Is VWF p.Pro770Ser (c.2308C>T) pathogenic?

VWF p.Pro770Ser (c.2308C>T) is classified Uncertain significance in VWF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). AlphaMissense: ambiguous (0.3509); Ultra-rare (popmax 0.0557%, eas); Associated with hemophilia A.

What condition is associated with VWF p.Pro770Ser (c.2308C>T)?

VWF p.Pro770Ser (c.2308C>T) is associated with hemophilia A (ClinVar).

How common is VWF p.Pro770Ser (c.2308C>T) in the general population?

VWF p.Pro770Ser (c.2308C>T) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

How is Hemophilia A inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about VWF p.Pro770Ser (c.2308C>T)?

AlphaMissense predicts ambiguous (score 0.3509) — an in-silico prediction, not a clinical call.

VWF p.Pro770Ser

c.2308C>T · rs149051646 · VCV1803277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3509 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, eas)

Conditions

hemophilia A

Computational evidence

Protein change
AlphaMissense	0.3509	ambiguous
REVEL	0.381	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 97 kb · p 0.18 · regional, not allelic
Overall
CADD	23.9	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 0.0557% East Asian · 25/44,880 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00211% 34/1,614,192 alleles · ultra-rare exomes 27/1,461,870 · genomes 7/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,795
South Asian	0.00659%	15,181
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	8.47e-05%	1,180,034

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.Pro770Ser
Coding: c.2308C>T
MANE Select: NM_000552
dbSNP: rs149051646
Type: single nucleotide variant
Location: chr12:6044425 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Residue 770: the 'amino-terminal' region; a β-strand

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

Disease context

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

For Hemophilia A (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

VWF p.Arg1306Trp Pathogenic ★★★ ⚠ same type
VWF p.Arg1308Cys Pathogenic ★★★ ⚠ same type
VWF p.Arg1315His Likely pathogenic ★★★ ⚠ same type
VWF p.Arg1315Leu Likely pathogenic ★★★ same type
VWF p.Arg1334Trp Likely pathogenic ★★★ ⚠ same type
VWF p.Arg1341Gln Pathogenic ★★★ ⚠ same type
VWF p.Arg1341Trp Pathogenic ★★★ ⚠ same type
VWF p.Arg1374His Pathogenic ★★★ ⚠ same type

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-pro770ser (accessed [today's date]).

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