Is OPA3 p.Pro45Ser (c.133C>T) pathogenic?

OPA3 p.Pro45Ser (c.133C>T) is classified Uncertain significance in OPA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.627); Very rare (popmax 8.47e-05%, nfe); Associated with optic atrophy 3.

What condition is associated with OPA3 p.Pro45Ser (c.133C>T)?

OPA3 p.Pro45Ser (c.133C>T) is associated with optic atrophy 3, 3-methylglutaconic aciduria type 3 (ClinVar).

How common is OPA3 p.Pro45Ser (c.133C>T) in the general population?

OPA3 p.Pro45Ser (c.133C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Autosomal dominant optic atrophy and cataract inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about OPA3 p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely pathogenic (score 0.627) — an in-silico prediction, not a clinical call.

OPA3 p.Pro45Ser

c.133C>T · VCV4791883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.627 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

optic atrophy 3

Computational evidence

Protein change
AlphaMissense	0.627	likely pathogenic
REVEL	0.699	pathogenic-leaning
SaProt	LLR -13.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.19 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.19e-05% 1/1,614,220 alleles · very rare exomes 1/1,461,882 · genomes 0/152,338 · 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: OPA3
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_025136
Type: single nucleotide variant
Location: chr19:45584632 (GRCh38)
Gene constraint: LOEUF 1.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.13

Full OPA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

optic atrophy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylglutaconic aciduria type 3

For Autosomal dominant optic atrophy and cataract (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

OPA3 p.Pro45= Likely benign ★ same residue
OPA3 p.Pro45Leu Uncertain significance ★ ⚠ same residue
OPA3 c.142+1G>A Likely pathogenic ★★ same condition
OPA3 c.143-1G>A Pathogenic ★★ same condition
OPA3 c.143-1G>C Pathogenic ★★ same condition
OPA3 p.Gln105Glu Pathogenic ★★ ⚠ same condition
OPA3 p.Met1Val Likely pathogenic ★★ same condition
OPA3 c.142+4A>T 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/opa3-p-pro45ser (accessed [today's date]).

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