Is OPA1 p.Val683= (c.2049A>G) pathogenic?

OPA1 p.Val683= (c.2049A>G) is classified Benign/Likely benign in OPA1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.19%, eas); Associated with autosomal dominant optic atrophy, classic form.

What condition is associated with OPA1 p.Val683= (c.2049A>G)?

OPA1 p.Val683= (c.2049A>G) is associated with autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Val683= (c.2049A>G) in the general population?

OPA1 p.Val683= (c.2049A>G) is low-frequency (popmax 2.19%, eas) (gnomAD).

How is Autosomal dominant optic atrophy, classic form inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

OPA1 p.Val683=

c.2049A>G · rs73069703 · VCV95716

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.19%, eas)

Conditions

autosomal dominant optic atrophy, classic form

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.33	GERP -1.6, phastCons 0.001
Overall
CADD	1.995	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.19% East Asian · 981/44,822 alleles

Filtering AF 2.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.03%

Overall 0.253% 4,081/1,613,918 alleles · low-frequency exomes 2,959/1,461,604 · genomes 1,122/152,314 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	2.19%	46
African / African-American	2.14%	47
South Asian	0.866%	115
Remaining individualsnot grpmax-eligible	0.408%	245
Ashkenazi Jewishnot grpmax-eligible	0.331%	302
Admixed American	0.323%	309
Middle Eastern	0.248%	404
European (non-Finnish)	0.012%	8,368

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.Val683=
Coding: c.2049A>G
MANE Select: NM_130837
dbSNP: rs73069703
Type: single nucleotide variant
Location: chr3:193654898 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 683: the 'stalk region' region

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

Disease context

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

For Autosomal dominant optic atrophy, classic form (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

OPA1 c.1035+5G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1149+1G>T Likely pathogenic ★★ same condition
OPA1 c.1230+5G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1681+1G>T Pathogenic ★★ same condition
OPA1 c.1935+1G>C Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2778+1G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2779-9A>G Pathogenic/Likely pathogenic ★★ same condition
OPA1 p.Arg290Ter 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-val683 (accessed [today's date]).

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