Is EYS p.Pro588Arg (c.1763C>G) pathogenic?

EYS p.Pro588Arg (c.1763C>G) is classified Uncertain significance in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely benign (0.1153); Very rare (popmax 0.00671%, eas); Associated with inherited retinal dystrophy.

What condition is associated with EYS p.Pro588Arg (c.1763C>G)?

EYS p.Pro588Arg (c.1763C>G) is associated with inherited retinal dystrophy (ClinVar).

How common is EYS p.Pro588Arg (c.1763C>G) in the general population?

EYS p.Pro588Arg (c.1763C>G) is very rare (popmax 0.00671%, eas) (gnomAD).

What do computational predictors say about EYS p.Pro588Arg (c.1763C>G)?

AlphaMissense predicts likely benign (score 0.1153) — an in-silico prediction, not a clinical call.

EYS p.Pro588Arg

c.1763C>G · rs1033362579 · VCV3027830

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00671%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1153	likely benign
REVEL	0.224	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -2
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	6.58	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00671% East Asian · 3/44,718 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000436% 7/1,605,618 alleles · very rare exomes 4/1,454,222 · genomes 3/151,396 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00671%	14,906
African / African-American	0.00537%	18,636

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.Pro588Arg
Coding: c.1763C>G
MANE Select: NM_001142800
dbSNP: rs1033362579
Type: single nucleotide variant
Location: chr6:65334983 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 588: the egf-like 6 domain

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EYS p.Pro588Thr Uncertain significance ★★ ⚠ same residue
EYS p.Pro588His Uncertain significance ★ ⚠ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1299+1G>T Pathogenic/Likely pathogenic ★★ same condition
EYS c.1766+1G>T Pathogenic/Likely pathogenic ★★ same condition
EYS c.2259+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.3243+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.5836-1G>C 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-pro588arg (accessed [today's date]).

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