# NM_000097.7(CPOX):c.991C>T (p.Arg331Trp)

https://sugi.bio/variant/cpox-p-arg331trp

## Summary

**CPOX p.Arg331Trp (c.991C>T)** is classified **Uncertain significance** in CPOX (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-26). AlphaMissense: ambiguous (0.4147); Very rare (popmax 0.000424%, nfe); Associated with hereditary coproporphyria.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs121917866 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the CPOX gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to hereditary coproporphyria.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CPOX is a diagnostic-grade gene on 10 Genomics England panels |

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

- Abdominal pain — Very frequent (99-80%)
- Elevated urinary delta-aminolevulinic acid — Very frequent (99-80%)
- Abnormal circulating porphyrin concentration — Very frequent (99-80%)
- Atypical scarring of skin — Frequent (79-30%)
- Nausea — Frequent (79-30%)
- Distal muscle weakness — Frequent (79-30%)
- Episodic vomiting — Frequent (79-30%)
- Proximal muscle weakness in lower limbs — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006619/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPOX](https://sugi.bio/atlas/gene/CPOX/) |
| Protein change (HGVS p.) | p.Arg331Trp |
| Coding change (HGVS c.) | c.991C>T |
| MANE Select transcript | [NM_000097](https://www.ncbi.nlm.nih.gov/nuccore/NM_000097) |
| dbSNP | [rs121917866](https://www.ncbi.nlm.nih.gov/snp/rs121917866/) |
| Variant type | single nucleotide variant |
| Location | chr3:98585622-98585622 (GRCh38) |
| ClinVar | [VCV451](https://www.ncbi.nlm.nih.gov/clinvar/variation/451/) |

**All HGVS expressions:** `LRG_1077:g.12990C>T`, `LRG_1077t1:c.991C>T`, `NC_000003.11:g.98304466G>A`, `NC_000003.12:g.98585622G>A`, `NG_015994.2:g.12990C>T`, `NM_000097.7:c.991C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4147) — no call either way
- REVEL 0.876 (moderately pathogenic-leaning)
- SaProt LLR -13.212 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 3.584, GERP 0.9, phastCons 1 — highly conserved
- CADD: **PHRED 26.3**. 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 0.76** across the covering region of the MANE Select transcript (98,580,686–98,591,027), spanning 10,341 bp. Chi-square p 7.6e-05. 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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,900 in the highest group · 5/1,461,752 alleles overall — very rare (popmax 0.000424%, 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}

**CPOX** population constraint: LOEUF 0.8, pLI 0.00050093, missense-Z 0.24182. *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):

- **CPOX-related hereditary coproporphyria** — Definitive (SD)

## Protein context {#protein}

Residue **331** lies in a UniProt-annotated variant site (in hcp); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 80.32, 63% of residues very-high.

**1 experimental structure(s)** (PDB): [2AEX](https://www.rcsb.org/structure/2AEX).

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

*Describes the biological roles of CPOX (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:** CPOX's established molecular role includes coproporphyrinogen oxidase activity.


### Pathways affected {#pathways}

CPOX participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |

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

**Molecular function:** coproporphyrinogen oxidase activity, protein homodimerization activity.

**Biological process:** obsolete protoporphyrinogen IX biosynthetic process, heme B biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-26.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2001–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2001-05-01 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-26 |

## Associated conditions {#conditions}

[hereditary coproporphyria](https://sugi.bio/atlas/disease/hereditary-coproporphyria/).

**Reported phenotype names (ClinVar):** Hereditary coproporphyria, Coproporphyria, Hereditary coproporphyria porphyria, Porphyria hepatica coproporphyria, Porphyria hepatica II, CPRO deficiency, COPROPORPHYRINOGEN OXIDASE DEFICIENCY, CPO DEFICIENCY, CPOX DEFICIENCY, CPX DEFICIENCY.

## Similar variants {#similar}

Related CPOX variant pages (same residue, condition, or type): [CPOX p.Gln160Ter](/variant/cpox-p-gln160ter), [CPOX p.Glu201Lys](/variant/cpox-p-glu201lys), [CPOX p.Lys404Glu](/variant/cpox-p-lys404glu), [CPOX p.Arg60Gly](/variant/cpox-p-arg60gly), [CPOX p.Thr56Met](/variant/cpox-p-thr56met), [CPOX p.Val16Gly](/variant/cpox-p-val16gly), [CPOX c.1172+14A>G](/variant/cpox-c-1172-plus-14a-g), [CPOX c.556+9G>A](/variant/cpox-c-556-plus-9g-a).

### 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 451). 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.*