# NM_006256.4(PKN2):c.2280A>G (p.Val760=)

https://sugi.bio/variant/pkn2-p-val760

## Summary

**PKN2 p.Val760= (c.2280A>G)** is classified **Likely benign** in PKN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). Very rare (popmax 0.00685%, eas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00685%, eas)

## For patients & families {#patients}

This is a change in the PKN2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PKN2](https://sugi.bio/atlas/gene/PKN2/) |
| Protein change (HGVS p.) | p.Val760= |
| Coding change (HGVS c.) | c.2280A>G |
| MANE Select transcript | [NM_006256](https://www.ncbi.nlm.nih.gov/nuccore/NM_006256) |
| Variant type | single nucleotide variant |
| Location | chr1:88821941-88821941 (GRCh38) |
| ClinVar | [VCV3889598](https://www.ncbi.nlm.nih.gov/clinvar/variation/3889598/) |

**All HGVS expressions:** `NC_000001.10:g.89287624A>G`, `NC_000001.11:g.88821941A>G`, `NM_001320707.2:c.2136A>G`, `NM_001320708.2:c.1809A>G`, `NM_001320709.2:c.2232A>G`, `NM_006256.4:c.2280A>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.46) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 5.335, GERP 0.517, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.51**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.46**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.46**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00685%** (eas) · FAF95 0.00182% · FAF99 0.000904% · 3/43,766 in the highest group · 3/1,574,154 alleles overall — very rare (popmax 0.00685%, eas).

*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}

**PKN2** population constraint: LOEUF 0.428, pLI 0.99967, missense-Z 2.713. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **760** lies in the protein kinase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 72.06, 33% of residues very-high.

**4 experimental structure(s)** (PDB): [4CRS](https://www.rcsb.org/structure/4CRS), [4RRV](https://www.rcsb.org/structure/4RRV), [6CCY](https://www.rcsb.org/structure/6CCY), [6GBE](https://www.rcsb.org/structure/6GBE).

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

*Describes the biological roles of PKN2 (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:** PKN2's established molecular role includes RNA binding. p.Val760= falls in the protein kinase domain.


### Pathways affected {#pathways}

PKN2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | other |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | other |
| [RHO GTPases activate PKNs](https://reactome.org/content/detail/R-HSA-5625740) | other |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | other |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | other |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | other |

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

**Molecular function:** RNA binding, protein serine/threonine kinase activity, kinase activity, histone deacetylase binding, cadherin binding, RNA polymerase binding.

**Biological process:** protein phosphorylation, epithelial cell migration, positive regulation of cytokinesis, apical junction assembly, positive regulation of viral genome replication, positive regulation of mitotic cell cycle.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related PKN2 variant pages (same residue, condition, or type): [PKN2 p.Ala30Thr](/variant/pkn2-p-ala30thr), [PKN2 p.Ala355Pro](/variant/pkn2-p-ala355pro), [PKN2 p.Ala923Thr](/variant/pkn2-p-ala923thr), [PKN2 p.Arg130His](/variant/pkn2-p-arg130his), [PKN2 p.Arg130Leu](/variant/pkn2-p-arg130leu), [PKN2 p.Arg20Gln](/variant/pkn2-p-arg20gln), [PKN2 p.Arg223Lys](/variant/pkn2-p-arg223lys), [PKN2 p.Arg223Ser](/variant/pkn2-p-arg223ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3889598). 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.*