# NM_016128.4(COPG1):c.2255T>C (p.Val752Ala)

https://sugi.bio/variant/copg1-p-val752ala

## Summary

**COPG1 p.Val752Ala (c.2255T>C)** is classified **Uncertain significance** in COPG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely pathogenic (0.737); Very rare (popmax 0.00449%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs745877931 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00449%, eas)

## For patients & families {#patients}

This is a change in the COPG1 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 | [COPG1](https://sugi.bio/atlas/gene/COPG1/) |
| Protein change (HGVS p.) | p.Val752Ala |
| Coding change (HGVS c.) | c.2255T>C |
| MANE Select transcript | [NM_016128](https://www.ncbi.nlm.nih.gov/nuccore/NM_016128) |
| dbSNP | [rs745877931](https://www.ncbi.nlm.nih.gov/snp/rs745877931/) |
| Variant type | single nucleotide variant |
| Location | chr3:129272903-129272903 (GRCh38) |
| ClinVar | [VCV2234946](https://www.ncbi.nlm.nih.gov/clinvar/variation/2234946/) |

**All HGVS expressions:** `NC_000003.11:g.128991746T>C`, `NC_000003.12:g.129272903T>C`, `NM_016128.4:c.2255T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.737)
- REVEL 0.378 (indeterminate)
- SaProt LLR -8.774 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.801, GERP 1.87, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.5**. 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 0.77** across the covering region of the MANE Select transcript (129,249,710–129,277,421), spanning 27,711 bp. Chi-square p 1.9e-14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00449%** (eas) · FAF95 0.00133% · FAF99 0.00111% · 2/44,554 in the highest group · 27/1,434,478 alleles overall — very rare (popmax 0.00449%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00449% | 22,277 |
| European (non-Finnish) | 0.00199% | 50,271 |
| Admixed American | 0.00167% | 59,888 |
| Remaining individuals (not grpmax-eligible) | 0.00163% | 61,498 |

*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}

**COPG1** population constraint: LOEUF 0.376, pLI 1, missense-Z 3.2467. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **non-severe combined immunodeficiency due to COPG1 deficiency** — Limited (AR)

## Protein context {#protein}

Residue **752** lies in a β-strand; the 'interaction with znf289/arfgap2' region.

AlphaFold model confidence (whole protein): pLDDT 88.09, 61% of residues very-high.

**1 experimental structure(s)** (PDB): [1R4X](https://www.rcsb.org/structure/1R4X).

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

*Describes the biological roles of COPG1 (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}

COPG1 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 |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-06.

**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 | 2021-07-06 |

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

## Similar variants {#similar}

Related COPG1 variant pages (same residue, condition, or type): [COPG1 p.Arg247His](/variant/copg1-p-arg247his), [COPG1 p.Leu864Met](/variant/copg1-p-leu864met), [COPG1 p.Thr64Met](/variant/copg1-p-thr64met), [COPG1 c.91-11T>C](/variant/copg1-c-91-minus-11t-c), [COPG1 c.939+13C>G](/variant/copg1-c-939-plus-13c-g), [COPG1 p.His221=](/variant/copg1-p-his221), [COPG1 p.Ile92=](/variant/copg1-p-ile92), [COPG1 p.Leu240Val](/variant/copg1-p-leu240val).

### 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 2234946). 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.*