# NM_004937.3(CTNS):c.877dup (p.Ser293fs)

https://sugi.bio/variant/ctns-p-ser293fs

## Summary

**CTNS p.Ser293fs (c.877dup)** is classified **Likely pathogenic** in CTNS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-27). No gnomAD frequency available for this variant; Associated with nephropathic cystinosis.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2507788947 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CTNS gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to nephropathic cystinosis.

*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) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CTNS is a diagnostic-grade gene on 12 Genomics England panels |

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

- Proteinuria — Very frequent (99-80%)
- Nephropathy — Very frequent (99-80%)
- Renal tubular dysfunction — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Hypothyroidism — Very frequent (99-80%)
- Delayed puberty — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010074/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTNS](https://sugi.bio/atlas/gene/CTNS/) |
| Protein change (HGVS p.) | p.Ser293fs |
| Coding change (HGVS c.) | c.877dup |
| MANE Select transcript | [NM_004937](https://www.ncbi.nlm.nih.gov/nuccore/NM_004937) |
| dbSNP | [rs2507788947](https://www.ncbi.nlm.nih.gov/snp/rs2507788947/) |
| Variant type | Duplication |
| Location | chr17:3659878-3659879 (GRCh38) |
| ClinVar | [VCV2681013](https://www.ncbi.nlm.nih.gov/clinvar/variation/2681013/) |

**All HGVS expressions:** `NC_000017.10:g.3563176dup`, `NC_000017.11:g.3659882dup`, `NG_012489.2:g.28415dup`, `NM_001031681.3:c.877dup`, `NM_001374492.1:c.877dup`, `NM_001374493.1:c.436dup`, `NM_001374494.1:c.436dup`, `NM_001374495.1:c.436dup`, `NM_001374496.1:c.436dup`, `NM_004937.3:c.877dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.385, GERP 0.688, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.754, pLI 0.0010072. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CTNS** population constraint: LOEUF 0.754, pLI 0.0010072, missense-Z 0.64366; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **cystinosis** — Definitive (AR)

## Protein context {#protein}

Residue **293** lies in the pq-loop 2 domain.

AlphaFold model confidence (whole protein): pLDDT 89.27, 75% of residues very-high.

**6 experimental structure(s)** (PDB): [8DKE](https://www.rcsb.org/structure/8DKE), [8DKI](https://www.rcsb.org/structure/8DKI), [8DKM](https://www.rcsb.org/structure/8DKM), [8DKW](https://www.rcsb.org/structure/8DKW), [8DKX](https://www.rcsb.org/structure/8DKX), [8DYP](https://www.rcsb.org/structure/8DYP) — incl. mutant structure 8DKW.

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

*Describes the biological roles of CTNS (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:** CTNS's established molecular role includes L-cystine transmembrane transporter activity. p.Ser293fs falls in the pq-loop 2 domain.


### Pathways affected {#pathways}

CTNS participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Miscellaneous transport and binding events](https://reactome.org/content/detail/R-HSA-5223345) | curated |
| [SLC-mediated transport of oligopeptides](https://reactome.org/content/detail/R-HSA-9959399) | curated |

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

**Molecular function:** L-cystine transmembrane transporter activity, solute:proton symporter activity.

**Biological process:** glutathione metabolic process, brain development, L-cystine transport, ATP metabolic process, regulation of melanin biosynthetic process, cognition.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-07-27 |

## Associated conditions {#conditions}

[nephropathic cystinosis](https://sugi.bio/atlas/disease/nephropathic-cystinosis/).

**Reported phenotype names (ClinVar):** Nephropathic cystinosis, CYSTINOSIN, DEFECT OF, LYSOSOMAL CYSTINE TRANSPORT PROTEIN, DEFECT OF, Abderhalden Lignac Kaufmann disease, Abderhalden-Kaufmann-Lignac syndrome.

## Similar variants {#similar}

Related CTNS variant pages (same residue, condition, or type): [CTNS p.Ser310fs](/variant/ctns-p-ser310fs), [CTNS p.Thr277fs](/variant/ctns-p-thr277fs), [CTNS p.Thr98fs](/variant/ctns-p-thr98fs), [CTNS p.Tyr281fs](/variant/ctns-p-tyr281fs), [CTNS p.Val233fs](/variant/ctns-p-val233fs), [CTNS p.Val257fs](/variant/ctns-p-val257fs), [CTNS p.Ser293Asn](/variant/ctns-p-ser293asn), [CTNS c.971-2dup](/variant/ctns-c-971-minus-2dup).

### 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 2681013). 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.*