Is EYS p.Cys183Phe (c.548G>T) pathogenic?

EYS p.Cys183Phe (c.548G>T) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-10-14). AlphaMissense: likely pathogenic (0.6179); Very rare (popmax 0.000254%, nfe).

How common is EYS p.Cys183Phe (c.548G>T) in the general population?

EYS p.Cys183Phe (c.548G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about EYS p.Cys183Phe (c.548G>T)?

AlphaMissense predicts likely pathogenic (score 0.6179) — an in-silico prediction, not a clinical call.

EYS p.Cys183Phe

c.548G>T · rs1766186534 · VCV962331

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.6179	likely pathogenic · top 10% in EYS
REVEL	0.71	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP 0.046, phastCons 0.98
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000254% European (non-Finnish) · 3/1,179,938 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,026 alleles · very rare exomes 3/1,461,776 · genomes 0/152,250 · 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.Cys183Phe
Coding: c.548G>T
MANE Select: NM_001142800
dbSNP: rs1766186534
Type: single nucleotide variant
Location: chr6:65494863 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 183: the egf-like 1 domain; a disulfide bond

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

Similar variants

EYS p.Cys183Gly Uncertain significance ★ ⚠ 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-cys183phe (accessed [today's date]).

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