Is EYS p.Cys757Phe (c.2270G>T) pathogenic?

EYS p.Cys757Phe (c.2270G>T) is classified Uncertain significance in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: ambiguous (0.4389); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EYS p.Cys757Phe (c.2270G>T)?

EYS p.Cys757Phe (c.2270G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EYS p.Cys757Phe (c.2270G>T) in the general population?

EYS p.Cys757Phe (c.2270G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EYS p.Cys757Phe (c.2270G>T)?

AlphaMissense predicts ambiguous (score 0.4389) — an in-silico prediction, not a clinical call.

EYS p.Cys757Phe

c.2270G>T · rs2533459552 · VCV3091327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4389 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4389	ambiguous
REVEL	0.673	pathogenic-leaning
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 -0.1	GERP -0.043
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	19.79	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.Cys757Phe
Coding: c.2270G>T
MANE Select: NM_001142800
dbSNP: rs2533459552
Type: single nucleotide variant
Location: chr6:64945904 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 757: the egf-like 9; calcium-binding domain; a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EYS p.Cys757Arg Uncertain significance ★★ same residue
EYS p.Cys757= Likely benign ★ same residue
EYS p.Ala1174Glu Uncertain significance ★★ same condition
EYS p.Ala1465Thr Uncertain significance ★★ ⚠ same condition
EYS p.Ala1520Asp Uncertain significance ★★ ⚠ same condition
EYS p.Ala1520Gly Uncertain significance ★★ ⚠ same condition
EYS p.Ala1984Thr Uncertain significance ★★ same condition
EYS p.Ala2728Val Uncertain significance ★★ ⚠ 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/eys-p-cys757phe (accessed [today's date]).

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