# NM_001323289.2(CDKL5):c.495dup (p.Ala166fs)

https://sugi.bio/variant/cdkl5-p-ala166fs

## Summary

**CDKL5 p.Ala166fs (c.495dup)** is classified **Pathogenic** in CDKL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-17). No gnomAD frequency available for this variant; Associated with developmental and epileptic encephalopathy, 2.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1925573011 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDKL5 gene that is considered disease-causing, submitted by 2 submitters, and is linked to developmental and epileptic encephalopathy, 2.

*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) | X-linked dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | CDKL5 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of CDKL5-deficiency disorder** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Generalized tonic seizure — Very frequent (99-80%)
- Everted lower lip vermilion — Frequent (79-30%)
- Broad forehead — Frequent (79-30%)
- Deeply set eye — Frequent (79-30%)
- Autistic behavior — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Reduced eye contact — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018617/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.Ala166fs |
| Coding change (HGVS c.) | c.495dup |
| MANE Select transcript | [NM_001323289](https://www.ncbi.nlm.nih.gov/nuccore/NM_001323289) |
| dbSNP | [rs1925573011](https://www.ncbi.nlm.nih.gov/snp/rs1925573011/) |
| Variant type | Duplication |
| Location | chrX:18584293-18584294 (GRCh38) |
| ClinVar | [VCV870173](https://www.ncbi.nlm.nih.gov/clinvar/variation/870173/) |

**All HGVS expressions:** `NC_000023.10:g.18602414dup`, `NC_000023.11:g.18584294dup`, `NG_008475.1:g.163690dup`, `NM_001037343.2:c.495dup`, `NM_001323289.2:c.495dup`, `NM_003159.3:c.495dup`

## 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 11.228, GERP 2.36, 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 **in exon 8 of 18**, so the transcript is predicted to undergo NMD.
- 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 **166** lies in the protein kinase domain.

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.Ala166fs 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-17.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-02-14 |
| Centre for Population Genomics, CPG | Pathogenic | criteria provided, single submitter | curation | 2024-12-17 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **166** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [RS1 p.Tyr166fs](/variant/rs1-p-tyr166fs), [RS1 p.Tyr166Ter](/variant/rs1-p-tyr166ter), [RS1 p.Tyr166del](/variant/rs1-p-tyr166del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDKL5 variant pages (same residue, condition, or type): [RS1 p.Tyr166fs](/variant/rs1-p-tyr166fs), [CDKL5 p.Ser438fs](/variant/cdkl5-p-ser438fs), [RS1 p.Tyr166Ter](/variant/rs1-p-tyr166ter), [CDKL5 c.65dupG](/variant/cdkl5-c-65dupg), [CDKL5 c.825+1dup](/variant/cdkl5-c-825-plus-1dup), [CDKL5 p.Arg558fs](/variant/cdkl5-p-arg558fs), [CDKL5 p.Asn293fs](/variant/cdkl5-p-asn293fs), [CDKL5 p.Glu170fs](/variant/cdkl5-p-glu170fs).

### 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 870173). 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.*