# NM_001009944.3(PKD1):c.4988_4990del (p.Ser1663del)

https://sugi.bio/variant/pkd1-p-ser1663del

## Summary

**PKD1 p.Ser1663del (c.4988_4990del)** is classified **Conflicting classifications of pathogenicity** in PKD1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-08-03). No gnomAD frequency available for this variant; Associated with polycystic kidney disease 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1596556896 · 3 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PKD1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, 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.Ser1663del |
| Coding change (HGVS c.) | c.4988_4990del |
| MANE Select transcript | [NM_001009944](https://www.ncbi.nlm.nih.gov/nuccore/NM_001009944) |
| dbSNP | [rs1596556896](https://www.ncbi.nlm.nih.gov/snp/rs1596556896/) |
| Variant type | Deletion |
| Location | chr16:2110177-2110179 (GRCh38) |
| ClinVar | [VCV636752](https://www.ncbi.nlm.nih.gov/clinvar/variation/636752/) |

**All HGVS expressions:** `NC_000016.10:g.2110179_2110181del`, `NC_000016.9:g.2160180_2160182del`, `NG_008617.1:g.30720_30722del`, `NM_000296.4:c.4988_4990del`, `NM_001009944.3:c.4988_4990del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 3.319, GERP 0.118, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- 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 **1663** lies in the pkd 12 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.Ser1663del falls in the pkd 12 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-08-03.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 3 submissions (2018–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| (GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada) | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-08-03 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-08-15 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-05-29 |

## 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, not provided, none provided, Polycystic Kidney, Autosomal Dominant, Polycystic Kidney Disease 1, Autosomal Dominant, Polycystic kidney disease 1, Polycystic kidney disease 1, severe, 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 2026-10-15); 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 636752). 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.*