# NM_001254.4(CDC6):c.1512A>G (p.Ser504=)

https://sugi.bio/variant/cdc6-p-ser504

## Summary

**CDC6 p.Ser504= (c.1512A>G)** is classified **Benign** in CDC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). Low-frequency (popmax 2.6%, sas); Associated with Meier-Gorlin syndrome 5.

**At a glance:** Benign · review: Multiple submitters · rsID rs4135031 · 3 submitters · 1 linked condition · low-frequency (popmax 2.6%, sas)

## For patients & families {#patients}

This is a change in the CDC6 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters, and is linked to Meier-Gorlin syndrome 5.

*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/0015712/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDC6](https://sugi.bio/atlas/gene/CDC6/) |
| Protein change (HGVS p.) | p.Ser504= |
| Coding change (HGVS c.) | c.1512A>G |
| MANE Select transcript | [NM_001254](https://www.ncbi.nlm.nih.gov/nuccore/NM_001254) |
| dbSNP | [rs4135031](https://www.ncbi.nlm.nih.gov/snp/rs4135031/) |
| Variant type | single nucleotide variant |
| Location | chr17:40301527-40301527 (GRCh38) |
| ClinVar | [VCV323059](https://www.ncbi.nlm.nih.gov/clinvar/variation/323059/) |

**All HGVS expressions:** `LRG_1257:g.18649A>G`, `LRG_1257t1:c.1512A>G`, `NC_000017.10:g.38457779A>G`, `NC_000017.11:g.40301527A>G`, `NG_028240.2:g.18649A>G`, `NM_001254.4:c.1512A>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 (below), not from a missing predictor score.
- Conservation: phyloP -1.717, GERP 0.724 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.432**. 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 **2.6%** (sas) · FAF95 2.51% · FAF99 2.47% · 2,365/91,084 in the highest group · 2,533/1,613,860 alleles overall — low-frequency (popmax 2.6%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 2.6% | 39 |
| Remaining individuals (not grpmax-eligible) | 0.182% | 548 |
| Middle Eastern | 0.0825% | 1,212 |
| Admixed American | 0.005% | 20,007 |
| African / African-American | 0.004% | 25,020 |
| European (non-Finnish) | 0.00356% | 28,088 |
| East Asian | 0.00223% | 44,882 |

*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}

**CDC6** population constraint: LOEUF 0.99, pLI 4.1027e-10, missense-Z 1.0039. *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):

- **Meier-Gorlin syndrome 5** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.85, 24% of residues very-high.

**7 experimental structure(s)** (PDB): [2CCH](https://www.rcsb.org/structure/2CCH), [2CCI](https://www.rcsb.org/structure/2CCI), [4I5L](https://www.rcsb.org/structure/4I5L), [4I5N](https://www.rcsb.org/structure/4I5N), [8HT7](https://www.rcsb.org/structure/8HT7), [8RWV](https://www.rcsb.org/structure/8RWV).

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

*Describes the biological roles of CDC6 (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:** CDC6's established molecular role includes protein serine/threonine kinase binding.


### Pathways affected {#pathways}

CDC6 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of ATR in response to replication stress](https://reactome.org/content/detail/R-HSA-176187) | curated |
| [Activation of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68962) | curated |
| [CDC6 association with the ORC:origin complex](https://reactome.org/content/detail/R-HSA-68689) | curated |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | curated |
| [G1/S-Specific Transcription](https://reactome.org/content/detail/R-HSA-69205) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | curated |
| [Transcription of E2F targets under negative control by DREAM complex](https://reactome.org/content/detail/R-HSA-1362277) | curated |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | electronic |

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

**Molecular function:** protein serine/threonine kinase binding.

**Biological process:** regulation of mitotic metaphase/anaphase transition, positive regulation of cytokinesis, positive regulation of chromosome segregation.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-06.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-06 |

## Associated conditions {#conditions}

[Meier-Gorlin syndrome 5](https://sugi.bio/atlas/disease/meier-gorlin-syndrome-5/).

**Reported phenotype names (ClinVar):** Meier-Gorlin syndrome 5, not provided, none provided.

## Similar variants {#similar}

Related CDC6 variant pages (same residue, condition, or type): [CDC6 p.Ser504Leu](/variant/cdc6-p-ser504leu), [CDC6 p.Arg378His](/variant/cdc6-p-arg378his), [CDC6 p.Lys531Glu](/variant/cdc6-p-lys531glu), [CDC6 p.Val282Ala](/variant/cdc6-p-val282ala), [CDC6 c.*653C>A](/variant/cdc6-c-star-653c-a), [CDC6 p.Asp295Asn](/variant/cdc6-p-asp295asn), [CDC6 p.Cys146=](/variant/cdc6-p-cys146), [CDC6 p.Pro55=](/variant/cdc6-p-pro55).

### 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 323059). 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.*