Is WFS1 p.Ser855= (c.2565A>T) pathogenic?

WFS1 p.Ser855= (c.2565A>T) is classified Likely benign in WFS1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-26). Ultra-rare (popmax 0.0134%, eas); Associated with autosomal dominant nonsyndromic hearing loss 6.

What condition is associated with WFS1 p.Ser855= (c.2565A>T)?

WFS1 p.Ser855= (c.2565A>T) is associated with autosomal dominant nonsyndromic hearing loss 6, type 2 diabetes mellitus, cataract 41 (ClinVar).

How common is WFS1 p.Ser855= (c.2565A>T) in the general population?

WFS1 p.Ser855= (c.2565A>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

WFS1 p.Ser855=

c.2565A>T · rs1046316 · VCV391382

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

autosomal dominant nonsyndromic hearing loss 6

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 -5.9	GERP -3.4
Overall
CADD	0.042	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,884 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00236% 38/1,612,838 alleles · ultra-rare exomes 29/1,460,546 · genomes 9/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,481
Remaining individualsnot grpmax-eligible	0.0112%	8,927
South Asian	0.00769%	13,011
Admixed American	0.005%	20,001
African / African-American	0.00133%	75,048
European (non-Finnish)	0.00119%	84,282

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.Ser855=
Coding: c.2565A>T
MANE Select: NM_006005
dbSNP: rs1046316
Type: single nucleotide variant
Location: chr4:6302360 (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

autosomal dominant nonsyndromic hearing loss 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus cataract 41 Wolfram syndrome 1 Wolfram-like syndrome

Similar variants

WFS1 p.Ser855Pro Benign/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+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

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-ser855 (accessed [today's date]).

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