# NM_001255.3(CDC20):c.856C>A (p.Arg286Ser)

https://sugi.bio/variant/cdc20-p-arg286ser

## Summary

**CDC20 p.Arg286Ser (c.856C>A)** is classified **Uncertain significance** in CDC20 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-11-30). AlphaMissense: likely pathogenic (0.9671); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs991296026 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDC20 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 | [CDC20](https://sugi.bio/atlas/gene/CDC20/) |
| Protein change (HGVS p.) | p.Arg286Ser |
| Coding change (HGVS c.) | c.856C>A |
| MANE Select transcript | [NM_001255](https://www.ncbi.nlm.nih.gov/nuccore/NM_001255) |
| dbSNP | [rs991296026](https://www.ncbi.nlm.nih.gov/snp/rs991296026/) |
| Variant type | single nucleotide variant |
| Location | chr1:43360740-43360740 (GRCh38) |
| ClinVar | [VCV1801376](https://www.ncbi.nlm.nih.gov/clinvar/variation/1801376/) |

**All HGVS expressions:** `NC_000001.10:g.43826411C>A`, `NC_000001.11:g.43360740C>A`, `NM_001255.3:c.856C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9671)
- REVEL 0.222 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.075 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 7.719, GERP 1.26, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.1**. 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 0.78** across the covering region of the MANE Select transcript (43,359,817–43,361,239), spanning 1,422 bp. Chi-square p 7.3e-05. 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}

**CDC20** population constraint: LOEUF 0.744, pLI 2.3736e-05, missense-Z 2.5053. *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 **286** lies in a UniProt-annotated variant site (in ozema14; severely decreased function in metaphase/anaphase transition of meiosis i; does not fully rescue metaphase i arrest in cdc20-knocked down mouse oocytes; decreased function in positive regulation of anaphase-promoting complex-dependent catabolic process; fails to localize to the kinetochore); a UniProt-annotated variant site (in ozema14); a UniProt-annotated variant site (found in a patient with mosaic variagated aneuploidy syndrome 1; uncertain significance; decreased interaction with bub1b during the formation of the mitotic checkpoint complex; shows normal kinetochore localization).

AlphaFold model confidence (whole protein): pLDDT 84.39, 61% of residues very-high.

**17 experimental structure(s)** (PDB): [4GGA](https://www.rcsb.org/structure/4GGA), [4GGC](https://www.rcsb.org/structure/4GGC), [4GGD](https://www.rcsb.org/structure/4GGD), [4N14](https://www.rcsb.org/structure/4N14), [5G04](https://www.rcsb.org/structure/5G04), [5KHR](https://www.rcsb.org/structure/5KHR) — incl. mutant structure 5KHR.

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

*Describes the biological roles of CDC20 (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:** CDC20's established molecular role includes anaphase-promoting complex binding.


### Pathways affected {#pathways}

CDC20 participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [APC-Cdc20 mediated degradation of Nek2A](https://reactome.org/content/detail/R-HSA-179409) | curated |
| [APC/C:Cdc20 mediated degradation of Cyclin B](https://reactome.org/content/detail/R-HSA-174048) | curated |
| [APC/C:Cdc20 mediated degradation of Securin](https://reactome.org/content/detail/R-HSA-174154) | curated |
| [APC/C:Cdc20 mediated degradation of mitotic proteins](https://reactome.org/content/detail/R-HSA-176409) | curated |
| [APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1](https://reactome.org/content/detail/R-HSA-174178) | curated |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase](https://reactome.org/content/detail/R-HSA-176407) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [Inactivation of APC/C via direct inhibition of the APC/C complex](https://reactome.org/content/detail/R-HSA-141430) | curated |
| [Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components](https://reactome.org/content/detail/R-HSA-141405) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [Phosphorylation of Emi1](https://reactome.org/content/detail/R-HSA-176417) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Regulation of APC/C activators between G1/S and early anaphase](https://reactome.org/content/detail/R-HSA-176408) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [SCF-beta-TrCP mediated degradation of Emi1](https://reactome.org/content/detail/R-HSA-174113) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |

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

**Molecular function:** anaphase-promoting complex binding, ubiquitin-like ligase-substrate adaptor activity.

**Biological process:** anaphase-promoting complex-dependent catabolic process, positive regulation of mitotic metaphase/anaphase transition, positive regulation of ubiquitin protein ligase activity, metaphase/anaphase transition of meiosis I.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2022-11-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Uncertain significance | no assertion criteria provided | literature only | 2022-11-30 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CDC20 variant pages (same residue, condition, or type): [CDC20 p.Glu484=](/variant/cdc20-p-glu484), [CDC20 p.Val361Ile](/variant/cdc20-p-val361ile), [CDC20 p.Cys364Ter](/variant/cdc20-p-cys364ter), [CDC20 c.556+1G>T](/variant/cdc20-c-556-plus-1g-t), [CDC20 p.Ala140Val](/variant/cdc20-p-ala140val), [CDC20 p.Ala242Val](/variant/cdc20-p-ala242val), [CDC20 p.Ala461Thr](/variant/cdc20-p-ala461thr), [CDC20 p.Arg162Gly](/variant/cdc20-p-arg162gly).

### 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 2026-10-14); 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 1801376). 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.*