# NM_177559.3(CSNK2A1):c.917G>A (p.Arg306Gln)

https://sugi.bio/variant/csnk2a1-p-arg306gln

## Summary

**CSNK2A1 p.Arg306Gln (c.917G>A)** is classified **Uncertain significance** in CSNK2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.1664); Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1416271899 · 1 submitter · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CSNK2A1 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 | [CSNK2A1](https://sugi.bio/atlas/gene/CSNK2A1/) |
| Protein change (HGVS p.) | p.Arg306Gln |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_177559](https://www.ncbi.nlm.nih.gov/nuccore/NM_177559) |
| dbSNP | [rs1416271899](https://www.ncbi.nlm.nih.gov/snp/rs1416271899/) |
| Variant type | single nucleotide variant |
| Location | chr20:487483-487483 (GRCh38) |
| ClinVar | [VCV3253579](https://www.ncbi.nlm.nih.gov/clinvar/variation/3253579/) |

**All HGVS expressions:** `NC_000020.10:g.468127C>T`, `NC_000020.11:g.487483C>T`, `NG_011970.2:g.61356G>A`, `NM_001362770.2:c.917G>A`, `NM_001362771.2:c.917G>A`, `NM_001895.4:c.917G>A`, `NM_177559.3:c.917G>A`, `NM_177560.3:c.509G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1664)
- REVEL 0.435 (indeterminate)
- SaProt LLR -9.398 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 7.725, GERP 2.44, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 30.0**. 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.*
- Regional missense constraint: **o/e 0.26** across the covering region of the MANE Select transcript (487,470–508,490), spanning 21,020 bp — the region is depleted of missense variation. Chi-square p 3.7e-44. 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 (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,030 in the highest group · 1/1,614,048 alleles overall — very rare (popmax 8.47e-05%, 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}

**CSNK2A1** population constraint: LOEUF 0.274, pLI 1, missense-Z 5.3272; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **306** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 90.78, 87% of residues very-high.

**316 experimental structure(s)** (PDB): [1JWH](https://www.rcsb.org/structure/1JWH), [1NA7](https://www.rcsb.org/structure/1NA7), [1PJK](https://www.rcsb.org/structure/1PJK), [2PVR](https://www.rcsb.org/structure/2PVR), [2ZJW](https://www.rcsb.org/structure/2ZJW), [3AMY](https://www.rcsb.org/structure/3AMY) — incl. mutant structure 1PJK.

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

*Describes the biological roles of CSNK2A1 (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:** CSNK2A1's established molecular role includes protein serine/threonine kinase activity. p.Arg306Gln falls in the protein kinase domain. In Reactome, CSNK2A1 is annotated in disease pathway(s) including **Maturation of hRSV A proteins**.

**Disease mechanism (Reactome):** CSNK2A1 loss or alteration is curated in [Maturation of hRSV A proteins](https://reactome.org/content/detail/R-HSA-9828806).

### Pathways affected {#pathways}

CSNK2A1 participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Maturation of hRSV A proteins](https://reactome.org/content/detail/R-HSA-9828806) | curated |
| [Condensation of Prometaphase Chromosomes](https://reactome.org/content/detail/R-HSA-2514853) | curated |
| [Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding](https://reactome.org/content/detail/R-HSA-6814122) | curated |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | curated |
| [Receptor Mediated Mitophagy](https://reactome.org/content/detail/R-HSA-8934903) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |
| [Regulation of PTEN stability and activity](https://reactome.org/content/detail/R-HSA-8948751) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | curated |
| [Signal transduction by L1](https://reactome.org/content/detail/R-HSA-445144) | curated |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [WNT mediated activation of DVL](https://reactome.org/content/detail/R-HSA-201688) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | electronic |
| [Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK](https://reactome.org/content/detail/R-HSA-9931529) | electronic |
| [Phosphorylation and nuclear translocation of the CRY:PER:kinase complex](https://reactome.org/content/detail/R-HSA-9931530) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine kinase activity, kinase activity, identical protein binding.

**Biological process:** double-strand break repair, DNA damage response, positive regulation of cell population proliferation, negative regulation of translation, peptidyl-serine phosphorylation, positive regulation of Wnt signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-27 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **306** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CSNK2A1 p.Arg306Ter](/variant/csnk2a1-p-arg306ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CSNK2A1 variant pages (same residue, condition, or type): [CSNK2A1 p.Arg306Ter](/variant/csnk2a1-p-arg306ter), [CSNK2A1 p.Arg107Ter](/variant/csnk2a1-p-arg107ter), [CSNK2A1 p.Arg134Ter](/variant/csnk2a1-p-arg134ter), [CSNK2A1 p.Arg191Gln](/variant/csnk2a1-p-arg191gln), [CSNK2A1 p.Arg280Ter](/variant/csnk2a1-p-arg280ter), [CSNK2A1 p.Arg312Gln](/variant/csnk2a1-p-arg312gln), [CSNK2A1 p.Arg312Trp](/variant/csnk2a1-p-arg312trp), [CSNK2A1 p.Arg333Ter](/variant/csnk2a1-p-arg333ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3253579). 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.*