Is EYS p.Cys975Ser (c.2923T>A) pathogenic?

EYS p.Cys975Ser (c.2923T>A) is classified Uncertain significance in EYS (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-20). AlphaMissense: likely pathogenic (0.7657); Very rare (popmax 0.000262%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with EYS p.Cys975Ser (c.2923T>A)?

EYS p.Cys975Ser (c.2923T>A) is associated with inherited retinal dystrophy (ClinVar).

How common is EYS p.Cys975Ser (c.2923T>A) in the general population?

EYS p.Cys975Ser (c.2923T>A) is very rare (popmax 0.000262%, nfe) (gnomAD).

What do computational predictors say about EYS p.Cys975Ser (c.2923T>A)?

AlphaMissense predicts likely pathogenic (score 0.7657) — an in-silico prediction, not a clinical call.

EYS p.Cys975Ser

c.2923T>A · VCV3249085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.7657	likely pathogenic · top 6% in EYS
REVEL	0.618	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.26	acceptor loss, 7 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.2	GERP 5.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	19.48	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 0.000262% European (non-Finnish) · 3/1,144,154 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000194% 3/1,547,150 alleles · very rare exomes 2/1,395,236 · genomes 1/151,914 · 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.Cys975Ser
Coding: c.2923T>A
MANE Select: NM_001142800
Type: single nucleotide variant
Location: chr6:64886766 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 975: the egf-like 15 domain; a disulfide bond

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.Cys975Arg 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
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-cys975ser (accessed [today's date]).

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