Is OPA1 p.Pro455Ser (c.1363C>T) pathogenic?

OPA1 p.Pro455Ser (c.1363C>T) is classified Pathogenic/Likely pathogenic in OPA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-20). AlphaMissense: likely pathogenic (0.9974); Absent from gnomAD v4.1; Associated with mitochondrial disease.

What condition is associated with OPA1 p.Pro455Ser (c.1363C>T)?

OPA1 p.Pro455Ser (c.1363C>T) is associated with mitochondrial disease (ClinVar).

How common is OPA1 p.Pro455Ser (c.1363C>T) in the general population?

OPA1 p.Pro455Ser (c.1363C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OPA1 p.Pro455Ser (c.1363C>T)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

OPA1 p.Pro455Ser

c.1363C>T · rs1553877864 · VCV426101

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial disease

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic ✓ concordant with ClinVar · top 7% in OPA1
REVEL	0.987	strongly pathogenic-leaning
SaProt	LLR -15.15	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	29.5	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 P400S vs ClinVar P455S) — 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.Pro455Ser
Coding: c.1363C>T
MANE Select: NM_130837
dbSNP: rs1553877864
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

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

Similar variants

OPA1 p.Pro455Leu Pathogenic/Likely pathogenic ★★ same residue
OPA1 p.Pro455Ala Pathogenic same residue
OPA1 p.Arg500His Pathogenic/Likely pathogenic ★★ ⚠ same condition
OPA1 p.Ser600Arg Pathogenic ★★ same condition
OPA1 p.Ile487Val Likely pathogenic ★ ⚠ same condition
OPA1 c.2873_2876del Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1035+1G>A Pathogenic ★★ same type
OPA1 c.1035+5G>A Pathogenic/Likely pathogenic ★★ 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/opa1-p-pro455ser (accessed [today's date]).

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