# NM_001323289.2(CDKL5):c.470C>T (p.Ala157Val)

https://sugi.bio/variant/cdkl5-p-ala157val

## Summary

**CDKL5 p.Ala157Val (c.470C>T)** is classified **Likely pathogenic** in CDKL5 (ClinVar, Expert panel, 6 submitters; last evaluated 2023-04-14). AlphaMissense: likely pathogenic (0.9995); No allele count reported in gnomAD v4.1 (AN 1,197,831); Associated with CDKL5 disorder.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs863225066 · 6 submitters · 2 linked conditions · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,197,831)

## For patients & families {#patients}

This is a change in the CDKL5 gene that is considered likely disease-causing, submitted by 6 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.Ala157Val |
| Coding change (HGVS c.) | c.470C>T |
| MANE Select transcript | [NM_001323289](https://www.ncbi.nlm.nih.gov/nuccore/NM_001323289) |
| dbSNP | [rs863225066](https://www.ncbi.nlm.nih.gov/snp/rs863225066/) |
| Variant type | single nucleotide variant |
| Location | chrX:18584269-18584269 (GRCh38) |
| ClinVar | [VCV217360](https://www.ncbi.nlm.nih.gov/clinvar/variation/217360/) |

**All HGVS expressions:** `NC_000023.10:g.18602389C>T`, `NC_000023.11:g.18584269C>T`, `NG_008475.1:g.163665C>T`, `NM_001037343.2:c.470C>T`, `NM_001323289.2:c.470C>T`, `NM_003159.3:c.470C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9995) — concordant with the pathogenic call
- REVEL 0.787 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.168 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.681, GERP 2.36, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in CDKL5 (of 5,644 modeled).
- CADD: **PHRED 27.2**. 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.*
- Regional missense constraint: **o/e 0.35** across the covering region of the MANE Select transcript (18,507,097–18,598,499), spanning 91,402 bp — the region is depleted of missense variation. Chi-square p 1.2e-21. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **no allele count reported in gnomAD v4.1 (AN 1,197,831)** — 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 **157** 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.Ala157Val 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}

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

**Submitter consensus:** conflicting (3 Uncertain significance, 3 Likely pathogenic).

**Submission history:** 6 submissions (2015–2023); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Rett and Angelman-like Disorders VCEP (CDKL5 disorder). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS4_Supporting`, `PS2`, `PP3`, `PM5`.
*Considered but not met:* `PP4_not`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The p.Ala157Val variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with infantile epilepsy (GeneDx Internal Database) (PS2).  The p.Ala157Val variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Ala157Val variant has been observed in individuals reported to have Rett syndrome or CDKL5 Deficiency disorder, however, additional clinical and segregation information was not provided (PMID: 32472944; 31313283) (PS4_supporting_met, PP4_not met). A pathogenic missense variant (p.Ala157Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (Invitae internal database). In summary, the p.Ala157Val variant in CDKL5 is classified as likely pathogenic for CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PP3, PM2_supporting, PS4_supporting,PM5).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50022 · approved 2023-04-14 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/c746091d-5bd3-4f1a-a94c-7ce585edbb14).*
*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 |
| --- | --- | --- | --- | --- |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Uncertain significance | no assertion criteria provided | clinical testing | 2015-02-13 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-03-31 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-05-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-12 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-12-01 |
| ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Likely pathogenic | reviewed by expert panel | curation | 2023-04-14 |

## 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.

## Same-residue context {#hotspot}

Residue **157** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDKL5 p.Ala157Pro](/variant/cdkl5-p-ala157pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDKL5 variant pages (same residue, condition, or type): [CDKL5 p.Ala157Pro](/variant/cdkl5-p-ala157pro), [RS1 p.Thr157=](/variant/rs1-p-thr157), [CDKL5 c.146-1G>A](/variant/cdkl5-c-146-minus-1g-a), [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.Asn71Asp](/variant/cdkl5-p-asn71asp).

### 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 217360). 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.*