# NM_004371.4(COPA):c.1826A>T (p.Asp609Val)

https://sugi.bio/variant/copa-p-asp609val

## Summary

**COPA p.Asp609Val (c.1826A>T)** is classified **Conflicting classifications of pathogenicity** in COPA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.9101); Very rare (popmax 0.00288%, nfe); Associated with autoimmune interstitial lung disease-arthritis syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs777845758 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00288%, nfe)

## For patients & families {#patients}

This is a change in the COPA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to autoimmune interstitial lung disease-arthritis syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Childhood, Infancy |
| Diagnostic panels | COPA is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017762/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COPA](https://sugi.bio/atlas/gene/COPA/) |
| Protein change (HGVS p.) | p.Asp609Val |
| Coding change (HGVS c.) | c.1826A>T |
| MANE Select transcript | [NM_004371](https://www.ncbi.nlm.nih.gov/nuccore/NM_004371) |
| dbSNP | [rs777845758](https://www.ncbi.nlm.nih.gov/snp/rs777845758/) |
| Variant type | single nucleotide variant |
| Location | chr1:160299106-160299106 (GRCh38) |
| ClinVar | [VCV2058240](https://www.ncbi.nlm.nih.gov/clinvar/variation/2058240/) |

**All HGVS expressions:** `LRG_1336:g.49459A>T`, `LRG_1336t1:c.1826A>T`, `NC_000001.10:g.160268896T>A`, `NC_000001.11:g.160299106T>A`, `NG_050927.1:g.49459A>T`, `NM_001098398.1:c.1853A>T`, `NM_001098398.2:c.1853A>T`, `NM_004371.4:c.1826A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9101)
- REVEL 0.639 (indeterminate)
- SaProt LLR -13.684 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.91, GERP 2.56, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.3**. 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 0.72** across the covering region of the MANE Select transcript (160,290,160–160,332,518), spanning 42,358 bp. Chi-square p 1.1e-24. 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 (T>C, Δ0.92 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 (gnomAD v4.1): grpmax **0.00288%** (nfe) · FAF95 0.00207% · FAF99 0.00183% · 34/1,179,870 in the highest group · 36/1,461,678 alleles overall — very rare (popmax 0.00288%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00288% | 34,702 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| African / African-American | 0.00133% | 74,992 |

*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}

**COPA** population constraint: LOEUF 0.098, pLI 1, missense-Z 4.8017. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.85, 46% of residues very-high.

**3 experimental structure(s)** (PDB): [6PBG](https://www.rcsb.org/structure/6PBG), [6TZT](https://www.rcsb.org/structure/6TZT), [6U3V](https://www.rcsb.org/structure/6U3V).

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

*Describes the biological roles of COPA (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}

COPA 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:** pancreatic juice secretion.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-25.

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

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-13 |

## Associated conditions {#conditions}

[autoimmune interstitial lung disease-arthritis syndrome](https://sugi.bio/atlas/disease/autoimmune-interstitial-lung-disease-arthritis-syndrome/).

**Reported phenotype names (ClinVar):** Autoimmune interstitial lung disease-arthritis syndrome, Inborn genetic diseases, Autoinflammation and autoimmunity, systemic, with immune dysregulation.

## Similar variants {#similar}

Related COPA variant pages (same residue, condition, or type): [COPA p.Arg233His](/variant/copa-p-arg233his), [COPA p.Glu241Lys](/variant/copa-p-glu241lys), [COPA p.Ala111Thr](/variant/copa-p-ala111thr), [COPA p.Ala176Val](/variant/copa-p-ala176val), [COPA p.Ala407Val](/variant/copa-p-ala407val), [COPA p.Ala422Thr](/variant/copa-p-ala422thr), [COPA p.Ala469Val](/variant/copa-p-ala469val), [COPA p.Ala510Thr](/variant/copa-p-ala510thr).

### 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 2058240). 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.*