Is WFS1 p.Pro44Ser (c.130C>T) pathogenic?

WFS1 p.Pro44Ser (c.130C>T) is classified Uncertain significance in WFS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-10). AlphaMissense: likely benign (0.0722); Very rare (popmax 8.59e-05%, nfe).

How common is WFS1 p.Pro44Ser (c.130C>T) in the general population?

WFS1 p.Pro44Ser (c.130C>T) is very rare (popmax 8.59e-05%, nfe) (gnomAD).

What do computational predictors say about WFS1 p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

WFS1 p.Pro44Ser

c.130C>T · rs766861457 · VCV2831051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.59e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83	GERP -2.8
Regional constraint	o/e 1.43	unconstrained · MANE · 25 kb · p 2.5e-52 · regional, not allelic
Overall
CADD	0.699	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.59e-05% European (non-Finnish) · 1/1,164,576 alleles

Overall 6.99e-05% 1/1,429,926 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: WFS1
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_006005
dbSNP: rs766861457
Type: single nucleotide variant
Location: chr4:6277585 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.85
Residue 44: the 'interaction with atp6v1a' region; the 'disordered' region

Full WFS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

WFS1 p.Pro44= Conflicting classifications of pathogenicity ★ same residue
WFS1 p.Pro44Thr Uncertain significance ★ ⚠ same residue
WFS1 c.233-1G>C Pathogenic/Likely pathogenic ★★ same type
WFS1 c.316-2A>G Pathogenic ★★ same type
WFS1 c.460+1G>A Pathogenic ★★ same type
WFS1 c.631+1G>A Likely pathogenic ★★ same type
WFS1 c.861+1G>A Pathogenic/Likely pathogenic ★★ same type
WFS1 c.861+2T>C 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/wfs1-p-pro44ser (accessed [today's date]).

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