# NM_018451.5(CPAP):c.672G>A (p.Pro224=)

https://sugi.bio/variant/cpap-p-pro224

## Summary

**CPAP p.Pro224= (c.672G>A)** is classified **Likely benign** in CPAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). Very rare (popmax 0.00446%, eas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the CPAP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [CPAP](https://sugi.bio/atlas/gene/CPAP/) |
| Protein change (HGVS p.) | p.Pro224= |
| Coding change (HGVS c.) | c.672G>A |
| MANE Select transcript | [NM_018451](https://www.ncbi.nlm.nih.gov/nuccore/NM_018451) |
| Variant type | single nucleotide variant |
| Location | chr13:24909983-24909983 (GRCh38) |
| ClinVar | [VCV4696094](https://www.ncbi.nlm.nih.gov/clinvar/variation/4696094/) |

**All HGVS expressions:** `NC_000013.10:g.25484121C>T`, `NC_000013.11:g.24909983C>T`, `NG_009165.2:g.17965G>A`, `NG_009165.3:g.36559G>A`, `NM_018451.5:c.672G>A`, `NR_047594.2:n.839G>A`, `NR_047595.2:n.839G>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 **acceptor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.306, GERP -3.36 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.83**. 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 **0.25**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,878 in the highest group · 9/1,461,870 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,439 |
| African / African-American | 0.00133% | 74,984 |
| South Asian | 0.0011% | 91,082 |
| European (non-Finnish) | 0.000424% | 236,007 |

*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}


Curated gene–disease validity (ClinGen):

- **microcephaly 6 with or without short stature** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 56.70, 24% of residues very-high.

**6 experimental structure(s)** (PDB): [5EIB](https://www.rcsb.org/structure/5EIB), [5ITZ](https://www.rcsb.org/structure/5ITZ), [7Q1E](https://www.rcsb.org/structure/7Q1E), [7Q1F](https://www.rcsb.org/structure/7Q1F), [7Z0F](https://www.rcsb.org/structure/7Z0F), [7Z0G](https://www.rcsb.org/structure/7Z0G).

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

*Describes the biological roles of CPAP (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:** CPAP's established molecular role includes transcription coactivator activity.


### Pathways affected {#pathways}

CPAP participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain](https://reactome.org/content/detail/R-HSA-6804115) | curated |

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

**Molecular function:** transcription coactivator activity, tubulin binding, protein kinase binding, protein domain specific binding, identical protein binding, gamma-tubulin binding.

**Biological process:** centriole replication, astral microtubule nucleation, positive regulation of receptor signaling pathway via JAK-STAT, regulation of centriole replication, positive regulation of centriole replication, microtubule polymerization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-04 |

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

## Similar variants {#similar}

Related CPAP variant pages (same residue, condition, or type): [CPAP p.Pro224Leu](/variant/cpap-p-pro224leu), [CPAP c.2693-2A>G](/variant/cpap-c-2693-minus-2a-g), [CPAP p.Arg1298Gln](/variant/cpap-p-arg1298gln), [CPAP p.Arg378Ter](/variant/cpap-p-arg378ter), [CPAP p.Arg566Ter](/variant/cpap-p-arg566ter), [CPAP p.Arg902Ter](/variant/cpap-p-arg902ter), [CPAP p.Arg958Ter](/variant/cpap-p-arg958ter), [CPAP p.Gln14Ter](/variant/cpap-p-gln14ter).

### 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 4696094). 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.*