# NM_000297.4(PKD2):c.2388A>G (p.Leu796=)

https://sugi.bio/variant/pkd2-p-leu796

## Summary

**PKD2 p.Leu796= (c.2388A>G)** is classified **Conflicting classifications of pathogenicity** in PKD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0384%, sas); Associated with autosomal dominant polycystic kidney disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs535577967 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0384%, sas)

## For patients & families {#patients}

This is a change in the PKD2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to autosomal dominant polycystic kidney disease.

*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) |
| Clinical trials | 117 registered for this condition — see ClinicalTrials.gov |

**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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PKD2](https://sugi.bio/atlas/gene/PKD2/) |
| Protein change (HGVS p.) | p.Leu796= |
| Coding change (HGVS c.) | c.2388A>G |
| MANE Select transcript | [NM_000297](https://www.ncbi.nlm.nih.gov/nuccore/NM_000297) |
| dbSNP | [rs535577967](https://www.ncbi.nlm.nih.gov/snp/rs535577967/) |
| Variant type | single nucleotide variant |
| Location | chr4:88067927-88067927 (GRCh38) |
| ClinVar | [VCV350029](https://www.ncbi.nlm.nih.gov/clinvar/variation/350029/) |

**All HGVS expressions:** `NC_000004.11:g.88989079A>G`, `NC_000004.12:g.88067927A>G`, `NG_008604.1:g.65260A>G`, `NM_000297.4:c.2388A>G`, `NR_156488.2:n.2366A>G`

## 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 0.03, GERP -2.01, phastCons 0.04 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.918**. 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: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0384%** (sas) · FAF95 0.0283% · FAF99 0.0249% · 35/91,074 in the highest group · 37/1,614,026 alleles overall — ultra-rare (popmax 0.0384%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0384% | 2,602 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |

*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}

**PKD2** population constraint: 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)

## Protein context {#protein}

Residue **796** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 69.85, 24% of residues very-high.

**4 experimental structure(s)** (PDB): [2COA](https://www.rcsb.org/structure/2COA), [3BGM](https://www.rcsb.org/structure/3BGM), [4NNX](https://www.rcsb.org/structure/4NNX), [4NNY](https://www.rcsb.org/structure/4NNY).

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

*Describes the biological roles of PKD2 (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:** PKD2's established molecular role includes protein kinase activity. p.Leu796= falls in the protein kinase domain.


### Pathways affected {#pathways}

PKD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sphingolipid de novo biosynthesis](https://reactome.org/content/detail/R-HSA-1660661) | curated |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, protein kinase C binding, protein serine kinase activity.

**Biological process:** positive regulation of endothelial cell proliferation, protein phosphorylation, positive regulation of endothelial cell migration, positive regulation of vascular endothelial growth factor receptor signaling pathway, positive regulation of interleukin-8 production, intracellular signal transduction.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-27.

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

**Submission history:** 3 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-27 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-07-03 |

## Associated conditions {#conditions}

[autosomal dominant polycystic kidney disease](https://sugi.bio/atlas/disease/autosomal-dominant-polycystic-kidney-disease/), [polycystic kidney disease 2](https://sugi.bio/atlas/disease/polycystic-kidney-disease-2/).

**Reported phenotype names (ClinVar):** Autosomal dominant polycystic kidney disease, Polycystic kidney disease 2, PKD2-related disorder, Polycystic Kidney Disease 2, Autosomal Dominant, POLYCYSTIC KIDNEY DISEASE, ADULT, TYPE II, POLYCYSTIC KIDNEY DISEASE 2 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE, PKD2-related condition.

## Same-residue context {#hotspot}

Residue **796** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PKD2 p.Leu796Ter](/variant/pkd2-p-leu796ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PKD2 variant pages (same residue, condition, or type): [PKD2 p.Leu796Ter](/variant/pkd2-p-leu796ter), [PKD2 p.Leu796Phe](/variant/pkd2-p-leu796phe), [PKD2 p.Leu796Ser](/variant/pkd2-p-leu796ser), [PKD2 c.1094+1G>A](/variant/pkd2-c-1094-plus-1g-a), [PKD2 c.1094+1G>C](/variant/pkd2-c-1094-plus-1g-c), [PKD2 c.1319+1G>A](/variant/pkd2-c-1319-plus-1g-a), [PKD2 c.1320-2A>C](/variant/pkd2-c-1320-minus-2a-c), [PKD2 c.1548+1G>A](/variant/pkd2-c-1548-plus-1g-a).

### 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 350029). 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.*