# NM_000097.7(CPOX):c.222G>A (p.Val74=)

https://sugi.bio/variant/cpox-p-val74

## Summary

**CPOX p.Val74= (c.222G>A)** is classified **Benign/Likely benign** in CPOX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-16). Rare (popmax 0.529%, afr).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs368067440 · 3 submitters · rare (popmax 0.529%, afr)

## For patients & families {#patients}

This is a change in the CPOX gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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.*

**Support & next steps:** [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.Val74= |
| Coding change (HGVS c.) | c.222G>A |
| MANE Select transcript | [NM_000097](https://www.ncbi.nlm.nih.gov/nuccore/NM_000097) |
| dbSNP | [rs368067440](https://www.ncbi.nlm.nih.gov/snp/rs368067440/) |
| Variant type | single nucleotide variant |
| Location | chr3:98593283-98593283 (GRCh38) |
| ClinVar | [VCV732948](https://www.ncbi.nlm.nih.gov/clinvar/variation/732948/) |

**All HGVS expressions:** `LRG_1077:g.5329G>A`, `LRG_1077t1:c.222G>A`, `NC_000003.11:g.98312127C>T`, `NC_000003.12:g.98593283C>T`, `NG_015994.2:g.5329G>A`, `NM_000097.7:c.222G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.261, GERP -0.984 — fast-evolving / accelerated position
- CADD: **PHRED 10.2**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.22**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.22**.
- Population frequency (gnomAD v4.1): grpmax **0.529%** (afr) · FAF95 0.485% · FAF99 0.467% · 371/70,118 in the highest group · 432/1,461,154 alleles overall — rare (popmax 0.529%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.529% | 189 |
| Middle Eastern | 0.0783% | 1,277 |
| Admixed American | 0.05% | 2,000 |
| Remaining individuals (not grpmax-eligible) | 0.0283% | 3,530 |
| East Asian | 0.00246% | 40,622 |
| European (non-Finnish) | 0.00188% | 53,079 |

*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 **74** lies in a UniProt-annotated variant site (in hcp).

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-16.

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

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-16 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-06-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CPOX variant pages (same residue, condition, or type): [CPOX p.Val74Leu](/variant/cpox-p-val74leu), [CPOX p.Cys239Ter](/variant/cpox-p-cys239ter), [CPOX p.Gln160Ter](/variant/cpox-p-gln160ter), [CPOX p.Glu201Lys](/variant/cpox-p-glu201lys), [CPOX p.Lys404Glu](/variant/cpox-p-lys404glu), [CPOX c.811+5G>C](/variant/cpox-c-811-plus-5g-c), [CPOX p.Ala293Thr](/variant/cpox-p-ala293thr), [CPOX p.Ala83Val](/variant/cpox-p-ala83val).

### 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 732948). 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.*