Is EYS p.Cys2139Arg (c.6415T>C) pathogenic?

EYS p.Cys2139Arg (c.6415T>C) is classified Likely pathogenic in EYS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-07). AlphaMissense: likely pathogenic (0.9723); Absent from gnomAD v4.1; Associated with retinitis pigmentosa 25.

What condition is associated with EYS p.Cys2139Arg (c.6415T>C)?

EYS p.Cys2139Arg (c.6415T>C) is associated with retinitis pigmentosa 25, retinitis pigmentosa (ClinVar).

How common is EYS p.Cys2139Arg (c.6415T>C) in the general population?

EYS p.Cys2139Arg (c.6415T>C) is absent from gnomAD v4.1 (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.Cys2139Arg (c.6415T>C)?

AlphaMissense predicts likely pathogenic (score 0.9723) — an in-silico prediction, not a clinical call.

EYS p.Cys2139Arg

c.6415T>C · rs1378663182 · VCV1066550

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9723 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

retinitis pigmentosa 25

Computational evidence

Protein change
AlphaMissense	0.9723	likely pathogenic ✓ concordant with ClinVar · top 1% in EYS
REVEL	0.882	moderately 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 4.1	GERP 0.25, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	23.6	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.Cys2139Arg
Coding: c.6415T>C
MANE Select: NM_001142800
dbSNP: rs1378663182
Type: single nucleotide variant
Location: chr6:64230601 (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

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

Also linked: retinitis pigmentosa

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.Cys2139Tyr 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-cys2139arg (accessed [today's date]).

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