Is WFS1 p.Pro7Ser (c.19C>T) pathogenic?

WFS1 p.Pro7Ser (c.19C>T) is classified Uncertain significance in WFS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-19). AlphaMissense: likely benign (0.0613); Very rare (popmax 0.00193%, amr); Associated with Wolfram syndrome 1.

What condition is associated with WFS1 p.Pro7Ser (c.19C>T)?

WFS1 p.Pro7Ser (c.19C>T) is associated with Wolfram syndrome 1, type 2 diabetes mellitus, cataract 41 (ClinVar).

How common is WFS1 p.Pro7Ser (c.19C>T) in the general population?

WFS1 p.Pro7Ser (c.19C>T) is very rare (popmax 0.00193%, amr) (gnomAD).

How is Wolfram syndrome inherited?

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

What do computational predictors say about WFS1 p.Pro7Ser (c.19C>T)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

WFS1 p.Pro7Ser

c.19C>T · rs1432704019 · VCV1386448

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00193%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wolfram syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -6.49	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 -0.74	GERP -2.4
Regional constraint	o/e 1.43	unconstrained · MANE · 25 kb · p 2.5e-52 · regional, not allelic
Overall
CADD	7.944	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 0.00193% Admixed American · 1/51,720 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000267%

Overall 0.000642% 10/1,556,804 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00193%	51,720
European (non-Finnish)	0.000782%	127,822

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.Pro7Ser
Coding: c.19C>T
MANE Select: NM_006005
dbSNP: rs1432704019
Type: single nucleotide variant
Location: chr4:6277474 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.85
Residue 7: the 'interaction with atp6v1a' region; the 'disordered' region

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

Disease context

Wolfram syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus cataract 41 autosomal dominant nonsyndromic hearing loss 6 Wolfram-like syndrome

For Wolfram syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

WFS1 p.Pro7Leu Uncertain significance ★★ ⚠ same residue
WFS1 p.Pro7= Likely benign ★★ same residue
WFS1 c.233-1G>C Pathogenic/Likely pathogenic ★★ same condition
WFS1 c.460+1G>A Pathogenic ★★ same condition
WFS1 c.861+2T>C Pathogenic ★★ same condition
WFS1 p.Ala126Thr Pathogenic/Likely pathogenic ★★ same condition
WFS1 p.Ala684Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
WFS1 p.Ala716Thr Pathogenic/Likely 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/wfs1-p-pro7ser (accessed [today's date]).

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