Is EYA3 p.Ser176Pro (c.526T>C) pathogenic?

EYA3 p.Ser176Pro (c.526T>C) is classified Uncertain significance in EYA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely benign (0.0542); Ultra-rare (popmax 0.0165%, mid).

How common is EYA3 p.Ser176Pro (c.526T>C) in the general population?

EYA3 p.Ser176Pro (c.526T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EYA3 p.Ser176Pro (c.526T>C)?

AlphaMissense predicts likely benign (score 0.0542) — an in-silico prediction, not a clinical call.

EYA3 p.Ser176Pro

c.526T>C · VCV3846921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0542	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.063	GERP -3.6, phastCons 0.071
Regional constraint	o/e 0.89	unconstrained · MANE · 47 kb · p 0.034 · regional, not allelic
Overall
CADD	9.431	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00843% 136/1,613,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
South Asian	0.0165%	6,072
European (non-Finnish)	0.00966%	10,349
Remaining individualsnot grpmax-eligible	0.0064%	15,626
Admixed American	0.00167%	60,008
African / African-American	0.00133%	75,050

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: EYA3
Protein: p.Ser176Pro
Coding: c.526T>C
MANE Select: NM_001990
Type: single nucleotide variant
Location: chr1:28017213 (GRCh38)
Gene constraint: LOEUF 0.609 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 66.28 · 2 PDB

Full EYA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EYA3 c.1083+2T>C Uncertain significance ★ same type
EYA3 p.Ala187Val Uncertain significance ★ ⚠ same type
EYA3 p.Ala463Val Uncertain significance ★ ⚠ same type
EYA3 p.Arg253Ser Uncertain significance ★ ⚠ same type
EYA3 p.Arg279Lys Uncertain significance ★ ⚠ same type
EYA3 p.Arg287Gln Uncertain significance ★ same type
EYA3 p.Arg287Trp Uncertain significance ★ ⚠ same type
EYA3 p.Arg420Gln Uncertain significance ★ ⚠ same type

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/eya3-p-ser176pro (accessed [today's date]).

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