# NM_000096.4(CP):c.2684G>C (p.Gly895Ala)

https://sugi.bio/variant/cp-p-gly895ala

## Summary

**CP p.Gly895Ala (c.2684G>C)** is classified **Conflicting classifications of pathogenicity** in CP (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-09-10). AlphaMissense: ambiguous (0.555); Rare (popmax 0.28%, amr); Associated with aceruloplasminemia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs139633388 · 18 submitters · 1 linked condition · AlphaMissense ambiguous · rare (popmax 0.28%, amr)

## For patients & families {#patients}

This is a change in the CP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 18 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.Gly895Ala |
| Coding change (HGVS c.) | c.2684G>C |
| MANE Select transcript | [NM_000096](https://www.ncbi.nlm.nih.gov/nuccore/NM_000096) |
| dbSNP | [rs139633388](https://www.ncbi.nlm.nih.gov/snp/rs139633388/) |
| Variant type | single nucleotide variant |
| Location | chr3:149178609-149178609 (GRCh38) |
| ClinVar | [VCV42054](https://www.ncbi.nlm.nih.gov/clinvar/variation/42054/) |

**All HGVS expressions:** `NC_000003.11:g.148896396C>G`, `NC_000003.12:g.149178609C>G`, `NG_011800.3:g.48437G>C`, `NM_000096.4:c.2684G>C`, `NR_046371.2:n.2508G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.555) — no call either way
- REVEL 0.947 (strongly pathogenic-leaning)
- SaProt LLR -9.534 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 7.711, GERP 2.22, phastCons 1 — highly conserved
- CADD: **PHRED 25.6**. 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 0.80** across the covering region of the MANE Select transcript (149,173,717–149,198,510), spanning 24,793 bp. Chi-square p 2.5e-07. 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 **0.28%** (amr) · FAF95 0.246% · FAF99 0.232% · 168/59,932 in the highest group · 2,940/1,611,726 alleles overall — rare (popmax 0.28%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.28% | 357 |
| European (non-Finnish) | 0.213% | 469 |
| Remaining individuals (not grpmax-eligible) | 0.179% | 557 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.125% | 799 |
| Finnish (not grpmax-eligible) | 0.119% | 839 |
| Middle Eastern | 0.033% | 3,030 |
| African / African-American | 0.0294% | 3,402 |
| South Asian | 0.0077% | 12,993 |
| East Asian | 0.00223% | 44,810 |

*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 **895** lies in a β-strand; the plastocyanin-like 5 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.Gly895Ala 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-09-10.

**Submitter consensus:** conflicting (15 Uncertain significance, 2 Likely benign, 1 Pathogenic).

**Submission history:** 18 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-03-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-17 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-12 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-09-10 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Mendelics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-27 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-07-17 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-08-09 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2023-02-05 |
| GeneReviews | Pathogenic | no assertion criteria provided | curation | 2013-04-18 |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-09-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Deficiency of ferroxidase, not specified, not provided, CP-related disorder, CP-related condition, AllHighlyPenetrant, none provided, Deficiency of ceruloplasmin, Aceruloplasminemia, Ceruloplasmin deficiency.

## Similar variants {#similar}

Related CP variant pages (same residue, condition, or type): [CP p.Gly895=](/variant/cp-p-gly895), [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 42054). 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.*