# NM_001253.4(CDC5L):c.1802A>G (p.Lys601Arg)

https://sugi.bio/variant/cdc5l-p-lys601arg

## Summary

**CDC5L p.Lys601Arg (c.1802A>G)** is classified **Uncertain significance** in CDC5L (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0758); Very rare (popmax 0.00339%, nfe); Associated with congenital anomaly of kidney and urinary tract.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs368161524 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00339%, nfe)

## For patients & families {#patients}

This is a change in the CDC5L gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to congenital anomaly of kidney and urinary tract.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019216/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDC5L](https://sugi.bio/atlas/gene/CDC5L/) |
| Protein change (HGVS p.) | p.Lys601Arg |
| Coding change (HGVS c.) | c.1802A>G |
| MANE Select transcript | [NM_001253](https://www.ncbi.nlm.nih.gov/nuccore/NM_001253) |
| dbSNP | [rs368161524](https://www.ncbi.nlm.nih.gov/snp/rs368161524/) |
| Variant type | single nucleotide variant |
| Location | chr6:44426633-44426633 (GRCh38) |
| ClinVar | [VCV224338](https://www.ncbi.nlm.nih.gov/clinvar/variation/224338/) |

**All HGVS expressions:** `NC_000006.11:g.44394370A>G`, `NC_000006.12:g.44426633A>G`, `NM_001253.4:c.1802A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0758)
- REVEL 0.071 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.914 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.183, GERP 2.29, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.8**. 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 0.78** across the covering region of the MANE Select transcript (44,403,820–44,446,708), spanning 42,888 bp. Chi-square p 4.7e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00339%** (nfe) · FAF95 0.00256% · FAF99 0.00225% · 40/1,179,640 in the highest group · 42/1,613,420 alleles overall — very rare (popmax 0.00339%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00339% | 29,491 |
| African / African-American | 0.00267% | 37,456 |

*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}

**CDC5L** population constraint: LOEUF 0.26, pLI 1, missense-Z 2.7719. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **601** lies in the 'interaction with dapk3' region; the 'interaction with ppp1r8' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 74.94, 25% of residues very-high.

**41 experimental structure(s)** (PDB): [2DIM](https://www.rcsb.org/structure/2DIM), [2DIN](https://www.rcsb.org/structure/2DIN), [5MQF](https://www.rcsb.org/structure/5MQF), [5XJC](https://www.rcsb.org/structure/5XJC), [5YZG](https://www.rcsb.org/structure/5YZG), [5Z56](https://www.rcsb.org/structure/5Z56) — incl. mutant structure 8CH6.

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

*Describes the biological roles of CDC5L (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:** CDC5L's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Lys601Arg falls in the interaction with dapk3 region. In Reactome, CDC5L is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** CDC5L loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

CDC5L participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, RNA binding, identical protein binding, WD40-repeat domain binding.

**Biological process:** DNA damage checkpoint signaling, mRNA splicing, via spliceosome, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Uncertain significance | criteria provided, single submitter | research |  |

## Associated conditions {#conditions}

[congenital anomaly of kidney and urinary tract](https://sugi.bio/atlas/disease/congenital-anomaly-of-kidney-and-urinary-tract/).

**Reported phenotype names (ClinVar):** Congenital anomaly of kidney and urinary tract, Congenital anomalies of kidney and urinary tract, Congenital anomalies of the kidney and urinary tract.

## Similar variants {#similar}

Related CDC5L variant pages (same residue, condition, or type): [CDC5L p.Ala93=](/variant/cdc5l-p-ala93), [CDC5L p.Asp236=](/variant/cdc5l-p-asp236), [CDC5L p.Leu721=](/variant/cdc5l-p-leu721), [CDC5L p.Ala234Val](/variant/cdc5l-p-ala234val), [CDC5L p.Ala457Thr](/variant/cdc5l-p-ala457thr), [CDC5L p.Ala485Thr](/variant/cdc5l-p-ala485thr), [CDC5L p.Arg202Lys](/variant/cdc5l-p-arg202lys), [CDC5L p.Arg202Thr](/variant/cdc5l-p-arg202thr).

### 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 224338). 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.*