# NM_001323289.2(CDKL5):c.2388C>T (p.Ser796=)

https://sugi.bio/variant/cdkl5-p-ser796

## Summary

**CDKL5 p.Ser796= (c.2388C>T)** is classified **Likely benign** in CDKL5 (ClinVar, Expert panel, 4 submitters; last evaluated 2023-04-14). Very rare (popmax 0.0044%, amr); Associated with CDKL5 disorder.

**At a glance:** Likely benign · review: Expert panel · rsID rs727503847 · 4 submitters · 2 linked conditions · very rare (popmax 0.0044%, amr)

## For patients & families {#patients}

This is a change in the CDKL5 gene that is classified as likely benign — not considered disease-causing, submitted by 4 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.Ser796= |
| Coding change (HGVS c.) | c.2388C>T |
| MANE Select transcript | [NM_001323289](https://www.ncbi.nlm.nih.gov/nuccore/NM_001323289) |
| dbSNP | [rs727503847](https://www.ncbi.nlm.nih.gov/snp/rs727503847/) |
| Variant type | single nucleotide variant |
| Location | chrX:18625139-18625139 (GRCh38) |
| ClinVar | [VCV166821](https://www.ncbi.nlm.nih.gov/clinvar/variation/166821/) |

**All HGVS expressions:** `NC_000023.10:g.18643259C>T`, `NC_000023.11:g.18625139C>T`, `NG_008475.1:g.204535C>T`, `NM_001037343.2:c.2388C>T`, `NM_001323289.2:c.2388C>T`, `NM_003159.3:c.2388C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.56) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.175, GERP -4.99, phastCons 0.989 — weakly conserved position
- CADD: **PHRED 14.07**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.56**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.56**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0044%** (amr) · FAF95 0.00073% · FAF99 0.000273% · 2/45,405 in the highest group · 6/1,204,977 alleles overall — very rare (popmax 0.0044%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0044% | 22,703 |
| European (non-Finnish) | 0.000448% | 223,212 |

*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 **796** lies in the 'disordered' region; a UniProt-annotated variant site (in dee2).

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.Ser796= falls in the disordered region.


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

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2015–2024); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Rett and Angelman-like Disorders VCEP (CDKL5 disorder). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS2`, `BP5`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The p.Ser796= variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ser796= variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database)(BP5). In summary, the p.Ser796= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50022 · approved 2023-04-14 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/64f0a058-01b0-4b3f-8cbc-0957e3e5ea8d).*
*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 |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-04-01 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-05-27 |
| ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Likely benign | reviewed by expert panel | curation | 2023-04-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-21 |

## 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, not specified, not provided, Angelman syndrome-like, Developmental and epileptic encephalopathy, 2, INFANTILE SPASM SYNDROME, X-LINKED 2, CDKL5 deficiency disorder, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related CDKL5 variant pages (same residue, condition, or type): [CDKL5 p.Ser796Cys](/variant/cdkl5-p-ser796cys), [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), [CDKL5 p.Arg948Ter](/variant/cdkl5-p-arg948ter).

### 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 166821). 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.*