Is OPA3 p.Ala77= (c.231T>C) pathogenic?

OPA3 p.Ala77= (c.231T>C) is classified Benign in OPA3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 84.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with optic atrophy 3.

What condition is associated with OPA3 p.Ala77= (c.231T>C)?

OPA3 p.Ala77= (c.231T>C) is associated with optic atrophy 3, 3-methylglutaconic aciduria type 3 (ClinVar).

How is Autosomal dominant optic atrophy and cataract inherited?

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

OPA3 p.Ala77=

Q: How common is OPA3 p.Ala77= (c.231T>C) in the general population?

OPA3 p.Ala77= (c.231T>C) is common (popmax 84.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.231T>C · rs3826860 · VCV21709

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 84.3%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

optic atrophy 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -10	GERP -3.3
Overall
CADD	0.822	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 84.3% East Asian · 37,804/44,848 alleles

Filtering AF 83.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 83.3%

Overall 66.4% 1,071,293/1,612,564 alleles · common exomes 963,907/1,460,402 · genomes 107,386/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	84.3%	1
Admixed American	80.6%	1
African / African-American	76.9%	1
Finnishnot grpmax-eligible	75.5%	1
South Asian	66.7%	1
Remaining individualsnot grpmax-eligible	66.2%	2
Amishnot grpmax-eligible	65.8%	2
European (non-Finnish)	64.1%	2
Ashkenazi Jewishnot grpmax-eligible	59.2%	2
Middle Eastern	57.8%	2

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: OPA3
Protein: p.Ala77=
Coding: c.231T>C
MANE Select: NM_025136
dbSNP: rs3826860
Type: single nucleotide variant
Location: chr19:45553823 (GRCh38)
Gene constraint: LOEUF 1.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.13

Full OPA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

optic atrophy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylglutaconic aciduria type 3

For Autosomal dominant optic atrophy and cataract (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

OPA3 p.Ala77fs Likely pathogenic ★ same residue
OPA3 c.142+1G>A Likely pathogenic ★★ same condition
OPA3 c.143-1G>A Pathogenic ★★ same condition
OPA3 c.143-1G>C Pathogenic ★★ same condition
OPA3 p.Gln105Glu Pathogenic ★★ ⚠ same condition
OPA3 p.Met1Val Likely pathogenic ★★ same condition
OPA3 c.142+4A>T Uncertain significance ★★ same condition
OPA3 c.143-5C>A Uncertain significance ★★ 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/opa3-p-ala77 (accessed [today's date]).

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