Is OPA1 p.Pro455Ala (c.1363C>G) pathogenic?

OPA1 p.Pro455Ala (c.1363C>G) is classified Pathogenic in OPA1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-01-01). AlphaMissense: likely pathogenic (0.9838); Absent from gnomAD v4.1; Associated with optic atrophy.

What condition is associated with OPA1 p.Pro455Ala (c.1363C>G)?

OPA1 p.Pro455Ala (c.1363C>G) is associated with optic atrophy (ClinVar).

How common is OPA1 p.Pro455Ala (c.1363C>G) in the general population?

OPA1 p.Pro455Ala (c.1363C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OPA1 p.Pro455Ala (c.1363C>G)?

AlphaMissense predicts likely pathogenic (score 0.9838) — an in-silico prediction, not a clinical call.

OPA1 p.Pro455Ala

c.1363C>G · VCV3250078

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9838 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

optic atrophy

Computational evidence

Protein change
AlphaMissense	0.9838	likely pathogenic ✓ concordant with ClinVar
REVEL	0.991	strongly pathogenic-leaning
SaProt	LLR -13.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Overall
CADD	28.0	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 P400A vs ClinVar P455A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OPA1
Protein: p.Pro455Ala
Coding: c.1363C>G
MANE Select: NM_130837
Type: single nucleotide variant
Location: chr3:193643430 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 400 UniProt numbering: the 'g3 motif' region; a UniProt-annotated variant site (in opa1); the dynamin-type g domain

Full OPA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

OPA1 p.Pro455Leu Pathogenic/Likely pathogenic ★★ same residue
OPA1 p.Pro455Ser Pathogenic/Likely pathogenic ★★ same residue
OPA1 c.1230+1G>A Pathogenic ★★ same condition
OPA1 c.1935+1G>C Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2779-9A>G Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.949-1G>A Pathogenic ★★ same condition
OPA1 p.Arg290Ter Pathogenic ★★ same condition
OPA1 p.Arg367Ter 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/opa1-p-pro455ala (accessed [today's date]).

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