Is OPA1 p.Arg71His (c.212G>A) pathogenic?

OPA1 p.Arg71His (c.212G>A) is classified Conflicting classifications of pathogenicity in OPA1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-08-25). AlphaMissense: likely benign (0.0917); Ultra-rare (popmax 0.0164%, mid); Associated with autosomal dominant optic atrophy, classic form.

What condition is associated with OPA1 p.Arg71His (c.212G>A)?

OPA1 p.Arg71His (c.212G>A) is associated with autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Arg71His (c.212G>A) in the general population?

OPA1 p.Arg71His (c.212G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Autosomal dominant optic atrophy, classic form inherited?

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

What do computational predictors say about OPA1 p.Arg71His (c.212G>A)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

OPA1 p.Arg71His

c.212G>A · rs766106312 · VCV214921

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant optic atrophy, classic form

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	GERP 1.1, phastCons 0.29
Overall
CADD	19.36	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00192% 31/1,613,688 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.0156%	6,411
Remaining individualsnot grpmax-eligible	0.0048%	20,823
European (non-Finnish)	0.00161%	62,096
African / African-American	0.00134%	74,892

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.Arg71His
Coding: c.212G>A
MANE Select: NM_130837
dbSNP: rs766106312
Type: single nucleotide variant
Location: chr3:193614902 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB

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 p.Arg71Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
OPA1 p.Arg71Gly Uncertain significance ★ ⚠ same residue
OPA1 p.Arg71Pro Uncertain significance ★ ⚠ same residue
OPA1 p.Arg71= Likely benign ★ 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

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-arg71his (accessed [today's date]).

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