Is EYS p.Cys2139Tyr (c.6416G>A) pathogenic?

EYS p.Cys2139Tyr (c.6416G>A) is classified Pathogenic/Likely pathogenic in EYS (ClinVar, Multiple submitters, 21 submitters; last evaluated 2026-01-30). AlphaMissense: likely pathogenic (0.9898); Ultra-rare (popmax 0.0712%, eas); Associated with EYS-related disorder.

What condition is associated with EYS p.Cys2139Tyr (c.6416G>A)?

EYS p.Cys2139Tyr (c.6416G>A) is associated with EYS-related disorder, retinitis pigmentosa 25, inherited retinal dystrophy (ClinVar).

How common is EYS p.Cys2139Tyr (c.6416G>A) in the general population?

EYS p.Cys2139Tyr (c.6416G>A) is ultra-rare (popmax 0.0712%, eas) (gnomAD).

What do computational predictors say about EYS p.Cys2139Tyr (c.6416G>A)?

AlphaMissense predicts likely pathogenic (score 0.9898) — an in-silico prediction, not a clinical call.

EYS p.Cys2139Tyr

c.6416G>A · rs749909863 · VCV189230

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 21 submitters

AlphaMissense

likely pathogenic

0.9898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0712%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

EYS-related disorder

Computational evidence

Protein change
AlphaMissense	0.9898	likely pathogenic ✓ concordant with ClinVar · top 1% in EYS
REVEL	0.755	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.85	GERP -0.22, phastCons 0.07
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	23.0	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 0.0712% East Asian · 29/40,718 alleles

Filtering AF 0.0509% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.044%

Overall 0.00538% 83/1,543,586 alleles · ultra-rare exomes 72/1,391,284 · genomes 11/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0712%	1,404
Remaining individualsnot grpmax-eligible	0.0067%	14,926
European (non-Finnish)	0.00403%	24,792
Admixed American	0.00394%	25,367
Finnishnot grpmax-eligible	0.00167%	59,800
South Asian	0.00119%	83,780

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.Cys2139Tyr
Coding: c.6416G>A
MANE Select: NM_001142800
dbSNP: rs749909863
Type: single nucleotide variant
Location: chr6:64230600 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 2139: a disulfide bond; a UniProt-annotated variant site (in rp25); the egf-like 21 domain

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

Disease context

EYS-related disorder

Also linked: retinitis pigmentosa 25 inherited retinal dystrophy retinitis pigmentosa

Similar variants

EYS p.Cys2139Arg 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+1G>T Pathogenic/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-cys2139tyr (accessed [today's date]).

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