# NM_001130145.3(YAP1):c.57G>A (p.Pro19=)

https://sugi.bio/variant/yap1-p-pro19

## Summary

**YAP1 p.Pro19= (c.57G>A)** is classified **Likely benign** in YAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-31). Very rare (popmax 0.000549%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.000549%, nfe)

## For patients & families {#patients}

This is a change in the YAP1 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 | [YAP1](https://sugi.bio/atlas/gene/YAP1/) |
| Protein change (HGVS p.) | p.Pro19= |
| Coding change (HGVS c.) | c.57G>A |
| MANE Select transcript | [NM_001130145](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130145) |
| Variant type | single nucleotide variant |
| Location | chr11:102110905-102110905 (GRCh38) |
| ClinVar | [VCV4913629](https://www.ncbi.nlm.nih.gov/clinvar/variation/4913629/) |

**All HGVS expressions:** `NC_000011.10:g.102110905G>A`, `NC_000011.9:g.101981636G>A`, `NG_029530.2:g.5445G>A`, `NM_001130145.3:c.57G>A`, `NM_001195044.2:c.57G>A`, `NM_001282097.2:c.57G>A`, `NM_001282098.2:c.57G>A`, `NM_001282099.2:c.57G>A`, `NM_001282100.2:c.57G>A`, `NM_001282101.2:c.57G>A`, `NM_006106.5:c.57G>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 (below), not from a missing predictor score.
- Conservation: phyloP 1.977, GERP -2.07, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.1**. 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: **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 **0.000549%** (nfe) · FAF95 0.000197% · FAF99 0.00013% · 6/1,093,846 in the highest group · 6/1,433,746 alleles overall — very rare (popmax 0.000549%, 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}

**YAP1** population constraint: LOEUF 0.212, pLI 1, missense-Z 1.3479; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **19** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 58.46, 2% of residues very-high.

**41 experimental structure(s)** (PDB): [1JMQ](https://www.rcsb.org/structure/1JMQ), [1K5R](https://www.rcsb.org/structure/1K5R), [1K9Q](https://www.rcsb.org/structure/1K9Q), [1K9R](https://www.rcsb.org/structure/1K9R), [2LAW](https://www.rcsb.org/structure/2LAW), [2LAX](https://www.rcsb.org/structure/2LAX) — incl. mutant structure 1JMQ.

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

*Describes the biological roles of YAP1 (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:** YAP1's established molecular role includes transcription cis-regulatory region binding. p.Pro19= falls in the disordered region.


### Pathways affected {#pathways}

YAP1 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Developmental Lineage of Pancreatic Ductal Cells](https://reactome.org/content/detail/R-HSA-9925563) | curated |
| [Developmental Lineage of Pancreatic Endocrine Mid Progenitor Cells](https://reactome.org/content/detail/R-HSA-9981148) | curated |
| [Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin](https://reactome.org/content/detail/R-HSA-9725554) | curated |
| [EGR2 and SOX10-mediated initiation of Schwann cell myelination](https://reactome.org/content/detail/R-HSA-9619665) | curated |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | curated |
| [RUNX3 regulates YAP1-mediated transcription](https://reactome.org/content/detail/R-HSA-8951671) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Signaling by Hippo](https://reactome.org/content/detail/R-HSA-2028269) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [YAP1- and WWTR1 (TAZ)-stimulated gene expression](https://reactome.org/content/detail/R-HSA-2032785) | curated |
| [Formation of axial mesoderm](https://reactome.org/content/detail/R-HSA-9796292) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |
| [Zygotic genome activation (ZGA)](https://reactome.org/content/detail/R-HSA-9819196) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, transcription coregulator activity, transcription coactivator activity, transcription corepressor activity, DNA-binding transcription factor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, DNA damage response, positive regulation of gene expression, negative regulation of gene expression, positive regulation of cell growth, response to progesterone.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-31 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related YAP1 variant pages (same residue, condition, or type): [YAP1 p.Pro19Ser](/variant/yap1-p-pro19ser), [YAP1 p.Gln238Ter](/variant/yap1-p-gln238ter), [YAP1 p.Ser105Pro](/variant/yap1-p-ser105pro), [YAP1 p.Thr145Ser](/variant/yap1-p-thr145ser), [YAP1 p.Val55Leu](/variant/yap1-p-val55leu), [YAP1 c.1276+42G>C](/variant/yap1-c-1276-plus-42g-c), [YAP1 c.322-157A>G](/variant/yap1-c-322-minus-157a-g), [YAP1 c.322-247C>T](/variant/yap1-c-322-minus-247c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4913629). 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.*