Is EYA4 p.Pro271Ala (c.811C>G) pathogenic?

EYA4 p.Pro271Ala (c.811C>G) is classified Uncertain significance in EYA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.0946); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EYA4 p.Pro271Ala (c.811C>G)?

EYA4 p.Pro271Ala (c.811C>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1J (ClinVar).

How common is EYA4 p.Pro271Ala (c.811C>G) in the general population?

EYA4 p.Pro271Ala (c.811C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EYA4 p.Pro271Ala (c.811C>G)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

EYA4 p.Pro271Ala

c.811C>G · rs752023028 · VCV465990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -5.83	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 3.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 254 kb · p 0.0025 · regional, not allelic
Overall
CADD	21.3	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 0.00167% Admixed American · 1/59,804 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000833%

Overall 0.00124% 20/1,608,026 alleles · very rare exomes 19/1,456,038 · genomes 1/151,988 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,804
European (non-Finnish)	0.00162%	61,843

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.Pro271Ala
Coding: c.811C>G
MANE Select: NM_004100
dbSNP: rs752023028
Type: single nucleotide variant
Location: chr6:133468572 (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.Pro271= 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-pro271ala (accessed [today's date]).

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