# NM_000096.4(CP):c.991C>A (p.Pro331Thr)

https://sugi.bio/variant/cp-p-pro331thr

## Summary

**CP p.Pro331Thr (c.991C>A)** is classified **Uncertain significance** in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.099); Very rare (popmax 8.48e-05%, nfe); Associated with aceruloplasminemia.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs376348284 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the CP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro331Thr |
| Coding change (HGVS c.) | c.991C>A |
| MANE Select transcript | [NM_000096](https://www.ncbi.nlm.nih.gov/nuccore/NM_000096) |
| dbSNP | [rs376348284](https://www.ncbi.nlm.nih.gov/snp/rs376348284/) |
| Variant type | single nucleotide variant |
| Location | chr3:149207408-149207408 (GRCh38) |
| ClinVar | [VCV1395240](https://www.ncbi.nlm.nih.gov/clinvar/variation/1395240/) |

**All HGVS expressions:** `NC_000003.11:g.148925195G>T`, `NC_000003.12:g.149207408G>T`, `NG_011800.3:g.19638C>A`, `NM_000096.4:c.991C>A`, `NR_046371.2:n.1028C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.099)
- REVEL 0.519 (indeterminate)
- SaProt LLR -8.248 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 8.699, GERP 2.22, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.3**. 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 1.02** across the covering region of the MANE Select transcript (149,198,511–149,221,792), spanning 23,281 bp. Chi-square p 0.56. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,838 in the highest group · 1/1,461,686 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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 **331** lies in the plastocyanin-like 2 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.Pro331Thr 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-27 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CP variant pages (same residue, condition, or type): [CP p.Pro331=](/variant/cp-p-pro331), [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).

### 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 1395240). 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.*