Is EYS p.Cys690Ser (c.2068T>A) pathogenic?

EYS p.Cys690Ser (c.2068T>A) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-04). AlphaMissense: ambiguous (0.5296); Rare (popmax 0.122%, afr); Associated with retinitis pigmentosa 25.

What condition is associated with EYS p.Cys690Ser (c.2068T>A)?

EYS p.Cys690Ser (c.2068T>A) is associated with retinitis pigmentosa 25 (ClinVar).

How common is EYS p.Cys690Ser (c.2068T>A) in the general population?

EYS p.Cys690Ser (c.2068T>A) is rare (popmax 0.122%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EYS p.Cys690Ser (c.2068T>A)?

AlphaMissense predicts ambiguous (score 0.5296) — an in-silico prediction, not a clinical call.

EYS p.Cys690Ser

c.2068T>A · rs370950723 · VCV811665

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5296 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.122%, afr)

Conditions

retinitis pigmentosa 25

Computational evidence

Protein change
AlphaMissense	0.5296	ambiguous
REVEL	0.706	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 4	GERP 2.2, phastCons 0.061
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	21.1	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 0.122% African / African-American · 89/73,140 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0936%

Overall 0.0069% 107/1,551,114 alleles · rare exomes 44/1,398,932 · genomes 63/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.122%	822
Remaining individualsnot grpmax-eligible	0.0183%	5,462
Admixed American	0.0118%	8,493
European (non-Finnish)	8.72e-05%	1,146,588

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.Cys690Ser
Coding: c.2068T>A
MANE Select: NM_001142800
dbSNP: rs370950723
Type: single nucleotide variant
Location: chr6:65057683 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 690: a disulfide bond; the egf-like 8; calcium-binding domain

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

Disease context

retinitis pigmentosa 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

EYS p.Cys690fs Pathogenic/Likely pathogenic ★★ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1056+3A>C Likely pathogenic ★★ same condition
EYS c.1057-1G>A Likely pathogenic ★★ same condition
EYS c.1184+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1184+1G>T Likely pathogenic ★★ same condition
EYS c.1185-1G>A Likely pathogenic ★★ same condition
EYS c.1299+2T>A 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/eys-p-cys690ser (accessed [today's date]).

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