Is WFS1 p.Phe341= (c.1023C>T) pathogenic?

WFS1 p.Phe341= (c.1023C>T) is classified Benign in WFS1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-03). Common (popmax 12.4%, mid) — too common for a highly-penetrant pathogenic allele; Associated with WFS1-Related Spectrum Disorders.

What condition is associated with WFS1 p.Phe341= (c.1023C>T)?

WFS1 p.Phe341= (c.1023C>T) is associated with WFS1-Related Spectrum Disorders, Wolfram syndrome 1, autosomal dominant nonsyndromic hearing loss 6 (ClinVar).

WFS1 p.Phe341=

Q: How common is WFS1 p.Phe341= (c.1023C>T) in the general population?

WFS1 p.Phe341= (c.1023C>T) is common (popmax 12.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1023C>T · rs56072215 · VCV45428

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 12.4%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

WFS1-Related Spectrum Disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.146	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.2	GERP -2.9
Overall
CADD	4.116	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.4% Middle Eastern · 749/6,062 alleles

Filtering AF 11.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.3%

Overall 6.84% 110,332/1,613,996 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	17.7%	6
Middle Easterngrpmax	12.4%	8
Ashkenazi Jewishnot grpmax-eligible	9.49%	11
European (non-Finnish)	7.77%	13
Remaining individualsnot grpmax-eligible	6.46%	15
South Asian	6.3%	16
Admixed American	3.83%	26
Finnishnot grpmax-eligible	2.86%	35
African / African-American	1.32%	76
East Asian	0.049%	2,039

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe341=
Coding: c.1023C>T
MANE Select: NM_006005
dbSNP: rs56072215
Type: single nucleotide variant
Location: chr4:6300818 (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

WFS1-Related Spectrum Disorders

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

Similar variants

WFS1 p.Phe341_Phe344del Uncertain significance ★★ 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-phe341 (accessed [today's date]).

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