Is EYA4 p.Pro88= (c.264C>G) pathogenic?

EYA4 p.Pro88= (c.264C>G) is classified Likely benign in EYA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EYA4 p.Pro88= (c.264C>G)?

EYA4 p.Pro88= (c.264C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is EYA4 p.Pro88= (c.264C>G) in the general population?

EYA4 p.Pro88= (c.264C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

EYA4 p.Pro88=

c.264C>G · VCV3276891

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.23	donor gain, 13 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.7	GERP 2.9, phastCons 1
Overall
CADD	11.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,868 alleles

Overall 0.000124% 2/1,612,972 alleles · very rare exomes 2/1,460,680 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
European (non-Finnish)	8.48e-05%	1,178,957

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.Pro88=
Coding: c.264C>G
MANE Select: NM_004100
Type: single nucleotide variant
Location: chr6:133448166 (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

Similar variants

EYA4 p.Pro88Arg Uncertain significance ★★ ⚠ same residue
EYA4 p.Pro88Leu Uncertain significance ★★ ⚠ same residue
EYA4 p.Pro88Thr Uncertain significance ★ ⚠ same residue
EYA4 c.1739-1G>A Likely pathogenic ★★ same condition
EYA4 c.-2A>G Uncertain significance ★★ same condition
EYA4 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
EYA4 p.Ala287Val Uncertain significance ★★ ⚠ same condition
EYA4 p.Ala292Thr 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-pro88 (accessed [today's date]).

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