Is OPA1 p.Ser684Ter (c.2051C>G) pathogenic?

OPA1 p.Ser684Ter (c.2051C>G) is classified Pathogenic/Likely pathogenic in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). Absent from gnomAD v4.1; Associated with autosomal dominant optic atrophy, classic form.

What condition is associated with OPA1 p.Ser684Ter (c.2051C>G)?

OPA1 p.Ser684Ter (c.2051C>G) is associated with autosomal dominant optic atrophy, classic form, optic atrophy (ClinVar).

How common is OPA1 p.Ser684Ter (c.2051C>G) in the general population?

OPA1 p.Ser684Ter (c.2051C>G) is absent from gnomAD v4.1 (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.Ser684Ter

c.2051C>G · rs2109138909 · VCV1691850

Pathogenic/Likely pathogenic Single submitter

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal dominant optic atrophy, classic form

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 22 of 31
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Ser684Ter
Coding: c.2051C>G
MANE Select: NM_130837
dbSNP: rs2109138909
Type: single nucleotide variant
Location: chr3:193654900 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 684: 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

Also linked: optic atrophy

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+1G>A 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

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-ser684ter (accessed [today's date]).

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