Is OTX2 p.Pro142Ser (c.424C>T) pathogenic?

OTX2 p.Pro142Ser (c.424C>T) is classified Uncertain significance in OTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-09). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.0011%, sas); Associated with Anophthalmia-microphthalmia syndrome.

What condition is associated with OTX2 p.Pro142Ser (c.424C>T)?

OTX2 p.Pro142Ser (c.424C>T) is associated with Anophthalmia-microphthalmia syndrome (ClinVar).

How common is OTX2 p.Pro142Ser (c.424C>T) in the general population?

OTX2 p.Pro142Ser (c.424C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about OTX2 p.Pro142Ser (c.424C>T)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

OTX2 p.Pro142Ser

c.424C>T · VCV4692923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Anophthalmia-microphthalmia syndrome

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.354	indeterminate
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 557 bp · p 0.76 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P134S vs ClinVar P142S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,076 alleles

Overall 0.000124% 2/1,614,130 alleles · very rare exomes 2/1,461,874 · genomes 0/152,256 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,076
European (non-Finnish)	8.47e-05%	1,180,012

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.Pro142Ser
Coding: c.424C>T
MANE Select: NM_021728
Type: single nucleotide variant
Location: chr14:56802205 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 134 UniProt numbering: a UniProt-annotated variant site (in mcops5); a UniProt-annotated variant site (in cphd6; uncertain significance; loss of transcriptional activity, when tested on bicoid binding sites; decreases transactivation mediated by the wild-type protein, when tested on bicoid binding sites; no effect on dna-binding); 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.Pro142Ala Uncertain significance ★★ ⚠ same residue
OTX2 p.Pro142= Likely benign ★★ same residue
OTX2 p.Pro142His Uncertain significance ★ ⚠ same residue
OTX2 p.Pro142Leu Uncertain significance ★ ⚠ same residue
OTX2 p.Pro142Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
OTX2 p.Pro142Thr Uncertain significance ★ ⚠ same residue
OTX2 p.Arg76Ter Pathogenic ★★ same condition
OTX2 p.Ser211Ter Pathogenic/Likely pathogenic ★★ 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-pro142ser (accessed [today's date]).

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