Is EYS p.Cys280Phe (c.839G>T) pathogenic?

EYS p.Cys280Phe (c.839G>T) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-25). AlphaMissense: ambiguous (0.5038); Absent from gnomAD v4.1.

How common is EYS p.Cys280Phe (c.839G>T) in the general population?

EYS p.Cys280Phe (c.839G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EYS p.Cys280Phe (c.839G>T)?

AlphaMissense predicts ambiguous (score 0.5038) — an in-silico prediction, not a clinical call.

EYS p.Cys280Phe

c.839G>T · rs1766004190 · VCV958208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5038 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5038	ambiguous
REVEL	0.527	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.26	GERP -1.4, phastCons 0.088
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	18.43	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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: EYS
Protein: p.Cys280Phe
Coding: c.839G>T
MANE Select: NM_001142800
dbSNP: rs1766004190
Type: single nucleotide variant
Location: chr6:65490617 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 280: the egf-like 3 domain; a disulfide bond

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

Similar variants

EYS p.Cys280= Likely benign ★ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same type
EYS c.1056+3A>C Likely pathogenic ★★ same type
EYS c.1057-1G>A Likely pathogenic ★★ same type
EYS c.1184+1G>A Pathogenic/Likely pathogenic ★★ same type
EYS c.1184+1G>T Likely pathogenic ★★ same type
EYS c.1185-1G>A Likely pathogenic ★★ same type
EYS c.1299+1G>T Pathogenic/Likely pathogenic ★★ same type

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/eys-p-cys280phe (accessed [today's date]).

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