Is EYS p.Phe290Leu (c.868T>C) pathogenic?

EYS p.Phe290Leu (c.868T>C) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-08). AlphaMissense: likely pathogenic (0.7462); Ultra-rare (popmax 0.0449%, eas).

How common is EYS p.Phe290Leu (c.868T>C) in the general population?

EYS p.Phe290Leu (c.868T>C) is ultra-rare (popmax 0.0449%, eas) (gnomAD).

What do computational predictors say about EYS p.Phe290Leu (c.868T>C)?

AlphaMissense predicts likely pathogenic (score 0.7462) — an in-silico prediction, not a clinical call.

EYS p.Phe290Leu

c.868T>C · rs373557623 · VCV966662

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7462 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0449%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.7462	likely pathogenic · top 7% in EYS
REVEL	0.265	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.11, phastCons 0.4
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	9.735	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 0.0449% East Asian · 20/44,570 alleles

Filtering AF 0.0297% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.00193% 31/1,604,978 alleles · ultra-rare exomes 26/1,457,256 · genomes 5/147,722 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0449%	2,229
Remaining individualsnot grpmax-eligible	0.0145%	6,915
Admixed American	0.00171%	58,626
European (non-Finnish)	8.5e-05%	1,176,590

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.Phe290Leu
Coding: c.868T>C
MANE Select: NM_001142800
dbSNP: rs373557623
Type: single nucleotide variant
Location: chr6:65405362 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 290: the egf-like 3 domain

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

Similar variants

EYS p.Phe290= 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
EYS c.1185-1G>A Likely pathogenic ★★ same type
EYS c.1299+1G>T Pathogenic/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-phe290leu (accessed [today's date]).

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