Is EYS p.Phe278Ser (c.833T>C) pathogenic?

EYS p.Phe278Ser (c.833T>C) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-05). AlphaMissense: likely pathogenic (0.6221); Ultra-rare (popmax 0.016%, afr); Associated with retinitis pigmentosa 25.

What condition is associated with EYS p.Phe278Ser (c.833T>C)?

EYS p.Phe278Ser (c.833T>C) is associated with retinitis pigmentosa 25 (ClinVar).

How common is EYS p.Phe278Ser (c.833T>C) in the general population?

EYS p.Phe278Ser (c.833T>C) is ultra-rare (popmax 0.016%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

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

What do computational predictors say about EYS p.Phe278Ser (c.833T>C)?

AlphaMissense predicts likely pathogenic (score 0.6221) — an in-silico prediction, not a clinical call.

EYS p.Phe278Ser

c.833T>C · rs142777049 · VCV1062404

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

retinitis pigmentosa 25

Computational evidence

Protein change
AlphaMissense	0.6221	likely pathogenic · top 10% in EYS
REVEL	0.446	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	21.0	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 0.016% African / African-American · 12/74,866 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000745% 12/1,611,314 alleles · ultra-rare exomes 6/1,459,146 · genomes 6/152,168 · 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.Phe278Ser
Coding: c.833T>C
MANE Select: NM_001142800
dbSNP: rs142777049
Type: single nucleotide variant
Location: chr6:65490623 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 278: the egf-like 3 domain

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

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.Phe278Leu 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
EYS c.1299+2T>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-phe278ser (accessed [today's date]).

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