# NM_000552.5(VWF):c.1077C>T (p.Pro359=)

https://sugi.bio/variant/vwf-p-pro359

## Summary

**VWF p.Pro359= (c.1077C>T)** is classified **Likely benign** in VWF (ClinVar, Expert panel, 4 submitters; last evaluated 2025-12-02). Rare (popmax 0.462%, mid); Associated with hereditary von Willebrand disease.

**At a glance:** Likely benign · review: Expert panel · rsID rs71582884 · 4 submitters · 1 linked condition · rare (popmax 0.462%, mid)

## For patients & families {#patients}

This is a change in the VWF gene that is classified as likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to hereditary von Willebrand disease.

*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, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (Worldwide) |
| Clinical trials | 82 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | VWF is a diagnostic-grade gene on 3 Genomics England panels |

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

- Abnormality of thrombocytes — Very frequent (99-80%)
- Abnormality of coagulation — Very frequent (99-80%)
- Reduced von Willebrand factor activity — Very frequent (99-80%)
- Abnormal platelet function — Very frequent (99-80%)
- Menorrhagia — Frequent (79-30%)
- Epistaxis — Frequent (79-30%)
- Gastrointestinal angiodysplasia — Frequent (79-30%)
- Bruising susceptibility — Frequent (79-30%)

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VWF](https://sugi.bio/atlas/gene/VWF/) |
| Protein change (HGVS p.) | p.Pro359= |
| Coding change (HGVS c.) | c.1077C>T |
| MANE Select transcript | [NM_000552](https://www.ncbi.nlm.nih.gov/nuccore/NM_000552) |
| dbSNP | [rs71582884](https://www.ncbi.nlm.nih.gov/snp/rs71582884/) |
| Variant type | single nucleotide variant |
| Location | chr12:6072363-6072363 (GRCh38) |
| ClinVar | [VCV310086](https://www.ncbi.nlm.nih.gov/clinvar/variation/310086/) |

**All HGVS expressions:** `LRG_587:g.57308C>T`, `LRG_587t1:c.1077C>T`, `NC_000012.11:g.6181529G>A`, `NC_000012.12:g.6072363G>A`, `NG_009072.2:g.57308C>T`, `NM_000552.4:c.1077C>T`, `NM_000552.5:c.1077C>T`

## 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 -14.724 — fast-evolving / accelerated position
- CADD: **PHRED 0.019**. 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 **0.462%** (mid) · FAF95 0.364% · FAF99 0.35% · 28/6,062 in the highest group · 1,119/1,614,080 alleles overall — rare (popmax 0.462%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.462% | 216 |
| South Asian | 0.397% | 252 |
| Remaining individuals (not grpmax-eligible) | 0.101% | 992 |
| Admixed American | 0.0983% | 1,017 |
| European (non-Finnish) | 0.049% | 2,042 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0439% | 2,277 |
| African / African-American | 0.012% | 8,335 |
| Finnish (not grpmax-eligible) | 0.0109% | 9,145 |

*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}

**VWF** population constraint: LOEUF 0.639, pLI 5.1954e-27, missense-Z 3.5269. *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):

- **hereditary von Willebrand disease** — Definitive (AD)
- **von Willebrand disease type 2B** — Definitive (AD)

## Protein context {#protein}


**48 experimental structure(s)** (PDB): [1AO3](https://www.rcsb.org/structure/1AO3), [1ATZ](https://www.rcsb.org/structure/1ATZ), [1AUQ](https://www.rcsb.org/structure/1AUQ), [1FE8](https://www.rcsb.org/structure/1FE8), [1FNS](https://www.rcsb.org/structure/1FNS), [1IJB](https://www.rcsb.org/structure/1IJB) — incl. mutant structure 1FNS.

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

*Describes the biological roles of VWF (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:** VWF's established molecular role includes protease binding. In Reactome, VWF is annotated in disease pathway(s) including **Defective F8 binding to von Willebrand factor**, **Defective F8 cleavage by thrombin**.

