Is OPA1 p.Ser763Arg (c.2289T>G) pathogenic?

OPA1 p.Ser763Arg (c.2289T>G) is classified Uncertain significance in OPA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-16). AlphaMissense: likely pathogenic (0.9978); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Ser763Arg (c.2289T>G)?

OPA1 p.Ser763Arg (c.2289T>G) is associated with Inborn genetic diseases (ClinVar).

How common is OPA1 p.Ser763Arg (c.2289T>G) in the general population?

OPA1 p.Ser763Arg (c.2289T>G) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about OPA1 p.Ser763Arg (c.2289T>G)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

OPA1 p.Ser763Arg

c.2289T>G · VCV3383804

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic · top 7% in OPA1
REVEL	0.7	pathogenic-leaning
SaProt	LLR -11.84	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 0.12	GERP -0.14, phastCons 0.98
Overall
CADD	20.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S708R vs ClinVar S763R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,944 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,016 alleles · very rare exomes 8/1,461,720 · genomes 0/152,296 · 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: OPA1
Protein: p.Ser763Arg
Coding: c.2289T>G
MANE Select: NM_130837
Type: single nucleotide variant
Location: chr3:193657190 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 708 UniProt numbering: the 'stalk region' region

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.Ser763Gly Uncertain significance ★ ⚠ same residue
OPA1 p.Ser763fs Pathogenic ★★ 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
OPA1 p.Arg639Leu Uncertain significance ★★ ⚠ same condition
OPA1 p.Arg682Lys 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-ser763arg (accessed [today's date]).

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