Is EYS p.Pro517Ser (c.1549C>T) pathogenic?

EYS p.Pro517Ser (c.1549C>T) is classified Conflicting classifications of pathogenicity in EYS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.0881); Ultra-rare (popmax 0.0188%, afr); Associated with Inborn genetic diseases.

What condition is associated with EYS p.Pro517Ser (c.1549C>T)?

EYS p.Pro517Ser (c.1549C>T) is associated with Inborn genetic diseases, retinitis pigmentosa 25 (ClinVar).

How common is EYS p.Pro517Ser (c.1549C>T) in the general population?

EYS p.Pro517Ser (c.1549C>T) is ultra-rare (popmax 0.0188%, afr) (gnomAD).

What do computational predictors say about EYS p.Pro517Ser (c.1549C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

EYS p.Pro517Ser

c.1549C>T · rs763331925 · VCV1035061

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; 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 -0.26	GERP -2.1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	0.096	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 0.0188% African / African-American · 14/74,600 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00908%

Overall 0.000993% 16/1,610,530 alleles · ultra-rare exomes 12/1,459,280 · genomes 4/151,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0188%	5,329
Admixed American	0.00168%	59,642
Remaining individualsnot grpmax-eligible	0.00161%	62,296

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.Pro517Ser
Coding: c.1549C>T
MANE Select: NM_001142800
dbSNP: rs763331925
Type: single nucleotide variant
Location: chr6:65344088 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 25

Similar variants

EYS p.Pro517= Likely benign ★ 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-pro517ser (accessed [today's date]).

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