# NM_003718.5(CDK13):c.2854_2858del (p.Pro952fs)

https://sugi.bio/variant/cdk13-p-pro952fs

## Summary

**CDK13 p.Pro952fs (c.2854_2858del)** is classified **Pathogenic** in CDK13 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03).

**At a glance:** Pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the CDK13 gene that is reported as disease-causing, but on limited review, 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 | [CDK13](https://sugi.bio/atlas/gene/CDK13/) |
| Protein change (HGVS p.) | p.Pro952fs |
| Coding change (HGVS c.) | c.2854_2858del |
| MANE Select transcript | [NM_003718](https://www.ncbi.nlm.nih.gov/nuccore/NM_003718) |
| Variant type | Deletion |
| Location | chr7:40078075-40078079 (GRCh38) |
| ClinVar | [VCV3721620](https://www.ncbi.nlm.nih.gov/clinvar/variation/3721620/) |

**All HGVS expressions:** `NC_000007.13:g.40117677_40117681del`, `NC_000007.14:g.40078078_40078082del`, `NG_052965.1:g.132719_132723del`, `NG_052965.2:g.132824_132828del`, `NM_003718.5:c.2854_2858del`, `NM_031267.4:c.2854_2858delCCAAA`

## Computational & population evidence {#evidence}

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

- **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 11.862, GERP 2.32, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.434, pLI 0.99987), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 14**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**CDK13** population constraint: LOEUF 0.434, pLI 0.99987, missense-Z -1.1078; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **952** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 50.59, 19% of residues very-high.

**2 experimental structure(s)** (PDB): [5EFQ](https://www.rcsb.org/structure/5EFQ), [7NXJ](https://www.rcsb.org/structure/7NXJ).

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

*Describes the biological roles of CDK13 (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:** CDK13's established molecular role includes RNA binding. p.Pro952fs falls in the protein kinase domain.


### Pathways affected {#pathways}

CDK13 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |

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

**Molecular function:** RNA binding, RNA polymerase II CTD heptapeptide repeat kinase activity, cyclin binding.

**Biological process:** regulation of signal transduction, hemopoiesis, positive regulation of transcription elongation by RNA polymerase II, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-03.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-03 |

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

## Similar variants {#similar}

Related CDK13 variant pages (same residue, condition, or type): [CDK13 p.Pro952Leu](/variant/cdk13-p-pro952leu), [CDK13 p.Leu61fs](/variant/cdk13-p-leu61fs), [CDK13 p.Ser1048_Asp1052delinsTyr](/variant/cdk13-p-ser1048-asp1052delinstyr), [CDK13 p.Ser662del](/variant/cdk13-p-ser662del), [CDK13 p.Ala561fs](/variant/cdk13-p-ala561fs), [CDK13 p.Arg110fs](/variant/cdk13-p-arg110fs), [CDK13 p.Arg301fs](/variant/cdk13-p-arg301fs), [CDK13 p.Arg396fs](/variant/cdk13-p-arg396fs).

### 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 3721620). 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.*