Is EYS p.Ser651Phe (c.1952C>T) pathogenic?

EYS p.Ser651Phe (c.1952C>T) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.1181); Ultra-rare (popmax 0.0188%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EYS p.Ser651Phe (c.1952C>T)?

EYS p.Ser651Phe (c.1952C>T) is associated with Inborn genetic diseases, retinitis pigmentosa 25 (ClinVar).

How common is EYS p.Ser651Phe (c.1952C>T) in the general population?

EYS p.Ser651Phe (c.1952C>T) is ultra-rare (popmax 0.0188%, nfe) (gnomAD).

What do computational predictors say about EYS p.Ser651Phe (c.1952C>T)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

EYS p.Ser651Phe

c.1952C>T · rs940468386 · VCV966459

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.236	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -0.095, phastCons 0.001
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	19.25	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.0188% European (non-Finnish) · 216/1,146,362 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.0146% 226/1,550,642 alleles · ultra-rare exomes 217/1,398,890 · genomes 9/151,752 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0188%	5,307
African / African-American	0.00685%	14,590
South Asian	0.00476%	21,009
Remaining individualsnot grpmax-eligible	0.00166%	60,100

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.Ser651Phe
Coding: c.1952C>T
MANE Select: NM_001142800
dbSNP: rs940468386
Type: single nucleotide variant
Location: chr6:65295934 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 651: the egf-like 7 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 25

Similar variants

EYS p.Ser651= 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
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-ser651phe (accessed [today's date]).

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