Is EYS p.Cys669Phe (c.2006G>T) pathogenic?

EYS p.Cys669Phe (c.2006G>T) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-07). AlphaMissense: likely benign (0.1737); Ultra-rare (popmax 0.0204%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EYS p.Cys669Phe (c.2006G>T)?

EYS p.Cys669Phe (c.2006G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EYS p.Cys669Phe (c.2006G>T) in the general population?

EYS p.Cys669Phe (c.2006G>T) is ultra-rare (popmax 0.0204%, nfe) (gnomAD).

What do computational predictors say about EYS p.Cys669Phe (c.2006G>T)?

AlphaMissense predicts likely benign (score 0.1737) — an in-silico prediction, not a clinical call.

EYS p.Cys669Phe

c.2006G>T · rs780193024 · VCV2144774

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1737	likely benign
REVEL	0.571	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP -3
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	14.93	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

Grpmax group 0.0204% European (non-Finnish) · 234/1,145,104 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0174%

Overall 0.0159% 246/1,547,184 alleles · ultra-rare exomes 239/1,395,500 · genomes 7/151,684 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0204%	4,894
Remaining individualsnot grpmax-eligible	0.0167%	5,994
African / African-American	0.00275%	36,407

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: EYS
Protein: p.Cys669Phe
Coding: c.2006G>T
MANE Select: NM_001142800
dbSNP: rs780193024
Type: single nucleotide variant
Location: chr6:65295880 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 669: a disulfide bond; the egf-like 7 domain

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.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
EYS p.Ala2729Val Uncertain significance ★★ ⚠ same condition
EYS p.Ala315Thr 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-cys669phe (accessed [today's date]).

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