# NM_001323289.2(CDKL5):c.290T>C (p.Leu97Pro)

https://sugi.bio/variant/cdkl5-p-leu97pro

## Summary

**CDKL5 p.Leu97Pro (c.290T>C)** is classified **Likely pathogenic** in CDKL5 (ClinVar, Expert panel, 3 submitters; last evaluated 2023-04-14). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs1925418549 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDKL5 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to CDKL5 disorder.

*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 | 12 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026021/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDKL5](https://sugi.bio/atlas/gene/CDKL5/) |
| Protein change (HGVS p.) | p.Leu97Pro |
| Coding change (HGVS c.) | c.290T>C |
| MANE Select transcript | [NM_001323289](https://www.ncbi.nlm.nih.gov/nuccore/NM_001323289) |
| dbSNP | [rs1925418549](https://www.ncbi.nlm.nih.gov/snp/rs1925418549/) |
| Variant type | single nucleotide variant |
| Location | chrX:18579855-18579855 (GRCh38) |
| ClinVar | [VCV870171](https://www.ncbi.nlm.nih.gov/clinvar/variation/870171/) |

**All HGVS expressions:** `NC_000023.10:g.18597975T>C`, `NC_000023.11:g.18579855T>C`, `NG_008475.1:g.159251T>C`, `NM_001037343.2:c.290T>C`, `NM_001323289.2:c.290T>C`, `NM_003159.3:c.290T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9998) — concordant with the pathogenic call
- REVEL 0.765 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.934 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.853, GERP 2.58, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in CDKL5 (of 5,644 modeled).
- CADD: **PHRED 27.2**. 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 0.35** across the covering region of the MANE Select transcript (18,507,097–18,598,499), spanning 91,402 bp — the region is depleted of missense variation. Chi-square p 1.2e-21. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


Curated gene–disease validity (ClinGen):

- **CDKL5 disorder** — Definitive (XL)

## Protein context {#protein}

Residue **97** lies in the protein kinase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 53.76, 23% of residues very-high.

**3 experimental structure(s)** (PDB): [4BGQ](https://www.rcsb.org/structure/4BGQ), [8CIE](https://www.rcsb.org/structure/8CIE), [9EPU](https://www.rcsb.org/structure/9EPU).

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

*Describes the biological roles of CDKL5 (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:** CDKL5's established molecular role includes protein kinase activity. p.Leu97Pro falls in the protein kinase domain.


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

**Molecular function:** protein kinase activity, ATP binding, kinase activity.

**Biological process:** modulation of chemical synaptic transmission, regulation of postsynapse organization, regulation of cilium assembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-04-14.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2020–2023); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Rett and Angelman-like Disorders VCEP (CDKL5 disorder). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS2`, `PP3`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The p.Leu97Pro variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in an individual (GeneDx Internal Database) (PS2). The p.Leu97Pro variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu97Pro variant in CDKL5 is classified as likely pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PM2_supporting, PP3).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50022 · approved 2023-04-14 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/417c9128-ca8a-4527-b13a-9798da802bd0).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-02-14 |
| ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Likely pathogenic | reviewed by expert panel | curation | 2023-04-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-04-15 |

## Associated conditions {#conditions}

[CDKL5 disorder](https://sugi.bio/atlas/disease/cdkl5-disorder/), [developmental and epileptic encephalopathy, 2](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-2/).

**Reported phenotype names (ClinVar):** CDKL5 disorder, Developmental and epileptic encephalopathy, 2, Angelman syndrome-like, INFANTILE SPASM SYNDROME, X-LINKED 2, CDKL5 deficiency disorder.

## Similar variants {#similar}

Related CDKL5 variant pages (same residue, condition, or type): [CDKL5 p.Leu97=](/variant/cdkl5-p-leu97), [RS1 p.Thr97Pro](/variant/rs1-p-thr97pro), [CDKL5 c.146-1G>A](/variant/cdkl5-c-146-minus-1g-a), [CDKL5 p.Ala157Pro](/variant/cdkl5-p-ala157pro), [CDKL5 p.Ala157Val](/variant/cdkl5-p-ala157val), [CDKL5 p.Ala40Val](/variant/cdkl5-p-ala40val), [CDKL5 p.Arg178Gln](/variant/cdkl5-p-arg178gln), [CDKL5 p.Arg717=](/variant/cdkl5-p-arg717).

### 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 870171). 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.*