Is WFS1 p.Ser855Pro (c.2563T>C) pathogenic?

WFS1 p.Ser855Pro (c.2563T>C) is classified Benign/Likely benign in WFS1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.0909); Rare (popmax 0.212%, sas); Associated with monogenic diabetes.

What condition is associated with WFS1 p.Ser855Pro (c.2563T>C)?

WFS1 p.Ser855Pro (c.2563T>C) is associated with monogenic diabetes, Wolfram syndrome 1, WFS1-related disorder (ClinVar).

How common is WFS1 p.Ser855Pro (c.2563T>C) in the general population?

WFS1 p.Ser855Pro (c.2563T>C) is rare (popmax 0.212%, sas) (gnomAD).

What do computational predictors say about WFS1 p.Ser855Pro (c.2563T>C)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

WFS1 p.Ser855Pro

c.2563T>C · rs141833472 · VCV549512

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.212%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.428	indeterminate
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -3.4
Regional constraint	o/e 1.43	unconstrained · MANE · 25 kb · p 2.5e-52 · regional, not allelic
Overall
CADD	4.438	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 0.212% South Asian · 193/91,086 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.0392% 632/1,613,052 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.212%	472
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.0343%	2,914
Remaining individualsnot grpmax-eligible	0.0336%	2,976
Admixed American	0.0133%	7,504
Finnishnot grpmax-eligible	0.00159%	62,912
African / African-American	0.00133%	75,076

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.Ser855Pro
Coding: c.2563T>C
MANE Select: NM_006005
dbSNP: rs141833472
Type: single nucleotide variant
Location: chr4:6302358 (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

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wolfram syndrome 1 WFS1-related disorder

Similar variants

WFS1 p.Ser855= 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
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-ser855pro (accessed [today's date]).

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