Is VWF p.Phe716Val (c.2146T>G) pathogenic?

VWF p.Phe716Val (c.2146T>G) is classified Uncertain significance in VWF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.7932); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with VWF p.Phe716Val (c.2146T>G)?

VWF p.Phe716Val (c.2146T>G) is associated with Inborn genetic diseases (ClinVar).

How common is VWF p.Phe716Val (c.2146T>G) in the general population?

VWF p.Phe716Val (c.2146T>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about VWF p.Phe716Val (c.2146T>G)?

AlphaMissense predicts likely pathogenic (score 0.7932) — an in-silico prediction, not a clinical call.

VWF p.Phe716Val

c.2146T>G · rs771858185 · VCV801296

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7932	likely pathogenic
REVEL	0.373	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 97 kb · p 0.18 · regional, not allelic
Overall
CADD	25.3	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 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000805% 13/1,614,144 alleles · very rare exomes 8/1,461,892 · genomes 5/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.004%	24,982
European (non-Finnish)	0.000339%	295,013

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.Phe716Val
Coding: c.2146T>G
MANE Select: NM_000552
dbSNP: rs771858185
Type: single nucleotide variant
Location: chr12:6052583 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Residue 716: a β-strand

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-phe716val (accessed [today's date]).

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