Is WFS1 p.Pro346= (c.1038G>A) pathogenic?

WFS1 p.Pro346= (c.1038G>A) is classified Benign/Likely benign in WFS1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0187%, afr); Associated with type 2 diabetes mellitus.

What condition is associated with WFS1 p.Pro346= (c.1038G>A)?

WFS1 p.Pro346= (c.1038G>A) is associated with type 2 diabetes mellitus, cataract 41, Wolfram syndrome 1 (ClinVar).

How common is WFS1 p.Pro346= (c.1038G>A) in the general population?

WFS1 p.Pro346= (c.1038G>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

WFS1 p.Pro346=

c.1038G>A · rs143886476 · VCV994102

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.059	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.1	GERP -3.2
Overall
CADD	5.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,972 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00149% 24/1,613,956 alleles · ultra-rare exomes 14/1,461,862 · genomes 10/152,094 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,355
Remaining individualsnot grpmax-eligible	0.0032%	31,251
Admixed American	0.00167%	60,000
Finnishnot grpmax-eligible	0.00156%	64,008
South Asian	0.0011%	91,058
European (non-Finnish)	0.000424%	235,994

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.Pro346=
Coding: c.1038G>A
MANE Select: NM_006005
dbSNP: rs143886476
Type: single nucleotide variant
Location: chr4:6300833 (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

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

WFS1 p.Pro346Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro346 (accessed [today's date]).

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