# NM_015375.3(DSTYK):c.1053dup (p.Gln352fs)

https://sugi.bio/variant/dstyk-p-gln352fs

## Summary

**DSTYK p.Gln352fs (c.1053dup)** is classified **Likely pathogenic** in DSTYK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). No gnomAD frequency available for this variant; Associated with congenital anomalies of kidney and urinary tract 1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2102413524 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DSTYK gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to congenital anomalies of kidney and urinary tract 1.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024873/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DSTYK](https://sugi.bio/atlas/gene/DSTYK/) |
| Protein change (HGVS p.) | p.Gln352fs |
| Coding change (HGVS c.) | c.1053dup |
| MANE Select transcript | [NM_015375](https://www.ncbi.nlm.nih.gov/nuccore/NM_015375) |
| dbSNP | [rs2102413524](https://www.ncbi.nlm.nih.gov/snp/rs2102413524/) |
| Variant type | Duplication |
| Location | chr1:205169433-205169434 (GRCh38) |
| ClinVar | [VCV1333318](https://www.ncbi.nlm.nih.gov/clinvar/variation/1333318/) |

**All HGVS expressions:** `NC_000001.10:g.205138562dup`, `NC_000001.11:g.205169434dup`, `NG_033904.1:g.47166dup`, `NM_015375.3:c.1053dup`, `NM_199462.3:c.1053dup`

## 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 11.774, GERP 2.05, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.445, pLI 0.99974), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 13**, 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}

**DSTYK** population constraint: LOEUF 0.445, pLI 0.99974, missense-Z 2.848. *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):

- **complex hereditary spastic paraplegia** — Moderate (AR)

## Protein context {#protein}

Residue **352** lies in a UniProt-annotated variant site (in cakut1; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 81.02, 41% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-03 |

## Associated conditions {#conditions}

[congenital anomalies of kidney and urinary tract 1](https://sugi.bio/atlas/disease/congenital-anomalies-of-kidney-and-urinary-tract-1/).

**Reported phenotype names (ClinVar):** Congenital anomalies of kidney and urinary tract 1, Renal hypodysplasia, nonsyndromic, 1, Congenital anomalies of kidney and urinary tract 1, susceptibility to.

## Similar variants {#similar}

Related DSTYK variant pages (same residue, condition, or type): [DSTYK p.Gln352His](/variant/dstyk-p-gln352his), [DSTYK p.Arg626Gln](/variant/dstyk-p-arg626gln), [DSTYK p.Gly32Asp](/variant/dstyk-p-gly32asp), [DSTYK p.Cys641Arg](/variant/dstyk-p-cys641arg), [DSTYK p.Phe676=](/variant/dstyk-p-phe676), [DSTYK p.Gln465Arg](/variant/dstyk-p-gln465arg), [DSTYK p.Gly493Ter](/variant/dstyk-p-gly493ter), [DSTYK c.1819-18T>A](/variant/dstyk-c-1819-minus-18t-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 1333318). 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.*