Is EYS p.Ala2736Pro (c.8206G>C) pathogenic?

EYS p.Ala2736Pro (c.8206G>C) is classified Conflicting classifications of pathogenicity in EYS (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-02-17). AlphaMissense: likely pathogenic (0.7736); Very rare (popmax 0.000872%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with EYS p.Ala2736Pro (c.8206G>C)?

EYS p.Ala2736Pro (c.8206G>C) is associated with inherited retinal dystrophy, retinitis pigmentosa 25, retinitis pigmentosa (ClinVar).

How common is EYS p.Ala2736Pro (c.8206G>C) in the general population?

EYS p.Ala2736Pro (c.8206G>C) is very rare (popmax 0.000872%, nfe) (gnomAD).

What do computational predictors say about EYS p.Ala2736Pro (c.8206G>C)?

AlphaMissense predicts likely pathogenic (score 0.7736) — an in-silico prediction, not a clinical call.

EYS p.Ala2736Pro

c.8206G>C · rs1250317776 · VCV867109

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000872%, nfe)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.7736	likely pathogenic · top 6% in EYS
REVEL	0.424	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.039	GERP -0.62, phastCons 0.002
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A2757P vs ClinVar A2736P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000872% European (non-Finnish) · 10/1,146,700 alleles

Filtering AF 0.000441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000322%

Overall 0.000645% 10/1,551,122 alleles · very rare exomes 10/1,398,896 · genomes 0/152,226 · 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: EYS
Protein: p.Ala2736Pro
Coding: c.8206G>C
MANE Select: NM_001142800
dbSNP: rs1250317776
Type: single nucleotide variant
Location: chr6:63726546 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 25 retinitis pigmentosa

Similar variants

EYS p.Ala2736Val Conflicting classifications of pathogenicity ★ ⚠ same residue
EYS p.Ala2736= Likely benign ★ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1056+3A>C Likely pathogenic ★★ same condition
EYS c.1057-1G>A Likely pathogenic ★★ same condition
EYS c.1184+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1184+1G>T Likely pathogenic ★★ same condition
EYS c.1185-1G>A Likely 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/eys-p-ala2736pro (accessed [today's date]).

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