Is OPA1 p.Phe649fs (c.1945_1948del) pathogenic?

OPA1 p.Phe649fs (c.19451948del) is classified Pathogenic in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-10). Associated with optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy.

How is Autosomal dominant optic atrophy plus syndrome inherited?

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

OPA1 p.Phe649fs

Q: What condition is associated with OPA1 p.Phe649fs (c.1945_1948del)?

OPA1 p.Phe649fs (c.1945_1948del) is associated with optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (ClinVar).

c.1945_1948del · VCV3377083

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 21 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.4	GERP -4.5

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

Variant & gene context

Gene: OPA1
Protein: p.Phe649fs
Coding: c.1945_1948del
MANE Select: NM_130837
Type: Deletion
Location: chr3:193648804 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 649: the 'stalk region' region

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

Disease context

optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant optic atrophy plus syndrome (Orphanet):

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

Similar variants

OPA1 c.2873_2876del Pathogenic/Likely pathogenic ★★ same condition
OPA1 p.Ser763fs Pathogenic ★★ same condition
OPA1 p.Thr698_Met699insTer Pathogenic ★ same condition
OPA1 p.Arg38_Ser43del Conflicting classifications of pathogenicity ★ same condition
OPA1 p.Phe649Ser Uncertain significance ★ ⚠ same residue
OPA1 p.Asp1005fs Pathogenic same condition
OPA1 p.Glu576fs Likely pathogenic same condition
OPA1 p.Thr504fs 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-phe649fs (accessed [today's date]).

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