Is VWF p.Ser614Phe (c.1841C>T) pathogenic?

VWF p.Ser614Phe (c.1841C>T) is classified Uncertain significance in VWF (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-01). AlphaMissense: likely benign (0.2814); Very rare (popmax 0.00713%, sas); Associated with hereditary von Willebrand disease.

What condition is associated with VWF p.Ser614Phe (c.1841C>T)?

VWF p.Ser614Phe (c.1841C>T) is associated with hereditary von Willebrand disease (ClinVar).

How common is VWF p.Ser614Phe (c.1841C>T) in the general population?

VWF p.Ser614Phe (c.1841C>T) is very rare (popmax 0.00713%, sas) (gnomAD).

How is Von Willebrand disease inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about VWF p.Ser614Phe (c.1841C>T)?

AlphaMissense predicts likely benign (score 0.2814) — an in-silico prediction, not a clinical call.

VWF p.Ser614Phe

c.1841C>T · rs776987924 · VCV627265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00713%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

hereditary von Willebrand disease

Computational evidence

Protein change
AlphaMissense	0.2814	likely benign
REVEL	0.665	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 97 kb · p 0.18 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00713% South Asian · 6/84,116 alleles

Filtering AF 0.00306% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.000432% 6/1,387,988 alleles · very rare

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.Ser614Phe
Coding: c.1841C>T
MANE Select: NM_000552
dbSNP: rs776987924
Type: single nucleotide variant
Location: chr12:6056961 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Residue 614: a β-strand; a disulfide bond

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

Disease context

hereditary von Willebrand disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Von Willebrand disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

VWF p.Arg1306Trp Pathogenic ★★★ ⚠ same condition
VWF p.Arg1308Cys Pathogenic ★★★ ⚠ same condition
VWF p.Arg1341Gln Pathogenic ★★★ ⚠ same condition
VWF p.Arg1374His Pathogenic ★★★ ⚠ same condition
VWF p.Arg1399Cys Pathogenic ★★★ same condition
VWF p.Arg1597Trp Pathogenic ★★★ same condition
VWF p.Arg1659Ter Pathogenic ★★★ same condition
VWF p.Arg324Ter Pathogenic ★★★ 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-ser614phe (accessed [today's date]).

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