Is WFS1 p.Ser3= (c.9C>T) pathogenic?

WFS1 p.Ser3= (c.9C>T) is classified Benign/Likely benign in WFS1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-01). Low-frequency (popmax 4.69%, afr); Associated with WFS1-Related Spectrum Disorders.

What condition is associated with WFS1 p.Ser3= (c.9C>T)?

WFS1 p.Ser3= (c.9C>T) is associated with WFS1-Related Spectrum Disorders, Wolfram syndrome 1, autosomal dominant nonsyndromic hearing loss 6 (ClinVar).

How common is WFS1 p.Ser3= (c.9C>T) in the general population?

WFS1 p.Ser3= (c.9C>T) is low-frequency (popmax 4.69%, afr) (gnomAD).

WFS1 p.Ser3=

c.9C>T · rs71524363 · VCV130752

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.69%, afr)

Conditions

WFS1-Related Spectrum Disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.40	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.92	GERP -2.4
Overall
CADD	13.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.69% African / African-American · 3,446/73,522 alleles

Filtering AF 4.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.5%

Overall 0.26% 4,041/1,554,850 alleles · low-frequency exomes 2,004/1,402,516 · genomes 2,037/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.69%	21
Middle Eastern	0.503%	199
Remaining individualsnot grpmax-eligible	0.411%	243
Admixed American	0.394%	254
South Asian	0.0201%	4,966
European (non-Finnish)	0.00835%	11,972
East Asian	0.00241%	41,444

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.Ser3=
Coding: c.9C>T
MANE Select: NM_006005
dbSNP: rs71524363
Type: single nucleotide variant
Location: chr4:6277464 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.85
Residue 3: the 'interaction with atp6v1a' region; the 'disordered' region

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

Disease context

WFS1-Related Spectrum Disorders

Also linked: Wolfram syndrome 1 autosomal dominant nonsyndromic hearing loss 6

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-ser3 (accessed [today's date]).

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