Is VWF p.Pro2591= (c.7773C>T) pathogenic?

VWF p.Pro2591= (c.7773C>T) is classified Conflicting classifications of pathogenicity in VWF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-12). Ultra-rare (popmax 0.025%, amr); Associated with Inborn genetic diseases.

What condition is associated with VWF p.Pro2591= (c.7773C>T)?

VWF p.Pro2591= (c.7773C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VWF p.Pro2591= (c.7773C>T) in the general population?

VWF p.Pro2591= (c.7773C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

VWF p.Pro2591=

c.7773C>T · VCV4541677

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -15	GERP -2.9
Overall
CADD	0.007	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/60,010 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00595% 96/1,613,366 alleles · ultra-rare exomes 84/1,461,252 · genomes 12/152,114 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,001
Remaining individualsnot grpmax-eligible	0.008%	12,498
African / African-American	0.00667%	14,992
European (non-Finnish)	0.00602%	16,619

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.Pro2591=
Coding: c.7773C>T
MANE Select: NM_000552
Type: single nucleotide variant
Location: chr12:5967600 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Residue 2591: the vwfc 3 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VWF p.Glu383Ter Pathogenic ★★ same condition
VWF p.Ala1207Ser Uncertain significance ★★ ⚠ same condition
VWF p.Ala1420Thr Uncertain significance ★★ same condition
VWF p.Ala2155Ser Uncertain significance ★★ ⚠ same condition
VWF p.Ala465Pro Uncertain significance ★★ same condition
VWF p.Ala54Val Uncertain significance ★★ ⚠ same condition
VWF p.Arg1342His Uncertain significance ★★ ⚠ same condition
VWF p.Arg1392Gln 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-pro2591 (accessed [today's date]).

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