# NM_001260.3(CDK8):c.129del

https://sugi.bio/variant/cdk8-c-129del

## Summary

**CDK8 c.129del** is classified **Uncertain significance** in CDK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). No gnomAD frequency available for this variant; Associated with intellectual developmental disorder with hypotonia and behavioral abnormalities.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2542394998 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDK8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to intellectual developmental disorder with hypotonia and behavioral abnormalities.

*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 | [CDK8](https://sugi.bio/atlas/gene/CDK8/) |
| Coding change (HGVS c.) | c.129del |
| MANE Select transcript | [NM_001260](https://www.ncbi.nlm.nih.gov/nuccore/NM_001260) |
| dbSNP | [rs2542394998](https://www.ncbi.nlm.nih.gov/snp/rs2542394998/) |
| Variant type | Deletion |
| Location | chr13:26337566-26337566 (GRCh38) |
| ClinVar | [VCV2439883](https://www.ncbi.nlm.nih.gov/clinvar/variation/2439883/) |

**All HGVS expressions:** `NC_000013.10:g.26911704del`, `NC_000013.11:g.26337567del`, `NM_001260.3:c.129del`

## 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 11.111, GERP 2.15, phastCons 1 — highly conserved position (PP3-type support)
- Non-coding constraint (Gnocchi): **Z 1.88**, o/e 0.86 (1 kb window 26,337,000–26,338,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CDK8** population constraint: LOEUF 0.646, pLI 0.46798, missense-Z 2.9169. *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 80.75, 63% of residues very-high.

**36 experimental structure(s)** (PDB): [3RGF](https://www.rcsb.org/structure/3RGF), [4CRL](https://www.rcsb.org/structure/4CRL), [4F6S](https://www.rcsb.org/structure/4F6S), [4F6U](https://www.rcsb.org/structure/4F6U), [4F6W](https://www.rcsb.org/structure/4F6W), [4F70](https://www.rcsb.org/structure/4F70).

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

*Describes the biological roles of CDK8 (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:** CDK8's established molecular role includes protein kinase activity. In Reactome, CDK8 is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**, **Constitutive Signaling by NOTCH1 PEST Domain Mutants**.

**Disease mechanism (Reactome):** CDK8 loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606), [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110).

### Pathways affected {#pathways}

CDK8 participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | curated |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| [Generic Transcription Pathway](https://reactome.org/content/detail/R-HSA-212436) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |
| [SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription](https://reactome.org/content/detail/R-HSA-2173796) | curated |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |
| [NOTCH1 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-2122947) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

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

**Molecular function:** protein kinase activity.

**Biological process:** positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-03 |

## Associated conditions {#conditions}

[intellectual developmental disorder with hypotonia and behavioral abnormalities](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-with-hypotonia-and-behavioral-abnormalities/).

**Reported phenotype names (ClinVar):** Intellectual developmental disorder with hypotonia and behavioral abnormalities.

## Similar variants {#similar}

Related CDK8 variant pages (same residue, condition, or type): [CDK8 p.Ser62Leu](/variant/cdk8-p-ser62leu), [CDK8 p.Asn433Lys](/variant/cdk8-p-asn433lys), [CDK8 p.Pro388Gln](/variant/cdk8-p-pro388gln), [CDK8 c.934-28G>A](/variant/cdk8-c-934-minus-28g-a), [CDK8 p.Ala188Gly](/variant/cdk8-p-ala188gly), [CDK8 p.Arg178Gln](/variant/cdk8-p-arg178gln), [CDK8 p.Asp173His](/variant/cdk8-p-asp173his), [CDK8 p.Gly30Val](/variant/cdk8-p-gly30val).

### 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 2439883). 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.*