# NM_018451.5(CPAP):c.776C>T (p.Ala259Val)

https://sugi.bio/variant/cpap-p-ala259val

## Summary

**CPAP p.Ala259Val (c.776C>T)** is classified **Benign/Likely benign** in CPAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-22). AlphaMissense: likely benign (0.0908); Rare (popmax 0.148%, sas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs532917061 · 2 submitters · AlphaMissense likely benign · rare (popmax 0.148%, sas)

## For patients & families {#patients}

This is a change in the CPAP gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 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 | [CPAP](https://sugi.bio/atlas/gene/CPAP/) |
| Protein change (HGVS p.) | p.Ala259Val |
| Coding change (HGVS c.) | c.776C>T |
| MANE Select transcript | [NM_018451](https://www.ncbi.nlm.nih.gov/nuccore/NM_018451) |
| dbSNP | [rs532917061](https://www.ncbi.nlm.nih.gov/snp/rs532917061/) |
| Variant type | single nucleotide variant |
| Location | chr13:24909879-24909879 (GRCh38) |
| ClinVar | [VCV1620822](https://www.ncbi.nlm.nih.gov/clinvar/variation/1620822/) |

**All HGVS expressions:** `NC_000013.10:g.25484017G>A`, `NC_000013.11:g.24909879G>A`, `NG_009165.2:g.18069C>T`, `NM_018451.5:c.776C>T`, `NR_047594.2:n.943C>T`, `NR_047595.2:n.943C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0908)
- REVEL 0.013 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.02 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.899, GERP -0.716, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.61**. 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 0.96** across the covering region of the MANE Select transcript (24,883,180–24,913,025), spanning 29,845 bp. Chi-square p 0.11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.35 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.148%** (sas) · FAF95 0.128% · FAF99 0.12% · 135/91,042 in the highest group · 199/1,613,652 alleles overall — rare (popmax 0.148%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.148% | 674 |
| East Asian | 0.00891% | 11,222 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,831 |
| European (non-Finnish) | 0.00458% | 21,846 |
| Admixed American | 0.00333% | 29,998 |
| African / African-American | 0.00133% | 74,980 |

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-22.

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

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-03-22 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-19 |

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

## Similar variants {#similar}

Related CPAP variant pages (same residue, condition, or type): [CPAP p.Ala259=](/variant/cpap-p-ala259), [CPAP p.Ala259_Ser260insTer](/variant/cpap-p-ala259-ser260inster), [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).

### 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 1620822). 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.*