Is EYS p.Cys554Ser (c.1660T>A) pathogenic?

EYS p.Cys554Ser (c.1660T>A) is classified Conflicting classifications of pathogenicity in EYS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.305); Rare (popmax 0.272%, afr); Associated with retinitis pigmentosa 25.

What condition is associated with EYS p.Cys554Ser (c.1660T>A)?

EYS p.Cys554Ser (c.1660T>A) is associated with retinitis pigmentosa 25 (ClinVar).

How common is EYS p.Cys554Ser (c.1660T>A) in the general population?

EYS p.Cys554Ser (c.1660T>A) is rare (popmax 0.272%, 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.Cys554Ser (c.1660T>A)?

AlphaMissense predicts likely benign (score 0.305) — an in-silico prediction, not a clinical call.

EYS p.Cys554Ser

c.1660T>A · rs145102275 · VCV287293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.305 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.272%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

retinitis pigmentosa 25

Computational evidence

Protein change
AlphaMissense	0.305	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.29	acceptor loss, 11 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.52	GERP -0.26
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	11.1	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 0.272% African / African-American · 204/74,908 alleles

Filtering AF 0.242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.23%

Overall 0.0139% 224/1,612,168 alleles · rare exomes 117/1,460,288 · genomes 107/151,880 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.272%	367
Middle Eastern	0.0166%	6,042
Remaining individualsnot grpmax-eligible	0.0112%	8,912
Admixed American	0.00837%	11,949
South Asian	0.0011%	91,052
European (non-Finnish)	0.000509%	196,491

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.Cys554Ser
Coding: c.1660T>A
MANE Select: NM_001142800
dbSNP: rs145102275
Type: single nucleotide variant
Location: chr6:65335086 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)

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.Cys554Arg 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-cys554ser (accessed [today's date]).

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