Is VWF p.Pro2145Ser (c.6433C>T) pathogenic?

VWF p.Pro2145Ser (c.6433C>T) is classified Uncertain significance in VWF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-11). AlphaMissense: likely benign (0.0738); Rare (popmax 0.296%, mid); Associated with thrombocytopenia.

What condition is associated with VWF p.Pro2145Ser (c.6433C>T)?

VWF p.Pro2145Ser (c.6433C>T) is associated with thrombocytopenia (ClinVar).

How common is VWF p.Pro2145Ser (c.6433C>T) in the general population?

VWF p.Pro2145Ser (c.6433C>T) is rare (popmax 0.296%, mid) (gnomAD).

What do computational predictors say about VWF p.Pro2145Ser (c.6433C>T)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

VWF p.Pro2145Ser

c.6433C>T · rs61750618 · VCV100439

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.296%, mid)

Conditions

thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.43	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.028	GERP -1.9
Regional constraint	o/e 0.89	unconstrained · MANE · 47 kb · p 0.00012 · regional, not allelic
Overall
CADD	0.267	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.296% Middle Eastern · 18/6,084 alleles

Filtering AF 0.191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.158%

Overall 0.0104% 168/1,614,070 alleles · rare exomes 160/1,461,888 · genomes 8/152,182 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.296%	338
South Asian	0.101%	990
Remaining individualsnot grpmax-eligible	0.0192%	5,207
Admixed American	0.005%	20,001
European (non-Finnish)	0.00364%	27,443

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.Pro2145Ser
Coding: c.6433C>T
MANE Select: NM_000552
dbSNP: rs61750618
Type: single nucleotide variant
Location: chr12:5994027 (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

thrombocytopenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VWF p.Pro2145Ala Uncertain significance ★ ⚠ same residue
VWF p.Arg854Gln Pathogenic ★★★ ⚠ same condition
VWF p.Pro1266Leu Likely benign ★★★ same condition
VWF p.Arg2464Cys Pathogenic/Likely pathogenic ★★ same condition
VWF p.Gln1311Ter Pathogenic ★★ same condition
VWF p.Leu2142Phe Uncertain significance ★★ same condition
VWF p.Thr1122Met Uncertain significance ★★ ⚠ same condition
VWF p.Val1279Ile 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-pro2145ser (accessed [today's date]).

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