Is EYS p.Ala2498Pro (c.7492G>C) pathogenic?

EYS p.Ala2498Pro (c.7492G>C) is classified Pathogenic/Likely pathogenic in EYS (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.798); Very rare (popmax 0.00978%, eas); Associated with inherited retinal dystrophy.

What condition is associated with EYS p.Ala2498Pro (c.7492G>C)?

EYS p.Ala2498Pro (c.7492G>C) is associated with inherited retinal dystrophy, retinitis pigmentosa 25, retinitis pigmentosa (ClinVar).

How common is EYS p.Ala2498Pro (c.7492G>C) in the general population?

EYS p.Ala2498Pro (c.7492G>C) is very rare (popmax 0.00978%, eas) (gnomAD).

What do computational predictors say about EYS p.Ala2498Pro (c.7492G>C)?

AlphaMissense predicts likely pathogenic (score 0.798) — an in-silico prediction, not a clinical call.

EYS p.Ala2498Pro

c.7492G>C · rs1311193836 · VCV972618

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00978%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.798	likely pathogenic ✓ concordant with ClinVar · top 5% in EYS
REVEL	0.814	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.044	GERP 0.38, phastCons 0.001
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	21.7	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 0.00978% East Asian · 4/40,916 alleles

Filtering AF 0.00328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00193%

Overall 0.000258% 4/1,551,756 alleles · very rare exomes 4/1,399,480 · genomes 0/152,276 · joint denominator

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.Ala2498Pro
Coding: c.7492G>C
MANE Select: NM_001142800
dbSNP: rs1311193836
Type: single nucleotide variant
Location: chr6:63789144 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 2498: the laminin g-like 3 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

Also linked: retinitis pigmentosa 25 retinitis pigmentosa

Similar variants

EYS p.Ala2498Glu Uncertain significance ★ same residue
EYS p.Ala2498Val Uncertain significance ★ 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

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-ala2498pro (accessed [today's date]).

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