Is WFS1 p.Pro475= (c.1425C>T) pathogenic?

WFS1 p.Pro475= (c.1425C>T) is classified Benign/Likely benign in WFS1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-08-14). Very rare (popmax 0.00746%, nfe); Associated with Wolfram syndrome 1.

What condition is associated with WFS1 p.Pro475= (c.1425C>T)?

WFS1 p.Pro475= (c.1425C>T) is associated with Wolfram syndrome 1, WFS1-related disorder (ClinVar).

How common is WFS1 p.Pro475= (c.1425C>T) in the general population?

WFS1 p.Pro475= (c.1425C>T) is very rare (popmax 0.00746%, nfe) (gnomAD).

How is Wolfram syndrome inherited?

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

WFS1 p.Pro475=

c.1425C>T · rs370846103 · VCV916194

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Conditions

Wolfram syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -2.9
Overall
CADD	0.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00746% European (non-Finnish) · 88/1,180,028 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00577% 93/1,611,924 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00746%	13,409
African / African-American	0.004%	24,981
Remaining individualsnot grpmax-eligible	0.0016%	62,470
South Asian	0.0011%	91,088

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.Pro475=
Coding: c.1425C>T
MANE Select: NM_006005
dbSNP: rs370846103
Type: single nucleotide variant
Location: chr4:6301220 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.85

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: WFS1-related disorder

For Wolfram syndrome (Orphanet):

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

Similar variants

WFS1 p.Pro475Leu Uncertain significance ★★ ⚠ same residue
WFS1 p.Pro475His Uncertain significance ★ ⚠ same residue
WFS1 p.Pro475Ser Uncertain significance ★ ⚠ same residue
WFS1 c.233-1G>C Pathogenic/Likely pathogenic ★★ same condition
WFS1 c.460+1G>A Pathogenic ★★ same condition
WFS1 c.861+1G>A Pathogenic/Likely pathogenic ★★ same condition
WFS1 c.861+2T>C Pathogenic ★★ same condition
WFS1 p.Ala126Thr 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-pro475 (accessed [today's date]).

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