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.114C>T (p.Phe38=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4 & BP7). A case carrying the c.114C>T (p.Phe38=) variant was also found to carry the ClinGen VWD VCEP curated pathogenic variant c.2435del. The case is asserted to be VWD 3 which is typically a biallelic variant but there is not a second variant in this case curated pathogenic (PMID 16321553). Additionally, there are 8 submissions to ClinVar for this variant but for the submissions indicating affected status as yes, all classify the variant as likely benign. 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 (VWD VCEP specifications v1l)
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 -5.4 | GERP -4.6 |
| Overall | ||
| CADD | 2.158 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.48% | 208 |
| Remaining individualsnot grpmax-eligible | 0.206% | 485 |
| Finnishnot grpmax-eligible | 0.108% | 928 |
| African / African-American | 0.0813% | 1,231 |
| Admixed American | 0.0217% | 4,617 |
| South Asian | 0.0176% | 5,692 |
| Middle Eastern | 0.0165% | 6,062 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00676% | 14,803 |
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.Phe38=
- Coding
- c.114C>T
- MANE Select
- NM_000552
- dbSNP
- rs2229443
- Type
- single nucleotide variant
- Location
- chr12:6121280 (GRCh38)
- Gene constraint
- LOEUF 0.639 · pLI <0.01 (gnomAD)
- Residue 38
- the vwfd 1 domain; a disulfide bond
Disease context
hereditary von Willebrand disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor 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-phe38 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown