Is VWA2 p.Pro104= (c.312C>T) pathogenic?

VWA2 p.Pro104= (c.312C>T) is classified Likely benign in VWA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-02-12). Ultra-rare (popmax 0.0333%, amr); Associated with VWA2-related disorder.

What condition is associated with VWA2 p.Pro104= (c.312C>T)?

VWA2 p.Pro104= (c.312C>T) is associated with VWA2-related disorder (ClinVar).

How common is VWA2 p.Pro104= (c.312C>T) in the general population?

VWA2 p.Pro104= (c.312C>T) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

VWA2 p.Pro104=

c.312C>T · rs376574990 · VCV3051516

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Conditions

VWA2-related disorder

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 0.42	GERP 0.75, phastCons 0.95
Overall
CADD	10.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/59,998 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.019% 307/1,614,020 alleles · ultra-rare exomes 287/1,461,838 · genomes 20/152,182 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,000
Remaining individualsnot grpmax-eligible	0.024%	4,166
European (non-Finnish)	0.0231%	4,338

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: VWA2
Protein: p.Pro104=
Coding: c.312C>T
MANE Select: NM_001272046
dbSNP: rs376574990
Type: single nucleotide variant
Location: chr10:114261236 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.02
Residue 104: the vwfa 1 domain

Full VWA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

VWA2-related disorder

Similar variants

VWA2 p.Ser16Phe Uncertain significance ★ ⚠ same condition
VWA2 p.Arg265Gln Uncertain significance ⚠ same condition
VWA2 c.-9T>A Benign same condition
VWA2 p.Ala92Thr Likely benign same condition
VWA2 p.Arg140= Likely benign same condition
VWA2 p.Arg69Met Likely benign same condition
VWA2 p.Asn216= Likely benign same condition
VWA2 p.Glu252= Likely benign 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/vwa2-p-pro104 (accessed [today's date]).

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