Is EYA4 p.Pro241= (c.723A>G) pathogenic?

EYA4 p.Pro241= (c.723A>G) is classified Conflicting classifications of pathogenicity in EYA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-08). Rare (popmax 0.132%, mid); Associated with Cardiovascular phenotype.

What condition is associated with EYA4 p.Pro241= (c.723A>G)?

EYA4 p.Pro241= (c.723A>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1J (ClinVar).

How common is EYA4 p.Pro241= (c.723A>G) in the general population?

EYA4 p.Pro241= (c.723A>G) is rare (popmax 0.132%, mid) (gnomAD).

EYA4 p.Pro241=

c.723A>G · rs556550485 · VCV228682

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.4	GERP 1.7, phastCons 1
Overall
CADD	15.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,054 alleles

Filtering AF 0.0657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.048%

Overall 0.00136% 22/1,613,614 alleles · rare exomes 20/1,461,358 · genomes 2/152,256 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	757
African / African-American	0.00533%	18,749
Remaining individualsnot grpmax-eligible	0.0048%	20,824
South Asian	0.0011%	91,072
European (non-Finnish)	0.000509%	196,605

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.Pro241=
Coding: c.723A>G
MANE Select: NM_004100
dbSNP: rs556550485
Type: single nucleotide variant
Location: chr6:133462763 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.79

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: dilated cardiomyopathy 1J

Similar variants

EYA4 p.Pro241Leu 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-pro241 (accessed [today's date]).

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