Is WFS1 p.Pro386= (c.1158C>T) pathogenic?

WFS1 p.Pro386= (c.1158C>T) is classified Benign/Likely benign in WFS1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-01). Rare (popmax 0.822%, afr); Associated with Wolfram syndrome 1.

What condition is associated with WFS1 p.Pro386= (c.1158C>T)?

WFS1 p.Pro386= (c.1158C>T) is associated with Wolfram syndrome 1 (ClinVar).

How common is WFS1 p.Pro386= (c.1158C>T) in the general population?

WFS1 p.Pro386= (c.1158C>T) is rare (popmax 0.822%, afr) (gnomAD).

How is Wolfram syndrome inherited?

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

WFS1 p.Pro386=

c.1158C>T · rs71524354 · VCV137912

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.822%, afr)

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 0.58	GERP 0.54, phastCons 0.097
Overall
CADD	7.536	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.822% African / African-American · 617/75,022 alleles

Filtering AF 0.769% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.747%

Overall 0.0433% 699/1,614,020 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.822%	122
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Middle Eastern	0.0495%	2,021
Admixed American	0.0351%	2,853
South Asian	0.0022%	45,543
European (non-Finnish)	0.00212%	47,201

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.Pro386=
Coding: c.1158C>T
MANE Select: NM_006005
dbSNP: rs71524354
Type: single nucleotide variant
Location: chr4:6300953 (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

For Wolfram syndrome (Orphanet):

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

Similar variants

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
WFS1 p.Arg26Ter Pathogenic/Likely pathogenic ★★ same condition
WFS1 p.Arg42Ter 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-pro386 (accessed [today's date]).

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