Is WFS1 p.Pro504Leu (c.1511C>T) pathogenic?

WFS1 p.Pro504Leu (c.1511C>T) is classified Pathogenic/Likely pathogenic in WFS1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.7965); Very rare (popmax 0.00667%, amr); Associated with WFS1-related disorder.

What condition is associated with WFS1 p.Pro504Leu (c.1511C>T)?

WFS1 p.Pro504Leu (c.1511C>T) is associated with WFS1-related disorder, type 2 diabetes mellitus, cataract 41 (ClinVar).

How common is WFS1 p.Pro504Leu (c.1511C>T) in the general population?

WFS1 p.Pro504Leu (c.1511C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about WFS1 p.Pro504Leu (c.1511C>T)?

AlphaMissense predicts likely pathogenic (score 0.7965) — an in-silico prediction, not a clinical call.

WFS1 p.Pro504Leu

c.1511C>T · rs28937892 · VCV4512

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.7965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

WFS1-related disorder

Computational evidence

Protein change
AlphaMissense	0.7965	likely pathogenic ✓ concordant with ClinVar
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -11.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 25 kb · p 2.5e-52 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,010 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00279% 45/1,611,276 alleles · very rare exomes 43/1,459,028 · genomes 2/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
European (non-Finnish)	0.0033%	30,257
Remaining individualsnot grpmax-eligible	0.0032%	31,229

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.Pro504Leu
Coding: c.1511C>T
MANE Select: NM_006005
dbSNP: rs28937892
Type: single nucleotide variant
Location: chr4:6301306 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.85
Residue 504: a UniProt-annotated variant site (in wfs1)

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

Disease context

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

Similar variants

WFS1 p.Pro504Thr Uncertain significance ★★ ⚠ same residue
WFS1 p.Pro504Arg Uncertain significance ★ ⚠ same residue
WFS1 p.Pro504Gln Uncertain significance ★ ⚠ same residue
WFS1 p.Pro504Ser Uncertain significance ★ ⚠ same residue
WFS1 p.Pro504= 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+1G>A 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-pro504leu (accessed [today's date]).

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