Is OTX2 p.Arg76Pro (c.227G>C) pathogenic?

OTX2 p.Arg76Pro (c.227G>C) is classified Uncertain significance in OTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-25). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is OTX2 p.Arg76Pro (c.227G>C) in the general population?

OTX2 p.Arg76Pro (c.227G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OTX2 p.Arg76Pro (c.227G>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

OTX2 p.Arg76Pro

c.227G>C · rs2503907317 · VCV2504301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 9% in OTX2
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -14.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 2,031 bp · p 1.4e-09 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R68P vs ClinVar R76P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OTX2
Protein: p.Arg76Pro
Coding: c.227G>C
MANE Select: NM_021728
dbSNP: rs2503907317
Type: single nucleotide variant
Location: chr14:56804234 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 68 UniProt numbering: a DNA-binding region

Full OTX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

OTX2 p.Arg76Ter Pathogenic ★★ same residue
OTX2 p.Arg76= Likely benign ★ same residue
OTX2 p.Glu87Lys Pathogenic/Likely pathogenic ★★ same type
OTX2 p.Ser211Ter Pathogenic/Likely pathogenic ★★ same type
OTX2 p.Tyr197Ter Pathogenic/Likely pathogenic ★★ same type
OTX2 p.Ala234Val Uncertain significance ★★ ⚠ same type
OTX2 p.Ala63Ser Uncertain significance ★★ ⚠ same type
OTX2 p.Arg102Cys 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/otx2-p-arg76pro (accessed [today's date]).

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