Is OPA1 p.Ala696= (c.2088G>A) pathogenic?

OPA1 p.Ala696= (c.2088G>A) is classified Conflicting classifications of pathogenicity in OPA1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-21). Rare (popmax 0.93%, eas); Associated with autosomal dominant optic atrophy, classic form.

What condition is associated with OPA1 p.Ala696= (c.2088G>A)?

OPA1 p.Ala696= (c.2088G>A) is associated with autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Ala696= (c.2088G>A) in the general population?

OPA1 p.Ala696= (c.2088G>A) is rare (popmax 0.93%, eas) (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.Ala696=

c.2088G>A · rs138114609 · VCV195515

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.93%, eas)

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 0.52	GERP -1.6, phastCons 0.83
Overall
CADD	11.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.93% East Asian · 417/44,824 alleles

Filtering AF 0.857% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.828%

Overall 0.0342% 552/1,613,824 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.93%	107
South Asian	0.0263%	3,795
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)	0.00848%	11,799
Admixed American	0.00333%	29,999
African / African-American	0.00267%	37,500

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.Ala696=
Coding: c.2088G>A
MANE Select: NM_130837
dbSNP: rs138114609
Type: single nucleotide variant
Location: chr3:193654937 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 696: the 'stalk region' region

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.Ala696Glu Uncertain significance ★ ⚠ same residue
OPA1 p.Ala696Val Uncertain significance ★ ⚠ 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.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-ala696 (accessed [today's date]).

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