Is WFS1 p.Pro52Ser (c.154C>T) pathogenic?

WFS1 p.Pro52Ser (c.154C>T) is classified Uncertain significance in WFS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0717); Ultra-rare (popmax 0.031%, afr); Associated with Inborn genetic diseases.

What condition is associated with WFS1 p.Pro52Ser (c.154C>T)?

WFS1 p.Pro52Ser (c.154C>T) is associated with Inborn genetic diseases, type 2 diabetes mellitus, cataract 41 (ClinVar).

How common is WFS1 p.Pro52Ser (c.154C>T) in the general population?

WFS1 p.Pro52Ser (c.154C>T) is ultra-rare (popmax 0.031%, afr) (gnomAD).

What do computational predictors say about WFS1 p.Pro52Ser (c.154C>T)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

WFS1 p.Pro52Ser

c.154C>T · rs111773340 · VCV1418122

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.031%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -6.85	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 0.87	GERP -1.3
Regional constraint	o/e 1.43	unconstrained · MANE · 25 kb · p 2.5e-52 · regional, not allelic
Overall
CADD	5.539	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 0.031% African / African-American · 23/74,260 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0179%

Overall 0.00159% 25/1,575,886 alleles · ultra-rare exomes 9/1,423,538 · genomes 16/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.031%	3,229
East Asian	0.00233%	42,936
European (non-Finnish)	8.61e-05%	1,160,988

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.Pro52Ser
Coding: c.154C>T
MANE Select: NM_006005
dbSNP: rs111773340
Type: single nucleotide variant
Location: chr4:6277609 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.85
Residue 52: the 'interaction with atp6v1a' region; the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus cataract 41 Wolfram syndrome 1 autosomal dominant nonsyndromic hearing loss 6 Wolfram-like syndrome

Similar variants

WFS1 p.Pro52Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
WFS1 p.Pro52Thr Conflicting classifications of pathogenicity ★ ⚠ 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-pro52ser (accessed [today's date]).

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