# NM_001791.4(CDC42):c.247T>C (p.Ser83Pro)

https://sugi.bio/variant/cdc42-p-ser83pro

## Summary

**CDC42 p.Ser83Pro (c.247T>C)** is classified **Pathogenic** in CDC42 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-01-28). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1; Associated with Takenouchi-Kosaki syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1553196101 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDC42 gene that is considered disease-causing, submitted by 4 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.Ser83Pro |
| Coding change (HGVS c.) | c.247T>C |
| MANE Select transcript | [NM_001791](https://www.ncbi.nlm.nih.gov/nuccore/NM_001791) |
| dbSNP | [rs1553196101](https://www.ncbi.nlm.nih.gov/snp/rs1553196101/) |
| Variant type | single nucleotide variant |
| Location | chr1:22086507-22086507 (GRCh38) |
| ClinVar | [VCV487652](https://www.ncbi.nlm.nih.gov/clinvar/variation/487652/) |

**All HGVS expressions:** `LRG_1326t1:c.247T>C`, `LRG_1326t2:c.247T>C`, `NC_000001.10:g.22413000T>C`, `NC_000001.11:g.22086507T>C`, `NG_047042.2:g.38799T>C`, `NM_001039802.2:c.247T>C`, `NM_001791.4:c.247T>C`, `NM_044472.3:c.247T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9973) — concordant with the pathogenic call
- REVEL 0.853 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.141 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.831, GERP 2.35, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.5**. 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 0.09** across the covering region of the MANE Select transcript (22,078,479–22,086,685), spanning 8,206 bp — the region is depleted of missense variation. Chi-square p 1.3e-23. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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 **83** lies in a β-strand.

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-01-28.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2017–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital | Pathogenic | criteria provided, single submitter | research | 2017-11-01 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2018-04-06 |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-28 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** not provided, Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, Abnormal facial shape, Abnormality of blood and blood-forming tissues, Abnormality of the immune system, Neurodevelopmental abnormality, Postnatal growth retardation, none provided, MACROTHROMBOCYTOPENIA AND MENTAL RETARDATION SYNDROME, Takenouchi-Kosaki syndrome.

## Similar variants {#similar}

Related CDC42 variant pages (same residue, condition, or type): [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.Tyr23Cys](/variant/cdc42-p-tyr23cys), [CDC42 p.Tyr64Cys](/variant/cdc42-p-tyr64cys), [CDC42 p.Asp76Asn](/variant/cdc42-p-asp76asn), [CDC42 p.Asp170=](/variant/cdc42-p-asp170).

### 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 487652). 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.*