Is OPA1 p.Arg500Pro (c.1499G>C) pathogenic?

OPA1 p.Arg500Pro (c.1499G>C) is classified Pathogenic in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-09-15). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Arg500Pro (c.1499G>C)?

OPA1 p.Arg500Pro (c.1499G>C) is associated with Inborn genetic diseases (ClinVar).

How common is OPA1 p.Arg500Pro (c.1499G>C) in the general population?

OPA1 p.Arg500Pro (c.1499G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OPA1 p.Arg500Pro (c.1499G>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

OPA1 p.Arg500Pro

c.1499G>C · rs80356529 · VCV521289

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 2% in OPA1
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -11.13	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 12	GERP 2.2, phastCons 1
Overall
CADD	33.0	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 R445P vs ClinVar R500P) — 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.Arg500Pro
Coding: c.1499G>C
MANE Select: NM_130837
dbSNP: rs80356529
Type: single nucleotide variant
Location: chr3:193643996 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 445 UniProt numbering: an α-helix; a UniProt-annotated variant site (in doa+ and opa1; decreased gtpase activity; loss of function in promoting mitochondrial fusion); the dynamin-type g domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OPA1 p.Arg500His Pathogenic/Likely pathogenic ★★ ⚠ same residue
OPA1 p.Arg500Gly Likely pathogenic ★ same residue
OPA1 p.Arg500Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
OPA1 p.Arg500Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
OPA1 c.1608+5G>A Uncertain significance ★★ same condition
OPA1 p.Ala364Val Uncertain significance ★★ ⚠ same condition
OPA1 p.Ala758Val Uncertain significance ★★ ⚠ same condition
OPA1 p.Arg216Cys 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/opa1-p-arg500pro (accessed [today's date]).

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