# NM_005189.3(CBX2):c.57C>A (p.Ser19Arg)

https://sugi.bio/variant/cbx2-p-ser19arg

## Summary

**CBX2 p.Ser19Arg (c.57C>A)** is classified **Uncertain significance** in CBX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.9492); No allele count reported in gnomAD v4.1 (AN 1,552,646).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,552,646)

## For patients & families {#patients}

This is a change in the CBX2 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 | [CBX2](https://sugi.bio/atlas/gene/CBX2/) |
| Protein change (HGVS p.) | p.Ser19Arg |
| Coding change (HGVS c.) | c.57C>A |
| MANE Select transcript | [NM_005189](https://www.ncbi.nlm.nih.gov/nuccore/NM_005189) |
| Variant type | single nucleotide variant |
| Location | chr17:79778292-79778292 (GRCh38) |
| ClinVar | [VCV4220049](https://www.ncbi.nlm.nih.gov/clinvar/variation/4220049/) |

**All HGVS expressions:** `NC_000017.10:g.77752091C>A`, `NC_000017.11:g.79778292C>A`, `NG_016986.1:g.5115C>A`, `NG_196981.1:g.440C>A`, `NG_196982.1:g.50C>A`, `NM_005189.3:c.57C>A`, `NM_032647.4:c.57C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9492)
- REVEL 0.295 (indeterminate)
- SaProt LLR -5.78 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 0.348, GERP -3.44, phastCons 0.993 — weakly conserved position
- CADD: **PHRED 24.3**. 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 0.61** across the covering region of the MANE Select transcript (79,778,236–79,779,420), spanning 1,184 bp. Chi-square p 0.00085. 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 (C>T, Δ0.91 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: **no allele count reported in gnomAD v4.1 (AN 1,552,646)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **19** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-06.

**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 | 2025-08-06 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## 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 4220049). 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.*