Is EYA4 p.Arg587Pro (c.1760G>C) pathogenic?

EYA4 p.Arg587Pro (c.1760G>C) is classified Uncertain significance in EYA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). AlphaMissense: likely pathogenic (0.9992); Very rare (popmax 0.000339%, nfe); Associated with dilated cardiomyopathy 1J.

What condition is associated with EYA4 p.Arg587Pro (c.1760G>C)?

EYA4 p.Arg587Pro (c.1760G>C) is associated with dilated cardiomyopathy 1J (ClinVar).

How common is EYA4 p.Arg587Pro (c.1760G>C) in the general population?

EYA4 p.Arg587Pro (c.1760G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EYA4 p.Arg587Pro (c.1760G>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

EYA4 p.Arg587Pro

Q: How is Sensorineural deafness with dilated cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1760G>C · rs746014018 · VCV842528

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1J

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 2% in EYA4
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -17.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 254 kb · p 0.0025 · regional, not allelic
Overall
CADD	33.0	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,752 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,734 alleles · very rare exomes 4/1,461,442 · genomes 0/152,292 · 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: EYA4
Protein: p.Arg587Pro
Coding: c.1760G>C
MANE Select: NM_004100
dbSNP: rs746014018
Type: single nucleotide variant
Location: chr6:133525175 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.79
Residue 587: a UniProt-annotated variant site (in dfna10)

Full EYA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dilated cardiomyopathy 1J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sensorineural deafness with dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

EYA4 p.Arg587Gln Uncertain significance ★★ ⚠ same residue
EYA4 c.1341-2A>G Likely pathogenic ★★ same condition
EYA4 c.1739-1G>A Likely pathogenic ★★ same condition
EYA4 p.Asp194Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
EYA4 p.Trp81Ter Pathogenic/Likely pathogenic ★★ same condition
EYA4 c.1282-13A>G Uncertain significance ★★ same condition
EYA4 c.1340+3A>G Uncertain significance ★★ same condition
EYA4 c.970+5A>G Uncertain significance ★★ 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/eya4-p-arg587pro (accessed [today's date]).

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