Is OTX2 p.Ser136Arg (c.408T>A) pathogenic?

OTX2 p.Ser136Arg (c.408T>A) is classified Uncertain significance in OTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-13). AlphaMissense: likely pathogenic (0.818); Absent from gnomAD v4.1; Associated with Anophthalmia-microphthalmia syndrome.

What condition is associated with OTX2 p.Ser136Arg (c.408T>A)?

OTX2 p.Ser136Arg (c.408T>A) is associated with Anophthalmia-microphthalmia syndrome (ClinVar).

How common is OTX2 p.Ser136Arg (c.408T>A) in the general population?

OTX2 p.Ser136Arg (c.408T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OTX2 p.Ser136Arg (c.408T>A)?

AlphaMissense predicts likely pathogenic (score 0.818) — an in-silico prediction, not a clinical call.

OTX2 p.Ser136Arg

c.408T>A · rs2503898062 · VCV2707403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.818 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Anophthalmia-microphthalmia syndrome

Computational evidence

Protein change
AlphaMissense	0.818	likely pathogenic
REVEL	0.722	pathogenic-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 557 bp · p 0.76 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S128R vs ClinVar S136R) — 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.Ser136Arg
Coding: c.408T>A
MANE Select: NM_021728
dbSNP: rs2503898062
Type: single nucleotide variant
Location: chr14:56802221 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 136: the 'disordered' region

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

Disease context

Anophthalmia-microphthalmia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OTX2 p.Ser136Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
OTX2 p.Arg76Ter Pathogenic ★★ same condition
OTX2 p.Ser211Ter Pathogenic/Likely pathogenic ★★ same condition
OTX2 p.Ala234Val Uncertain significance ★★ ⚠ same condition
OTX2 p.Arg102His Uncertain significance ★★ ⚠ same condition
OTX2 p.Arg48Trp Uncertain significance ★★ ⚠ same condition
OTX2 p.Leu64Met Uncertain significance ★★ ⚠ same condition
OTX2 p.Lys95Glu Uncertain significance ★★ ⚠ 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/otx2-p-ser136arg (accessed [today's date]).

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