# NM_001320.7(CSNK2B):c.101T>G (p.Phe34Cys)

https://sugi.bio/variant/csnk2b-p-phe34cys

## Summary

**CSNK2B p.Phe34Cys (c.101T>G)** is classified **Likely pathogenic** in CSNK2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 8.76e-05%, nfe).

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1374628000 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 8.76e-05%, nfe)

## For patients & families {#patients}

This is a change in the CSNK2B gene that is considered likely disease-causing, 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 | [CSNK2B](https://sugi.bio/atlas/gene/CSNK2B/) |
| Protein change (HGVS p.) | p.Phe34Cys |
| Coding change (HGVS c.) | c.101T>G |
| MANE Select transcript | [NM_001320](https://www.ncbi.nlm.nih.gov/nuccore/NM_001320) |
| dbSNP | [rs1374628000](https://www.ncbi.nlm.nih.gov/snp/rs1374628000/) |
| Variant type | single nucleotide variant |
| Location | chr6:31667896-31667896 (GRCh38) |
| ClinVar | [VCV1275774](https://www.ncbi.nlm.nih.gov/clinvar/variation/1275774/) |

**All HGVS expressions:** `NC_000006.11:g.31635673T>G`, `NC_000006.12:g.31667896T>G`, `NM_001282385.2:c.101T>G`, `NM_001320.7:c.101T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9999) — concordant with the pathogenic call
- REVEL 0.692 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.533 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.877, GERP 1.59, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in CSNK2B (of 1,284 modeled).
- CADD: **PHRED 32.0**. 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 0.39** across the covering region of the MANE Select transcript (31,666,832–31,669,923), spanning 3,091 bp. Chi-square p 1.2e-24. 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 **8.76e-05%** (nfe) · 1/1,141,416 in the highest group · 1/1,374,480 alleles overall — very rare (popmax 8.76e-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}

**CSNK2B** population constraint: LOEUF 0.237, pLI 0.99996, missense-Z 3.7843. *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):

- **Poirier-Bienvenu neurodevelopmental syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **34** lies in a UniProt-annotated variant site (in pobinds; associated in cis with c-86); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.70, 87% of residues very-high.

**10 experimental structure(s)** (PDB): [1DS5](https://www.rcsb.org/structure/1DS5), [1JWH](https://www.rcsb.org/structure/1JWH), [1QF8](https://www.rcsb.org/structure/1QF8), [3EED](https://www.rcsb.org/structure/3EED), [4DGL](https://www.rcsb.org/structure/4DGL), [4MD7](https://www.rcsb.org/structure/4MD7) — incl. mutant structure 3EED.

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

*Describes the biological roles of CSNK2B (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:** CSNK2B's established molecular role includes chromatin binding. In Reactome, CSNK2B is annotated in disease pathway(s) including **Maturation of hRSV A proteins**.

**Disease mechanism (Reactome):** CSNK2B loss or alteration is curated in [Maturation of hRSV A proteins](https://reactome.org/content/detail/R-HSA-9828806).

### Pathways affected {#pathways}

CSNK2B participates in **16 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 |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | 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:** chromatin binding, protein serine/threonine kinase activity, signaling receptor binding, protein domain specific binding, protein-macromolecule adaptor activity, identical protein binding.

**Biological process:** negative regulation of proteasomal ubiquitin-dependent protein catabolic process, positive regulation of activin receptor signaling pathway, adiponectin-activated signaling pathway, negative regulation of blood vessel endothelial cell migration, positive regulation of SMAD protein signal transduction, endothelial tube morphogenesis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-09-15.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-15 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Same-residue context {#hotspot}

Residue **34** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CSNK2B p.Phe34fs](/variant/csnk2b-p-phe34fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CSNK2B variant pages (same residue, condition, or type): [CSNK2B p.Phe34Leu](/variant/csnk2b-p-phe34leu), [CSNK2B p.Phe34fs](/variant/csnk2b-p-phe34fs), [CSNK2B c.175+1G>A](/variant/csnk2b-c-175-plus-1g-a), [CSNK2B c.291+1G>A](/variant/csnk2b-c-291-plus-1g-a), [CSNK2B c.291+1G>T](/variant/csnk2b-c-291-plus-1g-t), [CSNK2B c.292-2A>C](/variant/csnk2b-c-292-minus-2a-c), [CSNK2B c.292-2A>G](/variant/csnk2b-c-292-minus-2a-g), [CSNK2B c.292-2A>T](/variant/csnk2b-c-292-minus-2a-t).

### 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 1275774). 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.*