# NM_018249.6(CDK5RAP2):c.2376G>T (p.Arg792Ser)

https://sugi.bio/variant/cdk5rap2-p-arg792ser

## Summary

**CDK5RAP2 p.Arg792Ser (c.2376G>T)** is classified **Uncertain significance** in CDK5RAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-22). AlphaMissense: ambiguous (0.5328); Very rare (popmax 0.00667%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs779616922 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the CDK5RAP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CDK5RAP2](https://sugi.bio/atlas/gene/CDK5RAP2/) |
| Protein change (HGVS p.) | p.Arg792Ser |
| Coding change (HGVS c.) | c.2376G>T |
| MANE Select transcript | [NM_018249](https://www.ncbi.nlm.nih.gov/nuccore/NM_018249) |
| dbSNP | [rs779616922](https://www.ncbi.nlm.nih.gov/snp/rs779616922/) |
| Variant type | single nucleotide variant |
| Location | chr9:120453873-120453873 (GRCh38) |
| ClinVar | [VCV2083141](https://www.ncbi.nlm.nih.gov/clinvar/variation/2083141/) |

**All HGVS expressions:** `NC_000009.11:g.123216151C>A`, `NC_000009.12:g.120453873C>A`, `NG_008999.1:g.131287G>T`, `NM_001011649.3:c.2376G>T`, `NM_001272039.2:c.2104-5747G>T`, `NM_001410992.1:c.2277G>T`, `NM_001410993.1:c.2280G>T`, `NM_001410994.1:c.2373G>T`, `NM_018249.6:c.2376G>T`, `NR_073554.2:n.2642G>T`, `NR_073555.2:n.2565G>T`, `NR_073556.2:n.2772G>T`, `NR_073557.2:n.2645G>T`, `NR_073558.2:n.2642G>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5328) — no call either way
- REVEL 0.215 (benign-leaning)
- SaProt LLR -5.683 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.33) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.59, GERP -3.45, phastCons 0.998 — weakly conserved position
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in CDK5RAP2 (of 11,124 modeled).
- CADD: **PHRED 23.4**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (120,389,239–120,579,978), spanning 190,739 bp. Chi-square p 0.44. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.33**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.33**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.39** (loss), gain 0.01 / loss 0.39. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/60,004 in the highest group · 6/1,614,060 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00667% | 15,001 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| European (non-Finnish) | 8.47e-05% | 1,180,025 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-22 |

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

## Similar variants {#similar}

Related CDK5RAP2 variant pages (same residue, condition, or type): [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), [CDK5RAP2 p.Gln1301Ter](/variant/cdk5rap2-p-gln1301ter), [CDK5RAP2 p.Gln1474Ter](/variant/cdk5rap2-p-gln1474ter).

### 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 2083141). 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.*