# NM_004766.3(COPB2):c.2578_2580del (p.Pro860del)

https://sugi.bio/variant/copb2-p-pro860del

## Summary

**COPB2 p.Pro860del (c.2578_2580del)** is classified **Conflicting classifications of pathogenicity** in COPB2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-01). Rare (popmax 0.101%, afr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · rare (popmax 0.101%, afr)

## For patients & families {#patients}

This is a change in the COPB2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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 | [COPB2](https://sugi.bio/atlas/gene/COPB2/) |
| Protein change (HGVS p.) | p.Pro860del |
| Coding change (HGVS c.) | c.2578_2580del |
| MANE Select transcript | [NM_004766](https://www.ncbi.nlm.nih.gov/nuccore/NM_004766) |
| Variant type | Deletion |
| Location | chr3:139358245-139358247 (GRCh38) |
| ClinVar | [VCV4084912](https://www.ncbi.nlm.nih.gov/clinvar/variation/4084912/) |

**All HGVS expressions:** `NC_000003.11:g.139077089_139077091del`, `NC_000003.12:g.139358247_139358249del`, `NG_012174.1:g.19229_19231del`, `NM_001410834.1:c.2491_2493del`, `NM_004766.3:c.2578_2580del`, `NR_023350.1:n.2787_2789del`

## 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 1.003, GERP 1.29, phastCons 0.992 — weakly conserved position
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 17.58**. 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** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.101%** (afr) · FAF95 0.083% · FAF99 0.0763% · 76/74,932 in the highest group · 87/1,613,930 alleles overall — rare (popmax 0.101%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.101% | 986 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,501 |
| Admixed American | 0.005% | 19,998 |
| South Asian | 0.0022% | 45,536 |
| European (non-Finnish) | 8.47e-05% | 1,179,976 |

*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}

**COPB2** population constraint: LOEUF 0.177, pLI 1, missense-Z 3.4692. *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 **860** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 86.75, 61% of residues very-high.

**2 experimental structure(s)** (PDB): [8D30](https://www.rcsb.org/structure/8D30), [8D41](https://www.rcsb.org/structure/8D41).

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

*Describes the biological roles of COPB2 (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}

COPB2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-dependent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811434) | curated |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |

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

**Biological process:** retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum, intra-Golgi vesicle-mediated transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-01.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-22 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-01 |

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

## Similar variants {#similar}

Related COPB2 variant pages (same residue, condition, or type): [COPB2 p.Lys413fs](/variant/copb2-p-lys413fs), [COPB2 p.Val222fs](/variant/copb2-p-val222fs), [COPB2 c.1206-13_1206-3del](/variant/copb2-c-1206-minus-13-1206-minus-3del), [COPB2 c.1295-6del](/variant/copb2-c-1295-minus-6del), [COPB2 c.2485-30_2485-21del](/variant/copb2-c-2485-minus-30-2485-minus-21del), [COPB2 c.229-10_229-9del](/variant/copb2-c-229-minus-10-229-minus-9del).

### 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 4084912). 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.*