# NM_004937.3(CTNS):c.387G>A (p.Val129=)

https://sugi.bio/variant/ctns-p-val129

## Summary

**CTNS p.Val129= (c.387G>A)** is classified **Likely benign** in CTNS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-22). Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · rsID rs2150919602 · 1 submitter · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CTNS gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CTNS](https://sugi.bio/atlas/gene/CTNS/) |
| Protein change (HGVS p.) | p.Val129= |
| Coding change (HGVS c.) | c.387G>A |
| MANE Select transcript | [NM_004937](https://www.ncbi.nlm.nih.gov/nuccore/NM_004937) |
| dbSNP | [rs2150919602](https://www.ncbi.nlm.nih.gov/snp/rs2150919602/) |
| Variant type | single nucleotide variant |
| Location | chr17:3655278-3655278 (GRCh38) |
| ClinVar | [VCV1150328](https://www.ncbi.nlm.nih.gov/clinvar/variation/1150328/) |

**All HGVS expressions:** `NC_000017.10:g.3558572G>A`, `NC_000017.11:g.3655278G>A`, `NG_012489.2:g.23811G>A`, `NM_001031681.3:c.387G>A`, `NM_001374492.1:c.387G>A`, `NM_001374493.1:c.-55G>A`, `NM_001374494.1:c.-55G>A`, `NM_001374495.1:c.-55G>A`, `NM_001374496.1:c.-55G>A`, `NM_004937.3:c.387G>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 **donor loss** (Δ 0.62) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 6.33, GERP 1.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.49**. 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 **0.26**, donor loss **0.62**, acceptor gain **0.00**, donor gain **0.37**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.37**.
- Pangolin: Δ**0.50** (gain), gain 0.50 / loss 0.00. SpliceAI calls loss. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **129** lies in an α-helix; the pq-loop 1 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.Val129= falls in the pq-loop 1 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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-22.

**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 | 2022-01-22 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [ocular cystinosis](https://sugi.bio/atlas/disease/ocular-cystinosis/), [juvenile nephropathic cystinosis](https://sugi.bio/atlas/disease/juvenile-nephropathic-cystinosis/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Juvenile nephropathic cystinosis, Ocular cystinosis, Non-Nephropathic Cystinosis, Non-Nephropathic (Ocular) Cystinosis, Intermediate Cystinosis, CYSTINOSIS, LATE-ONSET JUVENILE OR ADOLESCENT NEPHROPATHIC TYPE, Later-Onset (Juvenile) Cystinosis.

## Similar variants {#similar}

Related CTNS variant pages (same residue, condition, or type): [CTNS p.Val129Glu](/variant/ctns-p-val129glu), [CTNS c.140+1G>T](/variant/ctns-c-140-plus-1g-t), [CTNS c.140+2T>C](/variant/ctns-c-140-plus-2t-c), [CTNS c.141-1G>A](/variant/ctns-c-141-minus-1g-a), [CTNS c.141-24T>C](/variant/ctns-c-141-minus-24t-c), [CTNS c.225+3A>T](/variant/ctns-c-225-plus-3a-t), [CTNS c.225+5G>A](/variant/ctns-c-225-plus-5g-a), [CTNS c.61+2T>C](/variant/ctns-c-61-plus-2t-c).

### 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 1150328). 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.*