# NM_001323289.2(CDKL5):c.144A>G (p.Glu48=)

https://sugi.bio/variant/cdkl5-p-glu48

## Summary

**CDKL5 p.Glu48= (c.144A>G)** is classified **Uncertain significance** in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). No allele count reported in gnomAD v4.1 (AN 880,750); Associated with developmental and epileptic encephalopathy, 2.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 880,750)

## For patients & families {#patients}

This is a change in the CDKL5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Glu48= |
| Coding change (HGVS c.) | c.144A>G |
| MANE Select transcript | [NM_001323289](https://www.ncbi.nlm.nih.gov/nuccore/NM_001323289) |
| Variant type | single nucleotide variant |
| Location | chrX:18564521-18564521 (GRCh38) |
| ClinVar | [VCV4855316](https://www.ncbi.nlm.nih.gov/clinvar/variation/4855316/) |

**All HGVS expressions:** `NC_000023.10:g.18582641A>G`, `NC_000023.11:g.18564521A>G`, `NG_008475.1:g.143917A>G`, `NM_001037343.2:c.144A>G`, `NM_001323289.2:c.144A>G`, `NM_003159.3:c.144A>G`

## 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 **donor loss** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.065, GERP 1.33, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.28**. 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 **0.26**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.26**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.02**.
- Pangolin: Δ**0.29** (loss), gain 0.04 / loss 0.29. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 880,750)** — 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 **48** 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.Glu48= 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-23.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-23 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CDKL5 variant pages (same residue, condition, or type): [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), [CDKL5 p.Asp193Gly](/variant/cdkl5-p-asp193gly).

### 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 4855316). 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.*