# NM_001220.5(CAMK2B):c.1468T>C (p.Ser490Pro)

https://sugi.bio/variant/camk2b-p-ser490pro

## Summary

**CAMK2B p.Ser490Pro (c.1468T>C)** is classified **Uncertain significance** in CAMK2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). AlphaMissense: likely benign (0.0666); Ultra-rare (popmax 0.0197%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0197%, mid)

## For patients & families {#patients}

This is a change in the CAMK2B 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 | [CAMK2B](https://sugi.bio/atlas/gene/CAMK2B/) |
| Protein change (HGVS p.) | p.Ser490Pro |
| Coding change (HGVS c.) | c.1468T>C |
| MANE Select transcript | [NM_001220](https://www.ncbi.nlm.nih.gov/nuccore/NM_001220) |
| Variant type | single nucleotide variant |
| Location | chr7:44228796-44228796 (GRCh38) |
| ClinVar | [VCV4740832](https://www.ncbi.nlm.nih.gov/clinvar/variation/4740832/) |

**All HGVS expressions:** `NC_000007.13:g.44268395A>G`, `NC_000007.14:g.44228796A>G`, `NG_029407.1:g.101836T>C`, `NM_001220.5:c.1468T>C`, `NM_001293170.2:c.1225+2210T>C`, `NM_172078.3:c.1225+2210T>C`, `NM_172079.3:c.1153+2210T>C`, `NM_172080.3:c.1150+2210T>C`, `NM_172081.3:c.1108+2210T>C`, `NM_172082.3:c.1153+2210T>C`, `NM_172083.3:c.1036+2210T>C`, `NM_172084.3:c.947-7895T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0666)
- REVEL 0.056 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.962 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 3.765, GERP 1.78, phastCons 0.995 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.1**. 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 1.05** across the covering region of the MANE Select transcript (44,220,887–44,239,646), spanning 18,759 bp. Chi-square p 0.35. 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 (A>C, Δ0.21 donor 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 **0.0197%** (mid) · FAF95 7.1e-05% · FAF99 2e-05% · 1/5,080 in the highest group · 4/1,330,538 alleles overall — ultra-rare (popmax 0.0197%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0197% | 5,080 |
| European (non-Finnish) | 0.000268% | 373,108 |

*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}

**CAMK2B** population constraint: LOEUF 0.45, pLI 0.99933, missense-Z 3.3648; ClinGen dosage — haploinsufficiency 1, triplosensitivity 0 (0–3 scale). *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 **490** lies in a UniProt-annotated variant site (in mrd54); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.35, 46% of residues very-high.

**4 experimental structure(s)** (PDB): [3BHH](https://www.rcsb.org/structure/3BHH), [7URW](https://www.rcsb.org/structure/7URW), [7URY](https://www.rcsb.org/structure/7URY), [7URZ](https://www.rcsb.org/structure/7URZ).

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

*Describes the biological roles of CAMK2B (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:** CAMK2B's established molecular role includes calcium/calmodulin-dependent protein kinase activity. p.Ser490Pro falls in the disordered region. In Reactome, CAMK2B is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**, **Paradoxical activation of RAF signaling by kinase inactive BRAF**.

**Disease mechanism (Reactome):** CAMK2B loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952).

### Pathways affected {#pathways}

CAMK2B participates in **22 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [HSF1-dependent transactivation](https://reactome.org/content/detail/R-HSA-3371571) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | curated |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Ion transport by P-type ATPases](https://reactome.org/content/detail/R-HSA-936837) | curated |
| [Phase 0 - rapid depolarisation](https://reactome.org/content/detail/R-HSA-5576892) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Trafficking of AMPA receptors](https://reactome.org/content/detail/R-HSA-399719) | curated |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde](https://reactome.org/content/detail/R-HSA-442729) | electronic |
| [CaMK IV-mediated phosphorylation of CREB](https://reactome.org/content/detail/R-HSA-111932) | electronic |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [Negative regulation of NMDA receptor-mediated neuronal transmission](https://reactome.org/content/detail/R-HSA-9617324) | electronic |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | electronic |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | electronic |
| [Unblocking of NMDA receptors, glutamate binding and activation](https://reactome.org/content/detail/R-HSA-438066) | electronic |

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

**Molecular function:** calcium/calmodulin-dependent protein kinase activity, identical protein binding, protein homodimerization activity.

**Biological process:** protein autophosphorylation, regulation of neuron migration.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-30 |

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

## Similar variants {#similar}

Related CAMK2B variant pages (same residue, condition, or type): [CAMK2B p.Ser490Ala](/variant/camk2b-p-ser490ala), [CAMK2B p.Ser490Cys](/variant/camk2b-p-ser490cys), [CAMK2B c.903+2T>C](/variant/camk2b-c-903-plus-2t-c), [CAMK2B p.Arg29Ter](/variant/camk2b-p-arg29ter), [CAMK2B p.Glu110Lys](/variant/camk2b-p-glu110lys), [CAMK2B p.Glu237Lys](/variant/camk2b-p-glu237lys), [CAMK2B p.Lys301Glu](/variant/camk2b-p-lys301glu), [CAMK2B p.Pro139Leu](/variant/camk2b-p-pro139leu).

### 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 4740832). 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.*