# NM_004766.3(COPB2):c.1050T>A (p.Ser350Arg)

https://sugi.bio/variant/copb2-p-ser350arg

## Summary

**COPB2 p.Ser350Arg (c.1050T>A)** is classified **Uncertain significance** in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely pathogenic (0.9927); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1941654746 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the COPB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Ser350Arg |
| Coding change (HGVS c.) | c.1050T>A |
| MANE Select transcript | [NM_004766](https://www.ncbi.nlm.nih.gov/nuccore/NM_004766) |
| dbSNP | [rs1941654746](https://www.ncbi.nlm.nih.gov/snp/rs1941654746/) |
| Variant type | single nucleotide variant |
| Location | chr3:139373257-139373257 (GRCh38) |
| ClinVar | [VCV3076232](https://www.ncbi.nlm.nih.gov/clinvar/variation/3076232/) |

**All HGVS expressions:** `NC_000003.11:g.139092099A>T`, `NC_000003.12:g.139373257A>T`, `NM_001410834.1:c.963T>A`, `NM_004766.3:c.1050T>A`, `NR_023350.1:n.1259T>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9927)
- REVEL 0.476 (indeterminate)
- SaProt LLR -13.11 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 0.857, GERP -1.44, phastCons 0.977 — weakly conserved position
- CADD: **PHRED 23.3**. 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 0.70** across the covering region of the MANE Select transcript (139,361,125–139,389,550), spanning 28,425 bp. Chi-square p 2.8e-18. 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 (A>C, Δ0.33 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **350** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-28.

**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 | 2023-12-28 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related COPB2 variant pages (same residue, condition, or type): [COPB2 p.Glu646Lys](/variant/copb2-p-glu646lys), [COPB2 p.Glu879Lys](/variant/copb2-p-glu879lys), [COPB2 p.Ile864Thr](/variant/copb2-p-ile864thr), [COPB2 p.Leu649Phe](/variant/copb2-p-leu649phe), [COPB2 p.Ser135Ala](/variant/copb2-p-ser135ala), [COPB2 p.Asn285Ser](/variant/copb2-p-asn285ser), [COPB2 p.Ala480Thr](/variant/copb2-p-ala480thr), [COPB2 p.Ala719Thr](/variant/copb2-p-ala719thr).

### 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 3076232). 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.*