Is OTX2 p.Pro141= (c.423C>A) pathogenic?

OTX2 p.Pro141= (c.423C>A) is classified Likely benign in OTX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-15). Very rare (popmax 0.00133%, afr); Associated with Anophthalmia-microphthalmia syndrome.

What condition is associated with OTX2 p.Pro141= (c.423C>A)?

OTX2 p.Pro141= (c.423C>A) is associated with Anophthalmia-microphthalmia syndrome (ClinVar).

How common is OTX2 p.Pro141= (c.423C>A) in the general population?

OTX2 p.Pro141= (c.423C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

OTX2 p.Pro141=

c.423C>A · rs372008404 · VCV1628664

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Anophthalmia-microphthalmia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.8	GERP 2.5, phastCons 1
Overall
CADD	12.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,910 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,614,024 alleles · very rare exomes 8/1,461,882 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-Americangrpmax	0.00133%	74,910
European (non-Finnish)	0.000678%	147,502

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro141=
Coding: c.423C>A
MANE Select: NM_021728
dbSNP: rs372008404
Type: single nucleotide variant
Location: chr14:56802206 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 141: 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.Pro141Thr Uncertain significance ★★ ⚠ same residue
OTX2 p.Pro141Ser 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
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-pro141 (accessed [today's date]).

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