaging)
- Conservation: phyloP 1.757, GERP -2.24, phastCons 0.892 — weakly conserved position
- CADD: **PHRED 26.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.49 acceptor loss), 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 **0.00835%** (amr) · FAF95 0.00348% · FAF99 0.00302% · 5/59,864 in the highest group · 67/1,612,034 alleles overall — very rare (popmax 0.00835%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00835% | 11,973 |
| African / African-American | 0.00803% | 12,459 |
| South Asian | 0.0044% | 22,718 |
| European (non-Finnish) | 0.00433% | 23,116 |
| East Asian | 0.00223% | 44,744 |

*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}


Curated gene–disease validity (ClinGen):

- **pycnodysostosis** — Definitive (AR)

## Protein context {#protein}

Residue **288** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 94.89, 91% of residues very-high.

**70 experimental structure(s)** (PDB): [1ATK](https://www.rcsb.org/structure/1ATK), [1AU0](https://www.rcsb.org/structure/1AU0), [1AU2](https://www.rcsb.org/structure/1AU2), [1AU3](https://www.rcsb.org/structure/1AU3), [1AU4](https://www.rcsb.org/structure/1AU4), [1AYU](https://www.rcsb.org/structure/1AYU) — incl. mutant structure 3H7D.

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

*Describes the biological roles of CTSO (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:** CTSO's established molecular role includes fibronectin binding.


### Pathways affected {#pathways}

CTSO participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Matrix Metalloproteinases](https://reactome.org/content/detail/R-HSA-1592389) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Processing of antigen in germinal center B cells](https://reactome.org/content/detail/R-HSA-9979719) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of keratinocytes](https://reactome.org/content/detail/R-HSA-8939242) | curated |
| [Trafficking and processing of endosomal TLR](https://reactome.org/content/detail/R-HSA-1679131) | curated |

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

**Molecular function:** fibronectin binding, cysteine-type endopeptidase activity, collagen binding, cysteine-type peptidase activity, proteoglycan binding.

**Biological process:** thyroid hormone generation, collagen catabolic process, obsolete proteolysis involved in protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-24 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CTSO variant pages (same residue, condition, or type): [CTSO p.Arg288Gln](/variant/ctso-p-arg288gln), [CTSK p.Gly288=](/variant/ctsk-p-gly288), [CTSK c.121-1G>A](/variant/ctsk-c-121-minus-1g-a), [CTSK c.121-2A>G](/variant/ctsk-c-121-minus-2a-g), [CTSK c.244-29A>G](/variant/ctsk-c-244-minus-29a-g), [CTSK c.244-2A>C](/variant/ctsk-c-244-minus-2a-c), [CTSK c.400-1G>C](/variant/ctsk-c-400-minus-1g-c), [CTSK c.784+1G>A](/variant/ctsk-c-784-plus-1g-a).

### 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 2261111). 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.*