Is VWF p.Ser589Phe (c.1766C>T) pathogenic?

VWF p.Ser589Phe (c.1766C>T) is classified Uncertain significance in VWF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-20). AlphaMissense: ambiguous (0.3682); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with VWF p.Ser589Phe (c.1766C>T)?

VWF p.Ser589Phe (c.1766C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VWF p.Ser589Phe (c.1766C>T) in the general population?

VWF p.Ser589Phe (c.1766C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VWF p.Ser589Phe (c.1766C>T)?

AlphaMissense predicts ambiguous (score 0.3682) — an in-silico prediction, not a clinical call.

VWF p.Ser589Phe

c.1766C>T · VCV4200015

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3682 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,547,950)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3682	ambiguous
REVEL	0.736	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 97 kb · p 0.18 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,547,950). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: VWF
Protein: p.Ser589Phe
Coding: c.1766C>T
MANE Select: NM_000552
Type: single nucleotide variant
Location: chr12:6057036 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Residue 589: a disulfide bond

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-ser589phe (accessed [today's date]).

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