# NM_001113575.2(CDKL3):c.361A>T (p.Ile121Phe)

https://sugi.bio/variant/cdkl3-p-ile121phe

## Summary

**CDKL3 p.Ile121Phe (c.361A>T)** is classified **Uncertain significance** in CDKL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.8676); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDKL3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDKL3](https://sugi.bio/atlas/gene/CDKL3/) |
| Protein change (HGVS p.) | p.Ile121Phe |
| Coding change (HGVS c.) | c.361A>T |
| MANE Select transcript | [NM_001113575](https://www.ncbi.nlm.nih.gov/nuccore/NM_001113575) |
| Variant type | single nucleotide variant |
| Location | chr5:134350427-134350427 (GRCh38) |
| ClinVar | [VCV4224714](https://www.ncbi.nlm.nih.gov/clinvar/variation/4224714/) |

**All HGVS expressions:** `LRG_1006:g.25621A>T`, `LRG_1006t1:c.-207A>T`, `LRG_1006t2:c.361A>T`, `NC_000005.10:g.134350427T>A`, `NC_000005.9:g.133686118T>A`, `NG_042179.2:g.25621A>T`, `NM_001113575.2:c.361A>T`, `NM_001300853.2:c.-207A>T`, `NM_001349363.2:c.-29+20571A>T`, `NM_001349364.2:c.-258+20571A>T`, `NM_001349365.2:c.-207+20571A>T`, `NM_001349366.2:c.-118+20571A>T`, `NM_016508.4:c.361A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8676)
- REVEL 0.624 (indeterminate)
- SaProt LLR -9.405 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.339, GERP 1.61, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.6**. 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 0.95** across the covering region of the MANE Select transcript (134,298,654–134,366,523), spanning 67,869 bp. Chi-square p 0.16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.26** (loss), gain 0.00 / loss 0.26. 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: **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}

**CDKL3** population constraint: LOEUF 1.523, pLI 1.0479e-12, missense-Z 0.24594. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **121** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 64.87, 42% of residues very-high.

**1 experimental structure(s)** (PDB): [3ZDU](https://www.rcsb.org/structure/3ZDU).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-21 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CDKL3 variant pages (same residue, condition, or type): [CDKL3 p.Ala195Thr](/variant/cdkl3-p-ala195thr), [CDKL3 p.Ala235Ser](/variant/cdkl3-p-ala235ser), [CDKL3 p.Arg101Gln](/variant/cdkl3-p-arg101gln), [CDKL3 p.Arg111Pro](/variant/cdkl3-p-arg111pro), [CDKL3 p.Arg148Gln](/variant/cdkl3-p-arg148gln), [CDKL3 p.Arg164His](/variant/cdkl3-p-arg164his), [CDKL3 p.Arg367Thr](/variant/cdkl3-p-arg367thr), [CDKL3 p.Arg463Ser](/variant/cdkl3-p-arg463ser).

### 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 4224714). 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.*