Is WFS1 p.Val415Phe (c.1243G>T) pathogenic?

WFS1 p.Val415Phe (c.1243G>T) is classified Likely pathogenic in WFS1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-05-26). AlphaMissense: likely pathogenic (0.5741); Absent from gnomAD v4.1; Associated with cataract 41.

What condition is associated with WFS1 p.Val415Phe (c.1243G>T)?

WFS1 p.Val415Phe (c.1243G>T) is associated with cataract 41 (ClinVar).

How common is WFS1 p.Val415Phe (c.1243G>T) in the general population?

WFS1 p.Val415Phe (c.1243G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about WFS1 p.Val415Phe (c.1243G>T)?

AlphaMissense predicts likely pathogenic (score 0.5741) — an in-silico prediction, not a clinical call.

WFS1 p.Val415Phe

c.1243G>T · rs749886570 · VCV1702534

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5741 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 41

Computational evidence

Protein change
AlphaMissense	0.5741	likely pathogenic ✓ concordant with ClinVar
REVEL	0.753	pathogenic-leaning
SaProt	LLR -5.05	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 25 kb · p 2.5e-52 · regional, not allelic
Overall
CADD	20.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: WFS1
Protein: p.Val415Phe
Coding: c.1243G>T
MANE Select: NM_006005
dbSNP: rs749886570
Type: single nucleotide variant
Location: chr4:6301038 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.85
Residue 415: a UniProt-annotated variant site (in wfs1; greatly reduces protein expression compared to wild-type)

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

Disease context

cataract 41 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

WFS1 p.Val415Ile Uncertain significance ★★ ⚠ same residue
WFS1 p.Val415Leu Uncertain significance ★★ ⚠ same residue
WFS1 p.Val415del Pathogenic ★★ same residue
WFS1 p.Arg26Ter Pathogenic/Likely pathogenic ★★ same condition
WFS1 p.Arg42Ter Pathogenic/Likely pathogenic ★★ same condition
WFS1 p.Arg558Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
WFS1 p.Arg558His Pathogenic/Likely pathogenic ★★ ⚠ same condition
WFS1 p.Asp211Asn 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-val415phe (accessed [today's date]).

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