Is EYS p.Cys992Ser (c.2974T>A) pathogenic?

EYS p.Cys992Ser (c.2974T>A) is classified Uncertain significance in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-05). AlphaMissense: likely pathogenic (0.8862); Absent from gnomAD v4.1.

How common is EYS p.Cys992Ser (c.2974T>A) in the general population?

EYS p.Cys992Ser (c.2974T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EYS p.Cys992Ser (c.2974T>A)?

AlphaMissense predicts likely pathogenic (score 0.8862) — an in-silico prediction, not a clinical call.

EYS p.Cys992Ser

c.2974T>A · VCV4892647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8862 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.8862	likely pathogenic · top 3% in EYS
REVEL	0.81	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; 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 4.7	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	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EYS
Protein: p.Cys992Ser
Coding: c.2974T>A
MANE Select: NM_001142800
Type: single nucleotide variant
Location: chr6:64886715 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 992: the egf-like 15 domain; a disulfide bond

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

Similar variants

EYS p.Cys992Ter Pathogenic ★ same residue
EYS p.Cys992Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
EYS p.Cys992= Likely benign ★ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same type
EYS c.1056+3A>C Likely pathogenic ★★ same type
EYS c.1057-1G>A Likely pathogenic ★★ same type
EYS c.1184+1G>A Pathogenic/Likely pathogenic ★★ same type
EYS c.1184+1G>T Likely pathogenic ★★ same type

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-cys992ser (accessed [today's date]).

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