Is VWF p.Pro2808fs (c.8419_8422dup) pathogenic?

VWF p.Pro2808fs (c.84198422dup) is classified Pathogenic/Likely pathogenic in VWF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-29). Very rare (popmax 0.000593%, nfe); Associated with VWF-related disorder.

What condition is associated with VWF p.Pro2808fs (c.8419_8422dup)?

VWF p.Pro2808fs (c.8419_8422dup) is associated with VWF-related disorder (ClinVar).

How common is VWF p.Pro2808fs (c.8419_8422dup) in the general population?

VWF p.Pro2808fs (c.8419_8422dup) is very rare (popmax 0.000593%, nfe) (gnomAD).

VWF p.Pro2808fs

c.8419_8422dup · rs1414503929 · VCV2628675

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

VWF-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (52 of 52) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.7	GERP 0.62, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,826 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,466 alleles · very rare exomes 6/1,461,252 · genomes 1/152,214 · joint denominator

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.Pro2808fs
Coding: c.8419_8422dup
MANE Select: NM_000552
dbSNP: rs1414503929
Type: Duplication
Location: chr12:5949034 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Residue 2808: the ctck domain; a β-strand

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

Disease context

VWF-related disorder

Similar variants

VWF p.Ala272fs Likely pathogenic ★ same condition
VWF p.Arg1205His Pathogenic ★★ ⚠ same condition
VWF p.Val2554fs Likely pathogenic ★★ same condition
VWF p.Arg2384Trp Uncertain significance ★★ ⚠ same condition
VWF p.Asn1722Asp Uncertain significance ★★ ⚠ same condition
VWF p.Cys2739Arg Uncertain significance ★★ ⚠ same condition
VWF p.Leu536Phe Uncertain significance ★★ same condition
VWF p.Pro1413Leu Uncertain significance ★★ 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-pro2808fs (accessed [today's date]).

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