Is EYA4 p.Ser347Pro (c.1039T>C) pathogenic?

EYA4 p.Ser347Pro (c.1039T>C) is classified Uncertain significance in EYA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1102); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with EYA4 p.Ser347Pro (c.1039T>C)?

EYA4 p.Ser347Pro (c.1039T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EYA4 p.Ser347Pro (c.1039T>C) in the general population?

EYA4 p.Ser347Pro (c.1039T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EYA4 p.Ser347Pro (c.1039T>C)?

AlphaMissense predicts likely benign (score 0.1102) — an in-silico prediction, not a clinical call.

EYA4 p.Ser347Pro

c.1039T>C · VCV4020619

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1102 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1102	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 254 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EYA4
Protein: p.Ser347Pro
Coding: c.1039T>C
MANE Select: NM_004100
Type: single nucleotide variant
Location: chr6:133481531 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.79
Residue 347: a UniProt-annotated variant site (in dfna10); the 'disordered' region

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.Ser347Thr Uncertain significance ★ ⚠ same residue
EYA4 p.Ser347Tyr 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
EYA4 p.Ala402Ser 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-ser347pro (accessed [today's date]).

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