Is EYA1 p.Cys495Ser (c.1483T>A) pathogenic?

EYA1 p.Cys495Ser (c.1483T>A) is classified Likely pathogenic in EYA1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). AlphaMissense: ambiguous (0.3989); Very rare (popmax 0.00133%, afr).

How common is EYA1 p.Cys495Ser (c.1483T>A) in the general population?

EYA1 p.Cys495Ser (c.1483T>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EYA1 p.Cys495Ser (c.1483T>A)?

AlphaMissense predicts ambiguous (score 0.3989) — an in-silico prediction, not a clinical call.

EYA1 p.Cys495Ser

c.1483T>A · rs1563630587 · VCV562332

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3989	ambiguous
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -6.46	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 156 kb · p 0.0003 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,056 alleles

Overall 6.2e-05% 1/1,613,774 alleles · very rare exomes 1/1,461,418 · genomes 0/152,356 · joint denominator

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.Cys495Ser
Coding: c.1483T>A
MANE Select: NM_000503
dbSNP: rs1563630587
Type: single nucleotide variant
Location: chr8:71215501 (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

Similar variants

EYA1 c.1050+1G>T Pathogenic ★★ same type
EYA1 c.1051-2A>G Pathogenic ★★ same type
EYA1 c.1199+1G>A Pathogenic/Likely pathogenic ★★ same type
EYA1 c.1200-1G>A Pathogenic ★★ same type
EYA1 c.1360+5G>A Pathogenic/Likely pathogenic ★★ same type
EYA1 c.1361-1G>A Pathogenic ★★ same type
EYA1 c.1475+1G>C Pathogenic ★★ same type
EYA1 c.1597+1G>A Pathogenic/Likely pathogenic ★★ 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/eya1-p-cys495ser (accessed [today's date]).

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