# NM_000096.4(CP):c.2066del (p.Pro689fs)

https://sugi.bio/variant/cp-p-pro689fs

## Summary

**CP p.Pro689fs (c.2066del)** is classified **Pathogenic/Likely pathogenic** in CP (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.0131%, nfe); Associated with neurodegeneration with brain iron accumulation.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs386134147 · 6 submitters · 2 linked conditions · ultra-rare (popmax 0.0131%, nfe)

## For patients & families {#patients}

This is a change in the CP gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to neurodegeneration with brain iron accumulation.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0011899/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CP](https://sugi.bio/atlas/gene/CP/) |
| Protein change (HGVS p.) | p.Pro689fs |
| Coding change (HGVS c.) | c.2066del |
| MANE Select transcript | [NM_000096](https://www.ncbi.nlm.nih.gov/nuccore/NM_000096) |
| dbSNP | [rs386134147](https://www.ncbi.nlm.nih.gov/snp/rs386134147/) |
| Variant type | Deletion |
| Location | chr3:149186531-149186531 (GRCh38) |
| ClinVar | [VCV42143](https://www.ncbi.nlm.nih.gov/clinvar/variation/42143/) |

**All HGVS expressions:** `NC_000003.11:g.148904319del`, `NC_000003.12:g.149186532del`, `NG_011800.2:g.40515del`, `NM_000096.3:c.2066del`, `NM_000096.3:c.2066delC`, `NM_000096.4:c.2066del`

## 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 -1.242, GERP -4.14 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.624, pLI 4.9953e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 19**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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 **0.0131%** (nfe) · FAF95 0.0114% · FAF99 0.0107% · 155/1,179,978 in the highest group · 156/1,614,030 alleles overall — ultra-rare (popmax 0.0131%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0131% | 7,613 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |

*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}

**CP** population constraint: LOEUF 0.624, pLI 4.9953e-07, missense-Z 1.607; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **aceruloplasminemia** — Definitive (AR)

## Protein context {#protein}

Residue **689** lies in the plastocyanin-like 4 domain; a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 93.79, 90% of residues very-high.

**4 experimental structure(s)** (PDB): [1KCW](https://www.rcsb.org/structure/1KCW), [2J5W](https://www.rcsb.org/structure/2J5W), [4EJX](https://www.rcsb.org/structure/4EJX), [4ENZ](https://www.rcsb.org/structure/4ENZ).

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

*Describes the biological roles of CP (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.*

**How this variant is thought to act:** CP's established molecular role includes ferroxidase activity. p.Pro689fs falls in the plastocyanin-like 4 domain. In Reactome, CP is annotated in disease pathway(s) including **Defective CP causes aceruloplasminemia (ACERULOP)**, **Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)**.

**Disease mechanism (Reactome):** CP loss or alteration is curated in [Defective CP causes aceruloplasminemia (ACERULOP)](https://reactome.org/content/detail/R-HSA-5619060), [Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)](https://reactome.org/content/detail/R-HSA-5619049).

### Pathways affected {#pathways}

CP participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CP causes aceruloplasminemia (ACERULOP)](https://reactome.org/content/detail/R-HSA-5619060) | curated |
| ⚕ [Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)](https://reactome.org/content/detail/R-HSA-5619049) | curated |
| [Iron uptake and transport](https://reactome.org/content/detail/R-HSA-917937) | curated |
| [Metal ion SLC transporters](https://reactome.org/content/detail/R-HSA-425410) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |

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

**Molecular function:** ferroxidase activity, glutathione peroxidase activity, oxidoreductase activity, acting on metal ions, oxygen as acceptor, phospholipid-hydroperoxide glutathione peroxidase activity, protein-folding chaperone binding.

**Biological process:** intracellular copper ion homeostasis, intracellular iron ion homeostasis.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-22.

**Submitter consensus:** conflicting (5 Pathogenic, 1 Likely pathogenic).

**Submission history:** 6 submissions (2013–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2023-10-25 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-05 |
| GeneReviews | Pathogenic | no assertion criteria provided | curation | 2013-04-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-31 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-14 |

## Associated conditions {#conditions}

[neurodegeneration with brain iron accumulation](https://sugi.bio/atlas/disease/neurodegeneration-with-brain-iron-accumulation/), [aceruloplasminemia](https://sugi.bio/atlas/disease/aceruloplasminemia/).

**Reported phenotype names (ClinVar):** Neurodegeneration with brain iron accumulation, Deficiency of ferroxidase, CP-related disorder, not provided, CP-related condition, none provided, Deficiency of ceruloplasmin, Ceruloplasmin deficiency, Familial apoceruloplasmin deficiency, Hereditary ceruloplasmin deficiency.

## Similar variants {#similar}

Related CP variant pages (same residue, condition, or type): [CP p.Pro689Ser](/variant/cp-p-pro689ser), [CP c.607+1del](/variant/cp-c-607-plus-1del), [CP p.Met1*](/variant/cp-p-met1-star), [CP c.2286-15_2286-14del](/variant/cp-c-2286-minus-15-2286-minus-14del), [CP c.2286-15del](/variant/cp-c-2286-minus-15del), [CP c.2286-4del](/variant/cp-c-2286-minus-4del), [CP c.2078-75_2241del](/variant/cp-c-2078-minus-75-2241del), [CP p.Ala675fs](/variant/cp-p-ala675fs).

### 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 42143). 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.*