# NM_001791.4(CDC42):c.510C>T (p.Asp170=)

https://sugi.bio/variant/cdc42-p-asp170

## Summary

**CDC42 p.Asp170= (c.510C>T)** is classified **Likely benign** in CDC42 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-09). Ultra-rare (popmax 0.015%, amr); Associated with Takenouchi-Kosaki syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs200782611 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.015%, amr)

## For patients & families {#patients}

This is a change in the CDC42 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to Takenouchi-Kosaki syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017884/index) · [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.Asp170= |
| Coding change (HGVS c.) | c.510C>T |
| MANE Select transcript | [NM_001791](https://www.ncbi.nlm.nih.gov/nuccore/NM_001791) |
| dbSNP | [rs200782611](https://www.ncbi.nlm.nih.gov/snp/rs200782611/) |
| Variant type | single nucleotide variant |
| Location | chr1:22091451-22091451 (GRCh38) |
| ClinVar | [VCV1596360](https://www.ncbi.nlm.nih.gov/clinvar/variation/1596360/) |

**All HGVS expressions:** `LRG_1326:g.70941C>T`, `LRG_1326t1:c.510C>T`, `NC_000001.10:g.22417944C>T`, `NC_000001.11:g.22091451C>T`, `NG_047042.3:g.70941C>T`, `NM_001039802.2:c.510C>T`, `NM_001791.4:c.510C>T`

## 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 -4.906, GERP -4.7 — fast-evolving / accelerated position
- CADD: **PHRED 8.701**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.015%** (amr) · FAF95 0.00774% · FAF99 0.00579% · 9/59,948 in the highest group · 26/1,612,962 alleles overall — ultra-rare (popmax 0.015%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.015% | 6,661 |
| South Asian | 0.00989% | 10,114 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,819 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,004 |
| East Asian | 0.00223% | 44,866 |
| European (non-Finnish) | 0.00017% | 589,577 |

*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 **170** 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-09.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-09 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-11 |

## Associated conditions {#conditions}

[Takenouchi-Kosaki syndrome](https://sugi.bio/atlas/disease/takenouchi-kosaki-syndrome/).

**Reported phenotype names (ClinVar):** Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, not provided, not specified, AllHighlyPenetrant, MACROTHROMBOCYTOPENIA AND MENTAL RETARDATION SYNDROME, Takenouchi-Kosaki syndrome, none provided.

## Same-residue context {#hotspot}

Residue **170** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDC42 p.Asp170Gly](/variant/cdc42-p-asp170gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDC42 variant pages (same residue, condition, or type): [CDC42 p.Asp170Gly](/variant/cdc42-p-asp170gly), [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), [CDC42 p.Tyr23Cys](/variant/cdc42-p-tyr23cys), [CDC42 p.Tyr64Cys](/variant/cdc42-p-tyr64cys).

### 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 1596360). 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.*