# NM_000096.4(CP):c.1038C>T (p.Ala346=)

https://sugi.bio/variant/cp-p-ala346

## Summary

**CP p.Ala346= (c.1038C>T)** is classified **Benign/Likely benign** in CP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-17). Rare (popmax 0.344%, sas); Associated with aceruloplasminemia.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs146895584 · 4 submitters · 1 linked condition · rare (popmax 0.344%, sas)

## For patients & families {#patients}

This is a change in the CP gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, 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.Ala346= |
| Coding change (HGVS c.) | c.1038C>T |
| MANE Select transcript | [NM_000096](https://www.ncbi.nlm.nih.gov/nuccore/NM_000096) |
| dbSNP | [rs146895584](https://www.ncbi.nlm.nih.gov/snp/rs146895584/) |
| Variant type | single nucleotide variant |
| Location | chr3:149206338-149206338 (GRCh38) |
| ClinVar | [VCV1164643](https://www.ncbi.nlm.nih.gov/clinvar/variation/1164643/) |

**All HGVS expressions:** `NC_000003.11:g.148924125G>A`, `NC_000003.12:g.149206338G>A`, `NG_011800.3:g.20708C>T`, `NM_000096.3:c.1038C>T`, `NM_000096.4:c.1038C>T`, `NR_046371.2:n.1075C>T`

## 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 0.531, GERP -4.44, phastCons 0.841 — weakly conserved position
- CADD: **PHRED 10.41**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.99 acceptor 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 **0.344%** (sas) · FAF95 0.312% · FAF99 0.3% · 313/91,066 in the highest group · 404/1,613,762 alleles overall — rare (popmax 0.344%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.344% | 291 |
| East Asian | 0.0959% | 1,043 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,125 |
| Admixed American | 0.0133% | 7,501 |
| African / African-American | 0.00267% | 37,508 |
| European (non-Finnish) | 0.00153% | 65,541 |

*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 **346** lies in a turn; the plastocyanin-like 2 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.Ala346= falls in the plastocyanin-like 2 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-17.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-09-26 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-17 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Deficiency of ferroxidase, CP-related disorder, Ovarian serous cystadenocarcinoma, not provided, Ceruloplasmin deficiency, Familial apoceruloplasmin deficiency, Hereditary ceruloplasmin deficiency, NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 10, Aceruloplasminemia, Deficiency of ceruloplasmin.

## Similar variants {#similar}

Related CP variant pages (same residue, condition, or type): [CP c.1208+1G>A](/variant/cp-c-1208-plus-1g-a), [CP c.2879-1G>T](/variant/cp-c-2879-minus-1g-t), [CP p.Arg901Ter](/variant/cp-p-arg901ter), [CP p.Gly195Arg](/variant/cp-p-gly195arg), [CP p.Gly650Arg](/variant/cp-p-gly650arg), [CP p.Gly708Ser](/variant/cp-p-gly708ser), [CP p.Leu919Pro](/variant/cp-p-leu919pro), [CP p.Val219Glu](/variant/cp-p-val219glu).

### 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 1164643). 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.*