**Disease mechanism (Reactome):** VWF loss or alteration is curated in [Defective F8 binding to von Willebrand factor](https://reactome.org/content/detail/R-HSA-9672393), [Defective F8 cleavage by thrombin](https://reactome.org/content/detail/R-HSA-9672391), [Defective VWF binding to collagen type I ](https://reactome.org/content/detail/R-HSA-9845622).

### Pathways affected {#pathways}

VWF participates in **26 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F8 binding to von Willebrand factor](https://reactome.org/content/detail/R-HSA-9672393) | curated |
| ⚕ [Defective F8 cleavage by thrombin](https://reactome.org/content/detail/R-HSA-9672391) | curated |
| ⚕ [Defective VWF binding to collagen type I ](https://reactome.org/content/detail/R-HSA-9845622) | curated |
| ⚕ [Defective VWF cleavage by ADAMTS13 variant](https://reactome.org/content/detail/R-HSA-9845621) | curated |
| ⚕ [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298) | curated |
| ⚕ [Enhanced binding of GP1BA variant to VWF multimer:collagen ](https://reactome.org/content/detail/R-HSA-9845620) | curated |
| ⚕ [Enhanced cleavage of VWF variant by ADAMTS13](https://reactome.org/content/detail/R-HSA-9845619) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | curated |
| [GRB2:SOS provides linkage to MAPK signaling for Integrins ](https://reactome.org/content/detail/R-HSA-354194) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [Integrin signaling](https://reactome.org/content/detail/R-HSA-354192) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Platelet Adhesion to exposed collagen](https://reactome.org/content/detail/R-HSA-75892) | curated |
| [Platelet Aggregation (Plug Formation)](https://reactome.org/content/detail/R-HSA-76009) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [p130Cas linkage to MAPK signaling for integrins](https://reactome.org/content/detail/R-HSA-372708) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |

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

**Molecular function:** protease binding, integrin binding, collagen binding, immunoglobulin binding, identical protein binding, protein-folding chaperone binding.

**Biological process:** cell adhesion, blood coagulation, hemostasis, platelet activation, cell-substrate adhesion, positive regulation of intracellular signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-12-02.

**Submitter consensus:** conflicting (3 Likely benign, 1 Likely Benign).

**Submission history:** 4 submissions (2022–2025); classifications have been stable.

**ClinGen expert panel:** Likely Benign — von Willebrand Disease VCEP (hereditary von Willebrand disease). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BP7`, `BP4`.
*Considered but not met:* `BS1`.
Inheritance: Undetermined mode of inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000552.5:c.1077C>T (p.Pro359=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4 & BP7). Three submitters have reported this variant to ClinVar but no phenotype details are available. There are no reports of affected cases in the literature and the variant is absent from LOVD. In summary, this variant meets the criteria to be classified as likely benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP4, BP7. (VCEP specifications version 1)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50051 · approved 2025-12-02 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/ebf8f52f-ecdc-469b-9a2d-d41227f0945a).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen | Likely Benign | reviewed by expert panel | curation | 2025-12-02 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-12 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-17 |

## Associated conditions {#conditions}

[hereditary von Willebrand disease](https://sugi.bio/atlas/disease/hereditary-von-willebrand-disease/).

**Reported phenotype names (ClinVar):** Hereditary von Willebrand disease, not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related VWF variant pages (same residue, condition, or type): [VWF p.Arg1306Trp](/variant/vwf-p-arg1306trp), [VWF p.Arg1308Cys](/variant/vwf-p-arg1308cys), [VWF p.Arg1341Gln](/variant/vwf-p-arg1341gln), [VWF p.Arg1374His](/variant/vwf-p-arg1374his), [VWF p.Arg1399Cys](/variant/vwf-p-arg1399cys), [VWF p.Arg1597Trp](/variant/vwf-p-arg1597trp), [VWF p.Arg1659Ter](/variant/vwf-p-arg1659ter), [VWF p.Arg324Ter](/variant/vwf-p-arg324ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 310086). 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.*