Is OPA1 p.Arg85His (c.254G>A) pathogenic?

OPA1 p.Arg85His (c.254G>A) is classified Conflicting classifications of pathogenicity in OPA1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0789); Rare (popmax 0.237%, afr); Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Arg85His (c.254G>A)?

OPA1 p.Arg85His (c.254G>A) is associated with Inborn genetic diseases, autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Arg85His (c.254G>A) in the general population?

OPA1 p.Arg85His (c.254G>A) is rare (popmax 0.237%, afr) (gnomAD).

What do computational predictors say about OPA1 p.Arg85His (c.254G>A)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

OPA1 p.Arg85His

c.254G>A · rs35630194 · VCV95721

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.237%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -7.89	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 -2.9	GERP -4
Overall
CADD	3.201	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 0.237% African / African-American · 178/75,022 alleles

Filtering AF 0.209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.198%

Overall 0.0149% 240/1,613,836 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.237%	421
Remaining individualsnot grpmax-eligible	0.0224%	4,464
Middle Eastern	0.0165%	6,062
East Asian	0.0134%	7,479
Admixed American	0.01%	9,998
European (non-Finnish)	0.0028%	35,752
South Asian	0.0022%	45,530

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.Arg85His
Coding: c.254G>A
MANE Select: NM_130837
dbSNP: rs35630194
Type: single nucleotide variant
Location: chr3:193614944 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant optic atrophy, classic form

Similar variants

OPA1 p.Arg85Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
OPA1 p.Arg85Leu Uncertain significance ★ ⚠ same residue
OPA1 p.Arg85Gly 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
OPA1 c.1935+1G>C 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-arg85his (accessed [today's date]).

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