Is EYS p.Trp1484Arg (c.4450T>C) pathogenic?

EYS p.Trp1484Arg (c.4450T>C) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-30). AlphaMissense: likely benign (0.3105); Very rare (popmax 0.00137%, afr).

How common is EYS p.Trp1484Arg (c.4450T>C) in the general population?

EYS p.Trp1484Arg (c.4450T>C) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about EYS p.Trp1484Arg (c.4450T>C)?

AlphaMissense predicts likely benign (score 0.3105) — an in-silico prediction, not a clinical call.

EYS p.Trp1484Arg

c.4450T>C · rs1260400598 · VCV2136432

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.3105	likely benign
REVEL	0.156	moderately 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 0.099
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	15.45	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 0.00137% African / African-American · 1/73,010 alleles

Filtering AF 0.000708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000554%

Overall 0.000967% 15/1,551,252 alleles · very rare exomes 14/1,399,156 · genomes 1/152,096 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	73,010
European (non-Finnish)	0.00122%	81,913

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.Trp1484Arg
Coding: c.4450T>C
MANE Select: NM_001142800
dbSNP: rs1260400598
Type: single nucleotide variant
Location: chr6:64591417 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 1484: a UniProt-annotated variant site (in rp25)

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

Similar variants

EYS p.Trp1484Ter Pathogenic ★★ same residue
EYS p.Trp1484Gly Uncertain significance ★ same residue
EYS p.Trp1484Leu Uncertain significance ★ same residue
EYS p.Trp1484_Leu1486delinsSerProVal 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

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-trp1484arg (accessed [today's date]).

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