# NM_018249.6(CDK5RAP2):c.625dup (p.Asp209fs)

https://sugi.bio/variant/cdk5rap2-p-asp209fs

## Summary

**CDK5RAP2 p.Asp209fs (c.625dup)** is classified **Pathogenic** in CDK5RAP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-01). Associated with microcephaly 3, primary, autosomal recessive.

**At a glance:** Pathogenic · review: No assertion criteria · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CDK5RAP2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to microcephaly 3, primary, autosomal recessive.

*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/0015373/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDK5RAP2](https://sugi.bio/atlas/gene/CDK5RAP2/) |
| Protein change (HGVS p.) | p.Asp209fs |
| Coding change (HGVS c.) | c.625dup |
| MANE Select transcript | [NM_018249](https://www.ncbi.nlm.nih.gov/nuccore/NM_018249) |
| Variant type | Duplication |
| Location | chr9:120536408-120536409 (GRCh38) |
| ClinVar | [VCV3336694](https://www.ncbi.nlm.nih.gov/clinvar/variation/3336694/) |

**All HGVS expressions:** `NC_000009.11:g.123298691dup`, `NC_000009.12:g.120536413dup`, `NG_008999.1:g.48751dup`, `NM_001011649.3:c.625dup`, `NM_001272039.2:c.625dup`, `NM_001410992.1:c.625dup`, `NM_001410993.1:c.625dup`, `NM_001410994.1:c.625dup`, `NM_018249.6:c.625dup`, `NR_073554.2:n.814dup`, `NR_073555.2:n.814dup`, `NR_073556.2:n.811dup`, `NR_073557.2:n.814dup`, `NR_073558.2:n.811dup`

## 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 -0.222, GERP -1.41, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.692, pLI 1.2853e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 38**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**CDK5RAP2** population constraint: LOEUF 0.692, pLI 1.2853e-20, missense-Z 1.1451; ClinGen dosage — haploinsufficiency 30, 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):

- **autosomal recessive primary microcephaly** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 60.11, 3% of residues very-high.

**5 experimental structure(s)** (PDB): [6X0V](https://www.rcsb.org/structure/6X0V), [8RX1](https://www.rcsb.org/structure/8RX1), [9G40](https://www.rcsb.org/structure/9G40), [9H9P](https://www.rcsb.org/structure/9H9P), [9SMX](https://www.rcsb.org/structure/9SMX) — incl. mutant structure 9SMX.

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

*Describes the biological roles of CDK5RAP2 (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:** CDK5RAP2's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

CDK5RAP2 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |

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

**Molecular function:** transcription cis-regulatory region binding, calmodulin binding, microtubule binding, tubulin binding, protein kinase binding, gamma-tubulin binding.

**Biological process:** microtubule cytoskeleton organization, microtubule bundle formation, chromosome segregation, centrosome cycle, centriole replication, microtubule organizing center organization.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-08-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Medical Genetics, Kayseri City Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2024-08-01 |

## Associated conditions {#conditions}

[microcephaly 3, primary, autosomal recessive](https://sugi.bio/atlas/disease/microcephaly-3-primary-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Microcephaly 3, primary, autosomal recessive.

## Similar variants {#similar}

Related CDK5RAP2 variant pages (same residue, condition, or type): [CDK5RAP2 p.Ala1627fs](/variant/cdk5rap2-p-ala1627fs), [CDK5RAP2 p.Glu290fs](/variant/cdk5rap2-p-glu290fs), [CDK5RAP2 c.4005-1G>A](/variant/cdk5rap2-c-4005-minus-1g-a), [CDK5RAP2 c.4963+1G>A](/variant/cdk5rap2-c-4963-plus-1g-a), [CDK5RAP2 p.Arg1403Ter](/variant/cdk5rap2-p-arg1403ter), [CDK5RAP2 p.Arg1481Ter](/variant/cdk5rap2-p-arg1481ter), [CDK5RAP2 p.Arg1558Ter](/variant/cdk5rap2-p-arg1558ter), [CDK5RAP2 p.Arg427Ter](/variant/cdk5rap2-p-arg427ter).

### 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 3336694). 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.*