Is OTX2 p.Pro148= (c.444G>C) pathogenic?

OTX2 p.Pro148= (c.444G>C) is classified Conflicting classifications of pathogenicity in OTX2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-23). Rare (popmax 0.425%, afr); Associated with Anophthalmia-microphthalmia syndrome.

What condition is associated with OTX2 p.Pro148= (c.444G>C)?

OTX2 p.Pro148= (c.444G>C) is associated with Anophthalmia-microphthalmia syndrome (ClinVar).

How common is OTX2 p.Pro148= (c.444G>C) in the general population?

OTX2 p.Pro148= (c.444G>C) is rare (popmax 0.425%, afr) (gnomAD).

OTX2 p.Pro148=

c.444G>C · rs147896150 · VCV196589

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.425%, afr)

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 -5.1	GERP -5.3
Overall
CADD	0.227	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.425% African / African-American · 319/75,020 alleles

Filtering AF 0.387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.372%

Overall 0.0266% 429/1,614,062 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.425%	235
Admixed American	0.0617%	1,622
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00322%	31,052

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.Pro148=
Coding: c.444G>C
MANE Select: NM_021728
dbSNP: rs147896150
Type: single nucleotide variant
Location: chr14:56802185 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99

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.Pro148Arg Uncertain significance ★ ⚠ same residue
OTX2 p.Pro148Leu 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

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-pro148 (accessed [today's date]).

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