# NM_001791.4(CDC42):c.359G>A (p.Arg120Lys)

https://sugi.bio/variant/cdc42-p-arg120lys

## Summary

**CDC42 p.Arg120Lys (c.359G>A)** is classified **Uncertain significance** in CDC42 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: likely pathogenic (0.8578); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2522222793 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDC42 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 | [CDC42](https://sugi.bio/atlas/gene/CDC42/) |
| Protein change (HGVS p.) | p.Arg120Lys |
| Coding change (HGVS c.) | c.359G>A |
| MANE Select transcript | [NM_001791](https://www.ncbi.nlm.nih.gov/nuccore/NM_001791) |
| dbSNP | [rs2522222793](https://www.ncbi.nlm.nih.gov/snp/rs2522222793/) |
| Variant type | single nucleotide variant |
| Location | chr1:22086739-22086739 (GRCh38) |
| ClinVar | [VCV2761642](https://www.ncbi.nlm.nih.gov/clinvar/variation/2761642/) |

**All HGVS expressions:** `LRG_1326:g.66229G>A`, `LRG_1326t1:c.359G>A`, `LRG_1326t2:c.359G>A`, `NC_000001.10:g.22413232G>A`, `NC_000001.11:g.22086739G>A`, `NG_047042.3:g.66229G>A`, `NM_001039802.2:c.359G>A`, `NM_001791.4:c.359G>A`, `NM_044472.3:c.359G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8578)
- REVEL 0.715 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.947 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.745, GERP 2.35, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 0.36** across the covering region of the MANE Select transcript (22,086,686–22,091,514), spanning 4,828 bp — the region is depleted of missense variation. Chi-square p 3e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.73 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CDC42** population constraint: LOEUF 0.611, pLI 0.872, missense-Z 2.9049. *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):

- **macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **120** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.30, 84% of residues very-high.

**48 experimental structure(s)** (PDB): [1A4R](https://www.rcsb.org/structure/1A4R), [1AJE](https://www.rcsb.org/structure/1AJE), [1AM4](https://www.rcsb.org/structure/1AM4), [1AN0](https://www.rcsb.org/structure/1AN0), [1CEE](https://www.rcsb.org/structure/1CEE), [1CF4](https://www.rcsb.org/structure/1CF4) — incl. mutant structure 1A4R.

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

*Describes the biological roles of CDC42 (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:** CDC42's established molecular role includes GTPase activity. In Reactome, CDC42 is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** CDC42 loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

CDC42 participates in **30 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | electronic |
| [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 |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | curated |
| [EGFR downregulation](https://reactome.org/content/detail/R-HSA-182971) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [G beta:gamma signalling through CDC42](https://reactome.org/content/detail/R-HSA-8964616) | curated |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | curated |
| [Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation](https://reactome.org/content/detail/R-HSA-8950505) | 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 |
| [RHO GTPases activate IQGAPs](https://reactome.org/content/detail/R-HSA-5626467) | curated |
| [RHO GTPases activate KTN1](https://reactome.org/content/detail/R-HSA-5625970) | curated |
| [RHO GTPases activate PAKs](https://reactome.org/content/detail/R-HSA-5627123) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | 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 |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | electronic |
| [Inactivation of CDC42 and RAC1](https://reactome.org/content/detail/R-HSA-428543) | electronic |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | electronic |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | electronic |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | electronic |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | electronic |

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

**Molecular function:** GTPase activity, GTP binding, protein kinase binding, thioesterase binding, GBD domain binding, apolipoprotein A-I receptor binding.

**Biological process:** phagocytosis, engulfment, actin filament organization, integrin-mediated signaling pathway, regulation of lamellipodium assembly, positive regulation of lamellipodium assembly, substantia nigra development.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-25 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CDC42 variant pages (same residue, condition, or type): [CDC42 p.Arg120Ile](/variant/cdc42-p-arg120ile), [CDC42 p.Ala159Val](/variant/cdc42-p-ala159val), [CDC42 p.Arg186Cys](/variant/cdc42-p-arg186cys), [CDC42 p.Arg66Gly](/variant/cdc42-p-arg66gly), [CDC42 p.Arg68Gln](/variant/cdc42-p-arg68gln), [CDC42 p.Cys81Phe](/variant/cdc42-p-cys81phe), [CDC42 p.Glu171Lys](/variant/cdc42-p-glu171lys), [CDC42 p.Ser83Pro](/variant/cdc42-p-ser83pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2761642). 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.*