# NM_001323289.2(CDKL5):c.1648C>T (p.Arg550Ter)

https://sugi.bio/variant/cdkl5-p-arg550ter

## Summary

**CDKL5 p.Arg550Ter (c.1648C>T)** is classified **Pathogenic** in CDKL5 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-06-04). Absent from gnomAD v4.1; Associated with CDKL5 disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs267608643 · 10 submitters · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDKL5 gene that is considered disease-causing, submitted by 10 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.Arg550Ter |
| Coding change (HGVS c.) | c.1648C>T |
| MANE Select transcript | [NM_001323289](https://www.ncbi.nlm.nih.gov/nuccore/NM_001323289) |
| dbSNP | [rs267608643](https://www.ncbi.nlm.nih.gov/snp/rs267608643/) |
| Variant type | single nucleotide variant |
| Location | chrX:18604572-18604572 (GRCh38) |
| ClinVar | [VCV143780](https://www.ncbi.nlm.nih.gov/clinvar/variation/143780/) |

**All HGVS expressions:** `NC_000023.10:g.18622692C>T`, `NC_000023.11:g.18604572C>T`, `NG_008475.1:g.183968C>T`, `NM_001037343.2:c.1648C>T`, `NM_001323289.1:c.1648C>T`, `NM_001323289.2:c.1648C>T`, `NM_003159.3:c.1648C>T`

## 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 4.073, GERP 1.62, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 18**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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: **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 **550** lies in the 'disordered' region.

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.Arg550Ter 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-04.

**Submitter consensus:** unanimous (11/11 Pathogenic).

**Submission history:** 11 submissions (2014–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Population Genomics, CPG | Pathogenic | criteria provided, single submitter | curation | 2024-08-21 |
| Undiagnosed Diseases Network, NIH | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-30 |
| Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Pathogenic | criteria provided, single submitter | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-01 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-02 |
| RettBASE | Pathogenic | no assertion criteria provided | curation | 2014-03-13 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-26 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-10-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-04 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-01 |

## 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/), [atypical Rett syndrome](https://sugi.bio/atlas/disease/atypical-rett-syndrome/).

**Reported phenotype names (ClinVar):** CDKL5 disorder, not provided, Atypical Rett syndrome, Developmental and epileptic encephalopathy, 2, Angelman syndrome-like, CDKL5-related disorder, CDKL5 deficiency disorder, INFANTILE SPASM SYNDROME, X-LINKED 2, none provided, Rett like syndrome.

## Similar variants {#similar}

Related CDKL5 variant pages (same residue, condition, or type): [CDKL5 p.Arg550Gln](/variant/cdkl5-p-arg550gln), [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 143780). 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.*