Is OPA1 p.Arg421Gln (c.1262G>A) pathogenic?

OPA1 p.Arg421Gln (c.1262G>A) is classified Conflicting classifications of pathogenicity in OPA1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-07-30). AlphaMissense: likely pathogenic (0.6241); Very rare (popmax 0.00134%, afr); Associated with Behr syndrome.

What condition is associated with OPA1 p.Arg421Gln (c.1262G>A)?

OPA1 p.Arg421Gln (c.1262G>A) is associated with Behr syndrome, autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Arg421Gln (c.1262G>A) in the general population?

OPA1 p.Arg421Gln (c.1262G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about OPA1 p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely pathogenic (score 0.6241) — an in-silico prediction, not a clinical call.

OPA1 p.Arg421Gln

c.1262G>A · rs535885178 · VCV380688

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Behr syndrome

Computational evidence

Protein change
AlphaMissense	0.6241	likely pathogenic
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -10.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R366Q vs ClinVar R421Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,894 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,714 alleles · very rare exomes 3/1,461,610 · genomes 1/152,104 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,894
European (non-Finnish)	0.000254%	393,280

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.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_130837
dbSNP: rs535885178
Type: single nucleotide variant
Location: chr3:193643006 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 366 UniProt numbering: an α-helix; the dynamin-type g domain

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

Disease context

Behr syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant optic atrophy, classic form

Similar variants

OPA1 p.Arg421Ter Pathogenic ★★ same residue
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.1935+1G>T Likely pathogenic ★★ same condition
OPA1 c.2778+1G>A 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-arg421gln (accessed [today's date]).

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