Is EYA4 p.Pro155Ser (c.463C>T) pathogenic?

EYA4 p.Pro155Ser (c.463C>T) is classified Uncertain significance in EYA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.2216); Very rare (popmax 0.00667%, amr); Associated with dilated cardiomyopathy 1J.

What condition is associated with EYA4 p.Pro155Ser (c.463C>T)?

EYA4 p.Pro155Ser (c.463C>T) is associated with dilated cardiomyopathy 1J (ClinVar).

How common is EYA4 p.Pro155Ser (c.463C>T) in the general population?

EYA4 p.Pro155Ser (c.463C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about EYA4 p.Pro155Ser (c.463C>T)?

AlphaMissense predicts likely benign (score 0.2216) — an in-silico prediction, not a clinical call.

EYA4 p.Pro155Ser

Q: How is Sensorineural deafness with dilated cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.463C>T · rs543278630 · VCV1405541

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

dilated cardiomyopathy 1J

Computational evidence

Protein change
AlphaMissense	0.2216	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.73 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 254 kb · p 0.0025 · regional, not allelic
Overall
CADD	28.3	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

Grpmax group 0.00667% Admixed American · 4/60,006 alleles

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

Overall 0.00031% 5/1,614,062 alleles · very rare exomes 2/1,461,744 · genomes 3/152,318 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
European (non-Finnish)	8.48e-05%	1,179,930

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.Pro155Ser
Coding: c.463C>T
MANE Select: NM_004100
dbSNP: rs543278630
Type: single nucleotide variant
Location: chr6:133462360 (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

dilated cardiomyopathy 1J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sensorineural deafness with dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

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
EYA4 c.971-3T>C 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-pro155ser (accessed [today's date]).

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