Is VWF p.Pro359= (c.1077C>T) pathogenic?

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.

What condition is associated with VWF p.Pro359= (c.1077C>T)?

VWF p.Pro359= (c.1077C>T) is associated with hereditary von Willebrand disease (ClinVar).

How common is VWF p.Pro359= (c.1077C>T) in the general population?

VWF p.Pro359= (c.1077C>T) is rare (popmax 0.462%, mid) (gnomAD).

How is Von Willebrand disease inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

VWF p.Pro359=

c.1077C>T · rs71582884 · VCV310086

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.462%, mid)

Conditions

hereditary von Willebrand disease

ClinGen expert panel — von Willebrand Disease VCEP

Likely Benign for hereditary von Willebrand disease. Applied ACMG criteria (verbatim):

BP7 BP4

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)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15
Overall
CADD	0.019	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.462% Middle Eastern · 28/6,062 alleles

Filtering AF 0.364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.35%

Overall 0.0693% 1,119/1,614,080 alleles · rare exomes 1,023/1,461,854 · genomes 96/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.462%	216
South Asian	0.397%	252
Remaining individualsnot grpmax-eligible	0.101%	992
Admixed American	0.0983%	1,017
European (non-Finnish)	0.049%	2,042
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277
African / African-American	0.012%	8,335
Finnishnot grpmax-eligible	0.0109%	9,145

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VWF
Protein: p.Pro359=
Coding: c.1077C>T
MANE Select: NM_000552
dbSNP: rs71582884
Type: single nucleotide variant
Location: chr12:6072363 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)

Full VWF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary von Willebrand disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Von Willebrand disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

VWF p.Arg1306Trp Pathogenic ★★★ ⚠ same condition
VWF p.Arg1308Cys Pathogenic ★★★ ⚠ same condition
VWF p.Arg1341Gln Pathogenic ★★★ ⚠ same condition
VWF p.Arg1374His Pathogenic ★★★ ⚠ same condition
VWF p.Arg1399Cys Pathogenic ★★★ same condition
VWF p.Arg1597Trp Pathogenic ★★★ same condition
VWF p.Arg1659Ter Pathogenic ★★★ same condition
VWF p.Arg324Ter Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vwf-p-pro359 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown