# NM_005189.3(CBX2):c.48C>T (p.Cys16=)

https://sugi.bio/variant/cbx2-p-cys16

## Summary

**CBX2 p.Cys16= (c.48C>T)** is classified **Likely benign** in CBX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). Ultra-rare (popmax 0.0224%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs781876862 · 1 submitter · ultra-rare (popmax 0.0224%, nfe)

## For patients & families {#patients}

This is a change in the CBX2 gene that is classified as likely benign — not considered 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 | [CBX2](https://sugi.bio/atlas/gene/CBX2/) |
| Protein change (HGVS p.) | p.Cys16= |
| Coding change (HGVS c.) | c.48C>T |
| MANE Select transcript | [NM_005189](https://www.ncbi.nlm.nih.gov/nuccore/NM_005189) |
| dbSNP | [rs781876862](https://www.ncbi.nlm.nih.gov/snp/rs781876862/) |
| Variant type | single nucleotide variant |
| Location | chr17:79778283-79778283 (GRCh38) |
| ClinVar | [VCV2421844](https://www.ncbi.nlm.nih.gov/clinvar/variation/2421844/) |

**All HGVS expressions:** `NC_000017.10:g.77752082C>T`, `NC_000017.11:g.79778283C>T`, `NG_016986.1:g.5106C>T`, `NM_005189.3:c.48C>T`, `NM_032647.4:c.48C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.255, GERP -0.68, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.89**. 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.*
- 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 **0.0224%** (nfe) · FAF95 0.0201% · FAF99 0.0192% · 258/1,152,858 in the highest group · 301/1,546,630 alleles overall — ultra-rare (popmax 0.0224%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0432% | 2,314 |
| European (non-Finnish) (grpmax) | 0.0224% | 4,468 |
| Remaining individuals (not grpmax-eligible) | 0.0201% | 4,988 |
| Admixed American | 0.00746% | 13,413 |
| South Asian | 0.00355% | 28,202 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00354% | 28,212 |
| African / African-American | 0.00277% | 36,043 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CBX2** population constraint: LOEUF 0.946, pLI 0.0097406, missense-Z -0.3128. *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 **16** lies in the chromo domain; a β-strand; the 'involved in the interaction with h3c15 and h3c1' region.

AlphaFold model confidence (whole protein): pLDDT 57.29, 14% of residues very-high.

**3 experimental structure(s)** (PDB): [2D9U](https://www.rcsb.org/structure/2D9U), [3H91](https://www.rcsb.org/structure/3H91), [5EPK](https://www.rcsb.org/structure/5EPK).

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

*Describes the biological roles of CBX2 (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.*


### Pathways affected {#pathways}

CBX2 participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [SUMOylation of RNA binding proteins](https://reactome.org/content/detail/R-HSA-4570464) | curated |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | curated |
| [SUMOylation of transcription cofactors](https://reactome.org/content/detail/R-HSA-3899300) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |
| [SUMOylation of DNA methylation proteins](https://reactome.org/content/detail/R-HSA-4655427) | electronic |

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

**Biological process:** negative regulation of transcription by RNA polymerase II, development of primary sexual characteristics.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-02-22 |

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

## Similar variants {#similar}

Related CBX2 variant pages (same residue, condition, or type): [CBX2 c.288+52G>T](/variant/cbx2-c-288-plus-52g-t), [CBX2 p.Arg137His](/variant/cbx2-p-arg137his), [CBX2 p.Gln349His](/variant/cbx2-p-gln349his), [CBX2 p.Gly133Ser](/variant/cbx2-p-gly133ser), [CBX2 p.Gly287Arg](/variant/cbx2-p-gly287arg), [CBX2 p.Gly332Asp](/variant/cbx2-p-gly332asp), [CBX2 p.Met260Val](/variant/cbx2-p-met260val), [CBX2 p.Met404Leu](/variant/cbx2-p-met404leu).

### 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 2421844). 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.*