Is OTX2 p.Ala56= (c.168G>T) pathogenic?

OTX2 p.Ala56= (c.168G>T) is classified Likely benign in OTX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-04). Very rare (popmax 8.47e-05%, nfe); Associated with Anophthalmia-microphthalmia syndrome.

What condition is associated with OTX2 p.Ala56= (c.168G>T)?

OTX2 p.Ala56= (c.168G>T) is associated with Anophthalmia-microphthalmia syndrome (ClinVar).

How common is OTX2 p.Ala56= (c.168G>T) in the general population?

OTX2 p.Ala56= (c.168G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

OTX2 p.Ala56=

c.168G>T · rs1354433789 · VCV1105456

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Anophthalmia-microphthalmia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -5.3
Overall
CADD	7.617	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.84e-05% 1/1,461,830 alleles · very rare

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: OTX2
Protein: p.Ala56=
Coding: c.168G>T
MANE Select: NM_021728
dbSNP: rs1354433789
Type: single nucleotide variant
Location: chr14:56804293 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 56: a DNA-binding 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.Ala56Glu Uncertain significance ★ ⚠ same residue
OTX2 p.Ala56Val Uncertain significance ★ ⚠ same residue
OTX2 p.Ala56Thr Uncertain significance ★ ⚠ 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

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-ala56 (accessed [today's date]).

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