Is EYA4 p.Ser296= (c.888G>A) pathogenic?

EYA4 p.Ser296= (c.888G>A) is classified Conflicting classifications of pathogenicity in EYA4 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-09). Ultra-rare (popmax 0.0267%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EYA4 p.Ser296= (c.888G>A)?

EYA4 p.Ser296= (c.888G>A) is associated with Cardiovascular phenotype, autosomal dominant nonsyndromic hearing loss 10, dilated cardiomyopathy 1J (ClinVar).

How common is EYA4 p.Ser296= (c.888G>A) in the general population?

EYA4 p.Ser296= (c.888G>A) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

EYA4 p.Ser296=

c.888G>A · rs768010410 · VCV355444

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.39	GERP -5.7
Overall
CADD	1.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/59,848 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00273% 44/1,612,856 alleles · ultra-rare exomes 43/1,460,842 · genomes 1/152,014 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,740
Middle Eastern	0.0165%	6,078
East Asian	0.00891%	11,219
Remaining individualsnot grpmax-eligible	0.00641%	15,604
South Asian	0.00549%	18,214
European (non-Finnish)	0.00119%	84,233

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.Ser296=
Coding: c.888G>A
MANE Select: NM_004100
dbSNP: rs768010410
Type: single nucleotide variant
Location: chr6:133468649 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.79
Residue 296: a UniProt-annotated variant site (in dfna10)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 10 dilated cardiomyopathy 1J

Similar variants

EYA4 p.Ser296Leu 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-ser296 (accessed [today's date]).

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