# NM_001009944.3(PKD1):c.3205_3235del (p.Pro1069fs)

https://sugi.bio/variant/pkd1-p-pro1069fs

## Summary

**PKD1 p.Pro1069fs (c.3205_3235del)** is classified **Pathogenic** in PKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-25). No gnomAD frequency available for this variant; Associated with polycystic kidney disease 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2092538008 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PKD1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to polycystic kidney disease 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | PKD1 is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Autosomal dominant polycystic kidney disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Very frequent (99-80%)
- Renal cyst — Very frequent (99-80%)
- Hepatic cysts — Very frequent (99-80%)
- Elevated circulating creatinine concentration — Very frequent (99-80%)
- Decreased glomerular filtration rate — Very frequent (99-80%)
- Hematuria — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Stage 5 chronic kidney disease — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018597/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PKD1](https://sugi.bio/atlas/gene/PKD1/) |
| Protein change (HGVS p.) | p.Pro1069fs |
| Coding change (HGVS c.) | c.3205_3235del |
| MANE Select transcript | [NM_001009944](https://www.ncbi.nlm.nih.gov/nuccore/NM_001009944) |
| dbSNP | [rs2092538008](https://www.ncbi.nlm.nih.gov/snp/rs2092538008/) |
| Variant type | Deletion |
| Location | chr16:2112400-2112430 (GRCh38) |
| ClinVar | [VCV972674](https://www.ncbi.nlm.nih.gov/clinvar/variation/972674/) |

**All HGVS expressions:** `NC_000016.10:g.2112407_2112437del`, `NC_000016.9:g.2162408_2162438del`, `NG_008617.1:g.28469_28499del`, `NM_000296.4:c.3205_3235del`, `NM_001009944.3:c.3205_3235del`

## 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 7.789, GERP 1.36, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.364, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 14 of 46**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr16:16354635, chr16:14915949, chr16:15125238). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- 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}

**PKD1** population constraint: LOEUF 0.364, pLI 1, missense-Z -5.6666; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **autosomal dominant polycystic kidney disease** — Definitive (AD)
- **autosomal recessive polycystic kidney disease** — Definitive (AR)

## Protein context {#protein}

Residue **1069** lies in the pkd 5 domain.

**13 experimental structure(s)** (PDB): [1B4R](https://www.rcsb.org/structure/1B4R), [6A70](https://www.rcsb.org/structure/6A70), [8Z6B](https://www.rcsb.org/structure/8Z6B), [8Z6F](https://www.rcsb.org/structure/8Z6F), [8Z6H](https://www.rcsb.org/structure/8Z6H), [8ZKH](https://www.rcsb.org/structure/8ZKH).

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

*Describes the biological roles of PKD1 (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:** PKD1's established molecular role includes protein kinase binding. p.Pro1069fs falls in the pkd 5 domain.


### Pathways affected {#pathways}

PKD1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [VxPx cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620916) | electronic |

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

**Molecular function:** protein kinase binding, protein domain specific binding, Wnt receptor activity, transmembrane transporter binding.

**Biological process:** calcium ion transport, mitochondrion organization, cell surface receptor signaling pathway, heart development, Wnt signaling pathway, spinal cord development.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-04-25.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| MVZ Martinsried, Medicover Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-04-25 |

## Associated conditions {#conditions}

[polycystic kidney disease 1](https://sugi.bio/atlas/disease/polycystic-kidney-disease-1/).

**Reported phenotype names (ClinVar):** Polycystic kidney disease, adult type, Polycystic Kidney Disease 1, Autosomal Dominant, Polycystic kidney disease 1, Polycystic kidney disease 1, severe, Polycystic Kidney, Autosomal Dominant, POLYCYSTIC KIDNEY DISEASE 1 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE, POLYCYSTIC KIDNEY DISEASE, ADULT, TYPE I.

## Similar variants {#similar}

Related PKD1 variant pages (same residue, condition, or type): [PKD1 c.10167+25_10167+43del](/variant/pkd1-c-10167-plus-25-10167-plus-43del), [PKD1 c.12003+14_12003+33del](/variant/pkd1-c-12003-plus-14-12003-plus-33del), [PKD1 c.3296-4_3304del](/variant/pkd1-c-3296-minus-4-3304del), [PKD1 c.8017-2_8017-1del](/variant/pkd1-c-8017-minus-2-8017-minus-1del), [PKD1 p.Ala1458fs](/variant/pkd1-p-ala1458fs), [PKD1 p.Ala3082fs](/variant/pkd1-p-ala3082fs), [PKD1 p.Ala4077fs](/variant/pkd1-p-ala4077fs), [PKD1 p.Ala5fs](/variant/pkd1-p-ala5fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 972674). 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.*