Is EYS p.Cys992Ter (c.2976T>A) pathogenic?

EYS p.Cys992Ter (c.2976T>A) is classified Pathogenic in EYS (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-13). Very rare (popmax 8.74e-05%, nfe); Associated with retinitis pigmentosa 25.

What condition is associated with EYS p.Cys992Ter (c.2976T>A)?

EYS p.Cys992Ter (c.2976T>A) is associated with retinitis pigmentosa 25, inherited retinal dystrophy (ClinVar).

How common is EYS p.Cys992Ter (c.2976T>A) in the general population?

EYS p.Cys992Ter (c.2976T>A) is very rare (popmax 8.74e-05%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EYS p.Cys992Ter

c.2976T>A · rs1554214453 · VCV438195

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.74e-05%, nfe)

Conditions

retinitis pigmentosa 25

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 19 of 43
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 2.4, phastCons 0.99
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.74e-05% European (non-Finnish) · 1/1,143,922 alleles

Overall 6.47e-05% 1/1,545,712 alleles · very rare exomes 1/1,393,592 · genomes 0/152,120 · 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.Cys992Ter
Coding: c.2976T>A
MANE Select: NM_001142800
dbSNP: rs1554214453
Type: single nucleotide variant
Location: chr6:64886713 (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

Disease context

retinitis pigmentosa 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

EYS p.Cys992Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
EYS p.Cys992Ser Uncertain significance ★ ⚠ same residue
EYS p.Cys992= 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

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-cys992ter (accessed [today's date]).

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