# NM_002577.4(PAK2):c.494C>G (p.Pro165Arg)

https://sugi.bio/variant/pak2-p-pro165arg

## Summary

**PAK2 p.Pro165Arg (c.494C>G)** is classified **Uncertain significance** in PAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.116); Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the PAK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [PAK2](https://sugi.bio/atlas/gene/PAK2/) |
| Protein change (HGVS p.) | p.Pro165Arg |
| Coding change (HGVS c.) | c.494C>G |
| MANE Select transcript | [NM_002577](https://www.ncbi.nlm.nih.gov/nuccore/NM_002577) |
| Variant type | single nucleotide variant |
| Location | chr3:196806604-196806604 (GRCh38) |
| ClinVar | [VCV4130224](https://www.ncbi.nlm.nih.gov/clinvar/variation/4130224/) |

**All HGVS expressions:** `NC_000003.11:g.196533475C>G`, `NC_000003.12:g.196806604C>G`, `NG_009227.1:g.71748C>G`, `NM_002577.4:c.494C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.116)
- REVEL 0.111 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.643 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.984, GERP 2.89, phastCons 0.946 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.6**. 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.*
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (196,803,157–196,814,537), spanning 11,380 bp. Chi-square p 5.6e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PAK2 (1,015 scored positions, the nearest 16 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,178,668 in the highest group · 1/1,612,526 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**PAK2** population constraint: LOEUF 0.662, pLI 0.83414, missense-Z 1.8583; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 1/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.06, 45% of residues very-high.

**9 experimental structure(s)** (PDB): [3PCS](https://www.rcsb.org/structure/3PCS), [9D51](https://www.rcsb.org/structure/9D51), [9LBF](https://www.rcsb.org/structure/9LBF), [9LBG](https://www.rcsb.org/structure/9LBG), [9M41](https://www.rcsb.org/structure/9M41), [9WS2](https://www.rcsb.org/structure/9WS2) — incl. mutant structure 9LBF.

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

*Describes the biological roles of PAK2 (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:** PAK2's established molecular role includes protein serine/threonine kinase activity. In Reactome, PAK2 is annotated in disease pathway(s) including **Nef and signal transduction**.

**Disease mechanism (Reactome):** PAK2 loss or alteration is curated in [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944).

### Pathways affected {#pathways}

PAK2 participates in **27 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | curated |
| [CD28 dependent Vav1 pathway](https://reactome.org/content/detail/R-HSA-389359) | curated |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [Ephrin signaling](https://reactome.org/content/detail/R-HSA-3928664) | curated |
| [Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation](https://reactome.org/content/detail/R-HSA-8950505) | curated |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | curated |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | curated |
| [RHOV GTPase cycle](https://reactome.org/content/detail/R-HSA-9013424) | curated |
| [Sema3A PAK dependent Axon repulsion](https://reactome.org/content/detail/R-HSA-399954) | curated |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |
| [VEGFR2 mediated vascular permeability](https://reactome.org/content/detail/R-HSA-5218920) | curated |
| [Activation of RAC1](https://reactome.org/content/detail/R-HSA-428540) | electronic |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | electronic |
| [RHO GTPases activate PAKs](https://reactome.org/content/detail/R-HSA-5627123) | electronic |
| [Regulation of PAK-2p34 activity by PS-GAP/RHG10](https://reactome.org/content/detail/R-HSA-211728) | electronic |
| [Regulation of activated PAK-2p34 by proteasome mediated degradation](https://reactome.org/content/detail/R-HSA-211733) | electronic |
| [Stimulation of the cell death response by PAK-2p34](https://reactome.org/content/detail/R-HSA-211736) | electronic |

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

**Molecular function:** protein serine/threonine kinase activity, protein kinase binding, protein tyrosine kinase activator activity, small GTPase binding, identical protein binding, cadherin binding.

**Biological process:** protein phosphorylation, adherens junction assembly, intracellular signal transduction, negative regulation of apoptotic process, protein autophosphorylation, regulation of cytoskeleton organization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-31.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-31 |

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

## Similar variants {#similar}

Related PAK2 variant pages (same residue, condition, or type): [PAK2 p.Asp425Asn](/variant/pak2-p-asp425asn), [PAK2 p.Gln279Pro](/variant/pak2-p-gln279pro), [PAK2 p.Ala347Thr](/variant/pak2-p-ala347thr), [PAK2 p.Ala90Gly](/variant/pak2-p-ala90gly), [PAK2 p.Arg104Gln](/variant/pak2-p-arg104gln), [PAK2 p.Arg186Leu](/variant/pak2-p-arg186leu), [PAK2 p.Arg350Gly](/variant/pak2-p-arg350gly), [PAK2 p.Arg524His](/variant/pak2-p-arg524his).

### 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 4130224). 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.*