# NM_015076.5(CDK19):c.248A>G (p.Lys83Arg)

https://sugi.bio/variant/cdk19-p-lys83arg

## Summary

**CDK19 p.Lys83Arg (c.248A>G)** is classified **Uncertain significance** in CDK19 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-01). AlphaMissense: likely benign (0.106); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1334230328 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the CDK19 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CDK19](https://sugi.bio/atlas/gene/CDK19/) |
| Protein change (HGVS p.) | p.Lys83Arg |
| Coding change (HGVS c.) | c.248A>G |
| MANE Select transcript | [NM_015076](https://www.ncbi.nlm.nih.gov/nuccore/NM_015076) |
| dbSNP | [rs1334230328](https://www.ncbi.nlm.nih.gov/snp/rs1334230328/) |
| Variant type | single nucleotide variant |
| Location | chr6:110670498-110670498 (GRCh38) |
| ClinVar | [VCV2286861](https://www.ncbi.nlm.nih.gov/clinvar/variation/2286861/) |

**All HGVS expressions:** `NC_000006.11:g.110991701T>C`, `NC_000006.12:g.110670498T>C`, `NM_001300960.2:c.248A>G`, `NM_001300963.2:c.68A>G`, `NM_001300964.2:c.68A>G`, `NM_015076.5:c.248A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.106)
- REVEL 0.14 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.057 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.894, GERP 1.55, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.1**. 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 0.54** across the covering region of the MANE Select transcript (110,632,127–110,815,136), spanning 183,009 bp. Chi-square p 3.7e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.22 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,348 in the highest group · 6/1,613,294 alleles overall — very rare (popmax 0.000509%, nfe).

*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}

**CDK19** population constraint: LOEUF 0.655, pLI 0.49182, missense-Z 2.7676. *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 **83** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 77.97, 59% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CDK19 (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:** p.Lys83Arg falls in the protein kinase domain. In Reactome, CDK19 is annotated in disease pathway(s) including **RSV-host interactions**.

**Disease mechanism (Reactome):** CDK19 loss or alteration is curated in [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110).

### Pathways affected {#pathways}

CDK19 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-01.

**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 | 2022-05-01 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CDK19 variant pages (same residue, condition, or type): [CDK19 p.Thr196Ala](/variant/cdk19-p-thr196ala), [CDK19 p.Lys47Asn](/variant/cdk19-p-lys47asn), [CDK19 p.Pro495Thr](/variant/cdk19-p-pro495thr), [CDK19 p.Arg112Cys](/variant/cdk19-p-arg112cys), [CDK19 p.Arg166Met](/variant/cdk19-p-arg166met), [CDK19 p.Arg441Gln](/variant/cdk19-p-arg441gln), [CDK19 p.Arg464Cys](/variant/cdk19-p-arg464cys), [CDK19 p.Arg464His](/variant/cdk19-p-arg464his).

### 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 2286861). 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.*