Is EYS p.Cys696Phe (c.2087G>T) pathogenic?

EYS p.Cys696Phe (c.2087G>T) is classified Uncertain significance in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely benign (0.2768); Very rare (popmax 0.00548%, afr).

How common is EYS p.Cys696Phe (c.2087G>T) in the general population?

EYS p.Cys696Phe (c.2087G>T) is very rare (popmax 0.00548%, afr) (gnomAD).

What do computational predictors say about EYS p.Cys696Phe (c.2087G>T)?

AlphaMissense predicts likely benign (score 0.2768) — an in-silico prediction, not a clinical call.

EYS p.Cys696Phe

c.2087G>T · VCV3607541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00548%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2768	likely benign
REVEL	0.875	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP -0.28
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	18.79	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

Grpmax group 0.00548% African / African-American · 4/72,972 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.000258% 4/1,550,974 alleles · very rare exomes 2/1,398,946 · genomes 2/152,028 · joint denominator

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.Cys696Phe
Coding: c.2087G>T
MANE Select: NM_001142800
Type: single nucleotide variant
Location: chr6:65057664 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 696: a disulfide bond; the egf-like 8; calcium-binding domain

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

Similar variants

EYS p.Cys696Ter Likely pathogenic ★ same residue
EYS p.Cys696Gly Uncertain significance ★ same residue
EYS p.Cys696= 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

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-cys696phe (accessed [today's date]).

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