Is OPA1 p.Arg682Lys (c.2045G>A) pathogenic?

OPA1 p.Arg682Lys (c.2045G>A) is classified Uncertain significance in OPA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.1735); Very rare (popmax 0.00347%, nfe); Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Arg682Lys (c.2045G>A)?

OPA1 p.Arg682Lys (c.2045G>A) is associated with Inborn genetic diseases (ClinVar).

How common is OPA1 p.Arg682Lys (c.2045G>A) in the general population?

OPA1 p.Arg682Lys (c.2045G>A) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about OPA1 p.Arg682Lys (c.2045G>A)?

AlphaMissense predicts likely benign (score 0.1735) — an in-silico prediction, not a clinical call.

OPA1 p.Arg682Lys

c.2045G>A · rs772040791 · VCV419924

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1735	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -4.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.3, phastCons 1
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 R627K vs ClinVar R682K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% European (non-Finnish) · 41/1,179,938 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00266% 43/1,613,792 alleles · very rare exomes 39/1,461,594 · genomes 4/152,198 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,779
Remaining individualsnot grpmax-eligible	0.0016%	62,468
South Asian	0.0011%	91,080

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.Arg682Lys
Coding: c.2045G>A
MANE Select: NM_130837
dbSNP: rs772040791
Type: single nucleotide variant
Location: chr3:193654894 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 627 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.Arg682Gly Uncertain significance ★ ⚠ same residue
OPA1 p.Arg682Ser Uncertain significance ★ ⚠ 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.Asn654Ser 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-arg682lys (accessed [today's date]).

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