# NM_004766.3(COPB2):c.247dup (p.Val83fs)

https://sugi.bio/variant/copb2-p-val83fs

## Summary

**COPB2 p.Val83fs (c.247dup)** is classified **Pathogenic** in COPB2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-08). No gnomAD frequency available for this variant; Associated with osteoporosis, childhood- or juvenile-onset, with developmental delay.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2107807701 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the COPB2 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to osteoporosis, childhood- or juvenile-onset, with developmental delay.

*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.Val83fs |
| Coding change (HGVS c.) | c.247dup |
| MANE Select transcript | [NM_004766](https://www.ncbi.nlm.nih.gov/nuccore/NM_004766) |
| dbSNP | [rs2107807701](https://www.ncbi.nlm.nih.gov/snp/rs2107807701/) |
| Variant type | Duplication |
| Location | chr3:139379154-139379155 (GRCh38) |
| ClinVar | [VCV1686976](https://www.ncbi.nlm.nih.gov/clinvar/variation/1686976/) |

**All HGVS expressions:** `NC_000003.11:g.139097997dup`, `NC_000003.12:g.139379155dup`, `NM_004766.2:c.247dupG`, `NM_004766.3:c.247dup`, `NR_023350.1:n.456dup`

## Computational & population evidence {#evidence}

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

- **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 11.181, GERP 2.47, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.177, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**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 **83** lies in a β-strand.

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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-08.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-05-24 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-08 |

## Associated conditions {#conditions}

[osteoporosis, childhood- or juvenile-onset, with developmental delay](https://sugi.bio/atlas/disease/osteoporosis-childhood-or-juvenile-onset-with-developmental-delay/).

**Reported phenotype names (ClinVar):** Osteoporosis, childhood- or juvenile-onset, with developmental delay, not provided, none provided.

## Similar variants {#similar}

Related COPB2 variant pages (same residue, condition, or type): [COPB2 p.His556fs](/variant/copb2-p-his556fs), [COPB2 p.Ser423fs](/variant/copb2-p-ser423fs), [COPB2 p.Thr636fs](/variant/copb2-p-thr636fs), [COPB2 p.Val83Met](/variant/copb2-p-val83met), [COPB2 c.1401+2T>A](/variant/copb2-c-1401-plus-2t-a), [COPB2 p.Glu493fs](/variant/copb2-p-glu493fs), [COPB2 c.751+4A>G](/variant/copb2-c-751-plus-4a-g), [COPB2 p.Leu439Ser](/variant/copb2-p-leu439ser).

### 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 1686976). 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.*