Is EYS p.Pro994Ala (c.2980C>G) pathogenic?

EYS p.Pro994Ala (c.2980C>G) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.0912); Rare (popmax 0.102%, eas); Associated with inherited retinal dystrophy.

What condition is associated with EYS p.Pro994Ala (c.2980C>G)?

EYS p.Pro994Ala (c.2980C>G) is associated with inherited retinal dystrophy (ClinVar).

How common is EYS p.Pro994Ala (c.2980C>G) in the general population?

EYS p.Pro994Ala (c.2980C>G) is rare (popmax 0.102%, eas) (gnomAD).

What do computational predictors say about EYS p.Pro994Ala (c.2980C>G)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

EYS p.Pro994Ala

c.2980C>G · rs749081001 · VCV2140273

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.29	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 0.46	GERP 2.2
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	16.14	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 0.102% East Asian · 41/40,356 alleles

Filtering AF 0.0769% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0683%

Overall 0.00298% 46/1,544,314 alleles · rare exomes 41/1,392,524 · genomes 5/151,790 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.102%	984
South Asian	0.00481%	20,770
Remaining individualsnot grpmax-eligible	0.00167%	59,772

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.Pro994Ala
Coding: c.2980C>G
MANE Select: NM_001142800
dbSNP: rs749081001
Type: single nucleotide variant
Location: chr6:64886709 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 994: the egf-like 15 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.Pro994= Likely benign ★ 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
EYS c.6191+2T>C 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-pro994ala (accessed [today's date]).

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