Is EYA4 p.Pro247Arg (c.740C>G) pathogenic?

EYA4 p.Pro247Arg (c.740C>G) is classified Uncertain significance in EYA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-26). AlphaMissense: ambiguous (0.3786); Very rare (popmax 0.00668%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EYA4 p.Pro247Arg (c.740C>G)?

EYA4 p.Pro247Arg (c.740C>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1J (ClinVar).

How common is EYA4 p.Pro247Arg (c.740C>G) in the general population?

EYA4 p.Pro247Arg (c.740C>G) is very rare (popmax 0.00668%, amr) (gnomAD).

What do computational predictors say about EYA4 p.Pro247Arg (c.740C>G)?

AlphaMissense predicts ambiguous (score 0.3786) — an in-silico prediction, not a clinical call.

EYA4 p.Pro247Arg

c.740C>G · rs767398384 · VCV2147950

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3786	ambiguous
REVEL	0.395	indeterminate
SaProt	LLR -8.48	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 254 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% Admixed American · 4/59,858 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000373% 6/1,607,086 alleles · very rare exomes 5/1,455,012 · genomes 1/152,074 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,965
Remaining individualsnot grpmax-eligible	0.00161%	62,184
European (non-Finnish)	8.51e-05%	1,174,558

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.Pro247Arg
Coding: c.740C>G
MANE Select: NM_004100
dbSNP: rs767398384
Type: single nucleotide variant
Location: chr6:133464794 (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.Pro247= Likely benign ★★ 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-pro247arg (accessed [today's date]).

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