Is OPA1 p.Arg448= (c.1342A>C) pathogenic?

OPA1 p.Arg448= (c.1342A>C) is classified Benign in OPA1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.35%, sas); Associated with autosomal dominant optic atrophy, classic form.

What condition is associated with OPA1 p.Arg448= (c.1342A>C)?

OPA1 p.Arg448= (c.1342A>C) is associated with autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Arg448= (c.1342A>C) in the general population?

OPA1 p.Arg448= (c.1342A>C) is low-frequency (popmax 2.35%, sas) (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.Arg448=

c.1342A>C · rs149752576 · VCV95709

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.35%, sas)

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 6.7	GERP 0.78, phastCons 1
Overall
CADD	13.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.35% South Asian · 2,140/91,018 alleles

Filtering AF 2.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.23%

Overall 0.415% 6,695/1,612,042 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.35%	43
East Asian	2.28%	44
Middle Eastern	1.82%	55
Ashkenazi Jewishnot grpmax-eligible	0.673%	149
Remaining individualsnot grpmax-eligible	0.503%	199
Admixed American	0.24%	417
European (non-Finnish)	0.221%	452
Finnishnot grpmax-eligible	0.166%	604
African / African-American	0.072%	1,389

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.Arg448=
Coding: c.1342A>C
MANE Select: NM_130837
dbSNP: rs149752576
Type: single nucleotide variant
Location: chr3:193643409 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 448: the dynamin-type g domain

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-arg448 (accessed [today's date]).

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