# NM_001256.6(CDC27):c.858A>G (p.Pro286=)

https://sugi.bio/variant/cdc27-p-pro286

## Summary

**CDC27 p.Pro286= (c.858A>G)** is classified **Benign/Likely benign** in CDC27 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-01). Low-frequency (popmax 2.32%, mid).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs61749925 · 3 submitters · low-frequency (popmax 2.32%, mid)

## For patients & families {#patients}

This is a change in the CDC27 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [CDC27](https://sugi.bio/atlas/gene/CDC27/) |
| Protein change (HGVS p.) | p.Pro286= |
| Coding change (HGVS c.) | c.858A>G |
| MANE Select transcript | [NM_001256](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256) |
| dbSNP | [rs61749925](https://www.ncbi.nlm.nih.gov/snp/rs61749925/) |
| Variant type | single nucleotide variant |
| Location | chr17:47154771-47154771 (GRCh38) |
| ClinVar | [VCV782550](https://www.ncbi.nlm.nih.gov/clinvar/variation/782550/) |

**All HGVS expressions:** `NC_000017.10:g.45232137T>C`, `NC_000017.11:g.47154771T>C`, `NM_001114091.4:c.858A>G`, `NM_001256.6:c.858A>G`, `NM_001293089.3:c.858A>G`, `NM_001293091.3:c.675A>G`, `NM_001353035.2:c.858A>G`, `NM_001353047.2:c.858A>G`, `NM_001353049.2:c.675A>G`, `NM_001353050.2:c.549A>G`, `NM_001353051.2:c.-334A>G`, `NR_148340.2:n.707A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 6.179, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.52**. 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 deltas (raw): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.00**. Largest is acceptor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **2.32%** (mid) · FAF95 2% · FAF99 1.88% · 137/5,910 in the highest group · 5,376/1,586,894 alleles overall — low-frequency (popmax 2.32%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 2.32% | 43 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.3% | 77 |
| Remaining individuals (not grpmax-eligible) | 0.422% | 237 |
| European (non-Finnish) | 0.361% | 277 |
| Admixed American | 0.331% | 302 |
| South Asian | 0.101% | 990 |
| African / African-American | 0.0967% | 1,034 |
| Finnish (not grpmax-eligible) | 0.0939% | 1,065 |

*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}

**CDC27** population constraint: LOEUF 0.38, pLI 0.96144, missense-Z 1.4195. *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 70.02, 51% of residues very-high.

**25 experimental structure(s)** (PDB): [3T1N](https://www.rcsb.org/structure/3T1N), [4RG6](https://www.rcsb.org/structure/4RG6), [4RG7](https://www.rcsb.org/structure/4RG7), [4RG9](https://www.rcsb.org/structure/4RG9), [4UI9](https://www.rcsb.org/structure/4UI9), [5A31](https://www.rcsb.org/structure/5A31) — incl. mutant structure 5KHR.

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

*Describes the biological roles of CDC27 (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:** CDC27's established molecular role includes protein phosphatase binding. In Reactome, CDC27 is annotated in disease pathway(s) including **Aberrant regulation of mitotic exit in cancer due to RB1 defects**.

**Disease mechanism (Reactome):** CDC27 loss or alteration is curated in [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136).

### Pathways affected {#pathways}

CDC27 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136) | curated |
| [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 |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | curated |
| [Autodegradation of Cdh1 by Cdh1:APC/C](https://reactome.org/content/detail/R-HSA-174084) | curated |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | 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 |
| [Inactivation of APC/C via direct inhibition of the APC/C complex](https://reactome.org/content/detail/R-HSA-141430) | curated |
| [Phosphorylation of the APC/C](https://reactome.org/content/detail/R-HSA-176412) | curated |
| [Regulation of APC/C activators between G1/S and early anaphase](https://reactome.org/content/detail/R-HSA-176408) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |

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

**Molecular function:** protein phosphatase binding.

**Biological process:** metaphase/anaphase transition of mitotic cell cycle, anaphase-promoting complex-dependent catabolic process, protein K48-linked ubiquitination, protein K11-linked ubiquitination, protein branched polyubiquitination.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-03-01.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2018–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-03-01 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-01 |

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

## Similar variants {#similar}

Related CDC27 variant pages (same residue, condition, or type): [CDC27 c.27+2T>C](/variant/cdc27-c-27-plus-2t-c), [CDC27 p.Ala586=](/variant/cdc27-p-ala586), [CDC27 p.Leu173=](/variant/cdc27-p-leu173), [CDC27 p.Pro421=](/variant/cdc27-p-pro421), [CDC27 p.Thr167=](/variant/cdc27-p-thr167), [CDC27 p.Thr171=](/variant/cdc27-p-thr171), [CDC27 p.Thr409=](/variant/cdc27-p-thr409), [CDC27 p.Thr446=](/variant/cdc27-p-thr446).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 782550). 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.*