Is OTX2 p.Pro148Arg (c.443C>G) pathogenic?

OTX2 p.Pro148Arg (c.443C>G) is classified Uncertain significance in OTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.2907); Very rare (popmax 0.000169%, nfe).

How common is OTX2 p.Pro148Arg (c.443C>G) in the general population?

OTX2 p.Pro148Arg (c.443C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about OTX2 p.Pro148Arg (c.443C>G)?

AlphaMissense predicts likely benign (score 0.2907) — an in-silico prediction, not a clinical call.

OTX2 p.Pro148Arg

c.443C>G · VCV4921825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2907	likely benign
REVEL	0.655	pathogenic-leaning
SaProt	LLR -10.52	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 557 bp · p 0.76 · regional, not allelic
Overall
CADD	31.0	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 P140R vs ClinVar P148R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,994 alleles · very rare exomes 1/1,461,846 · genomes 1/152,148 · joint denominator

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.Pro148Arg
Coding: c.443C>G
MANE Select: NM_021728
Type: single nucleotide variant
Location: chr14:56802186 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 140 UniProt numbering: the 'disordered' region

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

Similar variants

OTX2 p.Pro148= Conflicting classifications of pathogenicity ★ same residue
OTX2 p.Pro148Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
OTX2 p.Arg76Ter Pathogenic ★★ same type
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

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-pro148arg (accessed [today's date]).

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