# NM_001323289.2(CDKL5):c.2480_2486dup (p.Gln830fs)

https://sugi.bio/variant/cdkl5-p-gln830fs

## Summary

**CDKL5 p.Gln830fs (c.2480_2486dup)** is classified **Likely pathogenic** in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-11-01). No gnomAD frequency available for this variant; Associated with infantile spasms.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1555954752 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDKL5 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to infantile spasms.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked dominant |
| Clinical trials | 27 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CDKL5 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Infantile epileptic spasms syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myoclonus — Very frequent (99-80%)
- Developmental regression — Very frequent (99-80%)
- Hypsarrhythmia — Very frequent (99-80%)
- Infantile spasms — Very frequent (99-80%)
- Abnormality of the nervous system — Frequent (79-30%)
- Abnormal skin morphology — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007887/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.Gln830fs |
| Coding change (HGVS c.) | c.2480_2486dup |
| MANE Select transcript | [NM_001323289](https://www.ncbi.nlm.nih.gov/nuccore/NM_001323289) |
| dbSNP | [rs1555954752](https://www.ncbi.nlm.nih.gov/snp/rs1555954752/) |
| Variant type | Duplication |
| Location | chrX:18625224-18625225 (GRCh38) |
| ClinVar | [VCV547188](https://www.ncbi.nlm.nih.gov/clinvar/variation/547188/) |

**All HGVS expressions:** `NC_000023.10:g.18643351_18643357dup`, `NC_000023.11:g.18625231_18625237dup`, `NG_008475.1:g.204627_204633dup`, `NM_001037343.2:c.2480_2486dup`, `NM_001323289.2:c.2480_2486dup`, `NM_003159.2:c.2480_2486dupCAGATCT`, `NM_003159.3:c.2480_2486dup`

## Computational & population evidence {#evidence}

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

- **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 11.29, GERP 2.49, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (17 of 18, 23 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **830** 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.Gln830fs 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 pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2016-11-01.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Human Genetics, Inc, Center for Human Genetics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-11-01 |

## Associated conditions {#conditions}

[infantile spasms](https://sugi.bio/atlas/disease/infantile-spasms/).

**Reported phenotype names (ClinVar):** West syndrome, Infantile epileptic spasms syndrome.

## Similar variants {#similar}

Related CDKL5 variant pages (same residue, condition, or type): [CDKL5 p.Gln830His](/variant/cdkl5-p-gln830his), [CDKL5 p.Arg178Gln](/variant/cdkl5-p-arg178gln), [CDKL5 c.404-1G>C](/variant/cdkl5-c-404-minus-1g-c), [CDKL5 c.99+1G>T](/variant/cdkl5-c-99-plus-1g-t), [RS1 c.184+3207C>T](/variant/rs1-c-184-plus-3207c-t), [CDKL5 p.Thr533fs](/variant/cdkl5-p-thr533fs), [CDKL5 p.Met448Ile](/variant/cdkl5-p-met448ile), [CDKL5 p.Ser438fs](/variant/cdkl5-p-ser438fs).

### 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 547188). 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.*