Is VWF p.Pro653Ser (c.1957C>T) pathogenic?

VWF p.Pro653Ser (c.1957C>T) is classified Uncertain significance in VWF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-14). AlphaMissense: likely benign (0.0971); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with VWF p.Pro653Ser (c.1957C>T)?

VWF p.Pro653Ser (c.1957C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VWF p.Pro653Ser (c.1957C>T) in the general population?

VWF p.Pro653Ser (c.1957C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VWF p.Pro653Ser (c.1957C>T)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

VWF p.Pro653Ser

c.1957C>T · rs2497207522 · VCV2230174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.346	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 97 kb · p 0.18 · regional, not allelic
Overall
CADD	21.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VWF
Protein: p.Pro653Ser
Coding: c.1957C>T
MANE Select: NM_000552
dbSNP: rs2497207522
Type: single nucleotide variant
Location: chr12:6052772 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Residue 653: the til 2 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.Pro653Leu Uncertain significance ★ same residue
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

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-pro653ser (accessed [today's date]).

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