Is VWF p.Pro1127Ser (c.3379C>T) pathogenic?

VWF p.Pro1127Ser (c.3379C>T) is classified Uncertain significance in VWF (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-07). AlphaMissense: likely benign (0.1745); Ultra-rare (popmax 0.0329%, mid).

How common is VWF p.Pro1127Ser (c.3379C>T) in the general population?

VWF p.Pro1127Ser (c.3379C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about VWF p.Pro1127Ser (c.3379C>T)?

AlphaMissense predicts likely benign (score 0.1745) — an in-silico prediction, not a clinical call.

VWF p.Pro1127Ser

c.3379C>T · rs139579968 · VCV3053159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1745	likely benign
REVEL	0.748	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP 0.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 30 kb · p 3e-21 · regional, not allelic
Overall
CADD	26.1	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 0.0329% Middle Eastern · 2/6,074 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.0212% 342/1,613,670 alleles · ultra-rare exomes 302/1,461,418 · genomes 40/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,037
European (non-Finnish)	0.0256%	3,907
African / African-American	0.0254%	3,944
Remaining individualsnot grpmax-eligible	0.0176%	5,678
Admixed American	0.00667%	15,001
East Asian	0.00445%	22,448
South Asian	0.0022%	45,423

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.Pro1127Ser
Coding: c.3379C>T
MANE Select: NM_000552
dbSNP: rs139579968
Type: single nucleotide variant
Location: chr12:6023631 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)

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

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-pro1127ser (accessed [today's date]).

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