# NM_000096.4(CP):c.2309_2316dup (p.Phe773fs)

https://sugi.bio/variant/cp-p-phe773fs

## Summary

**CP p.Phe773fs (c.2309_2316dup)** is classified **Pathogenic** in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). Associated with aceruloplasminemia.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CP gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to aceruloplasminemia.

*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 recessive |
| Age of onset (of this condition) | Adult, Elderly |
| Prevalence | 1-9 / 1 000 000 (Japan) |
| Clinical trials | 44 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CP is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of Aceruloplasminemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Increased circulating ferritin concentration — Very frequent (99-80%)
- Hypochromic microcytic anemia — Very frequent (99-80%)
- Refractory anemia — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Aceruloplasminemia — Very frequent (99-80%)
- Retinal degeneration — Frequent (79-30%)
- Macular degeneration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009499/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.Phe773fs |
| Coding change (HGVS c.) | c.2309_2316dup |
| MANE Select transcript | [NM_000096](https://www.ncbi.nlm.nih.gov/nuccore/NM_000096) |
| Variant type | Duplication |
| Location | chr3:149183574-149183575 (GRCh38) |
| ClinVar | [VCV4730932](https://www.ncbi.nlm.nih.gov/clinvar/variation/4730932/) |

**All HGVS expressions:** `NC_000003.11:g.148901362_148901369dup`, `NC_000003.12:g.149183575_149183582dup`, `NG_011800.3:g.43464_43471dup`, `NM_000096.4:c.2309_2316dup`, `NR_046371.2:n.2133_2140dup`

## 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 4.622, GERP 1.9, phastCons 0.999 — highly conserved position (PP3-type support)
- 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 13 of 19**, 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.

*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 gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **773** lies in a turn; the plastocyanin-like 5 domain.

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.Phe773fs falls in the plastocyanin-like 5 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-11.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-11 |

## Associated conditions {#conditions}

[aceruloplasminemia](https://sugi.bio/atlas/disease/aceruloplasminemia/).

**Reported phenotype names (ClinVar):** Deficiency of ferroxidase, NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 10, Deficiency of ceruloplasmin, Aceruloplasminemia, Ceruloplasmin deficiency, Familial apoceruloplasmin deficiency, Hereditary ceruloplasmin deficiency.

## Same-residue context {#hotspot}

Residue **773** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [HPS3 p.Thr773fs](/variant/hps3-p-thr773fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CP variant pages (same residue, condition, or type): [HPS3 p.Thr773fs](/variant/hps3-p-thr773fs), [CP c.2286-14dup](/variant/cp-c-2286-minus-14dup), [CP p.Arg902fs](/variant/cp-p-arg902fs), [CP p.Glu410Ter](/variant/cp-p-glu410ter), [CP c.1209-11dup](/variant/cp-c-1209-minus-11dup), [CP c.2554+19dup](/variant/cp-c-2554-plus-19dup), [CP c.3018+9_3018+12dup](/variant/cp-c-3018-plus-9-3018-plus-12dup), [CP p.Asp203fs](/variant/cp-p-asp203fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4730932). 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.*