Is EYA1 p.Pro216= (c.648G>A) pathogenic?

EYA1 p.Pro216= (c.648G>A) is classified Benign/Likely benign in EYA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). Rare (popmax 0.168%, afr); Associated with otofaciocervical syndrome 1.

What condition is associated with EYA1 p.Pro216= (c.648G>A)?

EYA1 p.Pro216= (c.648G>A) is associated with otofaciocervical syndrome 1, branchio-oto-renal syndrome, branchiootic syndrome 1 (ClinVar).

How common is EYA1 p.Pro216= (c.648G>A) in the general population?

EYA1 p.Pro216= (c.648G>A) is rare (popmax 0.168%, afr) (gnomAD).

EYA1 p.Pro216=

c.648G>A · rs148973681 · VCV363657

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.168%, afr)

Conditions

otofaciocervical syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP -10	GERP -3.6
Overall
CADD	0.607	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.168% African / African-American · 126/75,016 alleles

Filtering AF 0.144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.0471% 760/1,614,008 alleles · rare exomes 665/1,461,758 · genomes 95/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.168%	595
Middle Eastern	0.066%	1,515
Remaining individualsnot grpmax-eligible	0.0528%	1,894
European (non-Finnish)	0.0491%	2,038
East Asian	0.0111%	8,976
Admixed American	0.00833%	12,000
South Asian	0.00769%	13,012
Finnishnot grpmax-eligible	0.00156%	64,016

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: EYA1
Protein: p.Pro216=
Coding: c.648G>A
MANE Select: NM_000503
dbSNP: rs148973681
Type: single nucleotide variant
Location: chr8:71299225 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68

Full EYA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

otofaciocervical syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: branchio-oto-renal syndrome branchiootic syndrome 1

Similar variants

EYA1 p.Pro216Arg Conflicting classifications of pathogenicity ★ same residue
EYA1 p.Pro216Leu Uncertain significance ★ ⚠ same residue
EYA1 c.1050+1G>T Pathogenic ★★ same condition
EYA1 c.1051-2A>G Pathogenic ★★ same condition
EYA1 c.1199+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYA1 c.1200-1G>A Pathogenic ★★ same condition
EYA1 c.1360+5G>A Pathogenic/Likely pathogenic ★★ same condition
EYA1 c.1361-1G>A Pathogenic ★★ 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/eya1-p-pro216 (accessed [today's date]).

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