# NM_004937.3(CTNS):c.226G>A (p.Val76Ile)

https://sugi.bio/variant/ctns-p-val76ile

## Summary

**CTNS p.Val76Ile (c.226G>A)** is classified **Uncertain significance** in CTNS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-19). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.00034%, nfe); Associated with cystinosis.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs1567709217 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00034%, nfe)

## For patients & families {#patients}

This is a change in the CTNS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to 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 | 39 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/0006236/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.Val76Ile |
| Coding change (HGVS c.) | c.226G>A |
| MANE Select transcript | [NM_004937](https://www.ncbi.nlm.nih.gov/nuccore/NM_004937) |
| dbSNP | [rs1567709217](https://www.ncbi.nlm.nih.gov/snp/rs1567709217/) |
| Variant type | single nucleotide variant |
| Location | chr17:3654998-3654998 (GRCh38) |
| ClinVar | [VCV990029](https://www.ncbi.nlm.nih.gov/clinvar/variation/990029/) |

**All HGVS expressions:** `NC_000017.10:g.3558292G>A`, `NC_000017.11:g.3654998G>A`, `NG_012489.2:g.23531G>A`, `NM_001031681.3:c.226G>A`, `NM_001374492.1:c.226G>A`, `NM_001374493.1:c.-216G>A`, `NM_001374494.1:c.-216G>A`, `NM_001374495.1:c.-216G>A`, `NM_001374496.1:c.-216G>A`, `NM_004937.3:c.226G>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** (0.0847)
- REVEL 0.369 (indeterminate)
- SaProt LLR -6.955 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 8.479, GERP 1.86, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.88**. 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 0.96** across the covering region of the MANE Select transcript (3,640,207–3,660,366), spanning 20,159 bp. Chi-square p 0.4. 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, Δ0.72 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 **0.00034%** (nfe) · FAF95 8e-05% · FAF99 5.4e-05% · 4/1,177,748 in the highest group · 4/1,459,428 alleles overall — very rare (popmax 0.00034%, nfe).

*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 **76** lies in a β-strand.

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.


### 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}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-04-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-04-19 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cystinosis, Cystine diathesis, Cystine storage disease, Cystinoses.

## Similar variants {#similar}

Related CTNS variant pages (same residue, condition, or type): [CTNS p.Val76Ala](/variant/ctns-p-val76ala), [CTNS c.140+2T>C](/variant/ctns-c-140-plus-2t-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+5G>A](/variant/ctns-c-61-plus-5g-a), [CTNS c.681+1G>A](/variant/ctns-c-681-plus-1g-a), [CTNS c.682-1G>T](/variant/ctns-c-682-minus-1g-t), [CTNS c.853-2A>G](/variant/ctns-c-853-minus-2a-g).

### 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 990029). 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.*