Is OPA3 p.Ala117= (c.351T>C) pathogenic?

OPA3 p.Ala117= (c.351T>C) is classified Likely benign in OPA3 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-20). Very rare (popmax 0.00721%, nfe); Associated with 3-methylglutaconic aciduria type 3.

What condition is associated with OPA3 p.Ala117= (c.351T>C)?

OPA3 p.Ala117= (c.351T>C) is associated with 3-methylglutaconic aciduria type 3, optic atrophy 3 (ClinVar).

How common is OPA3 p.Ala117= (c.351T>C) in the general population?

OPA3 p.Ala117= (c.351T>C) is very rare (popmax 0.00721%, nfe) (gnomAD).

How is 3-methylglutaconic aciduria type 3 inherited?

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

OPA3 p.Ala117=

c.351T>C · rs760489108 · VCV1592754

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00721%, nfe)

Conditions

3-methylglutaconic aciduria type 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 -8.1	GERP -3.3
Overall
CADD	0.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00721% European (non-Finnish) · 85/1,179,206 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00572% 92/1,608,036 alleles · very rare exomes 89/1,455,812 · genomes 3/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00721%	13,873
African / African-American	0.00534%	18,726
Remaining individualsnot grpmax-eligible	0.00481%	20,777

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.Ala117=
Coding: c.351T>C
MANE Select: NM_025136
dbSNP: rs760489108
Type: single nucleotide variant
Location: chr19:45553703 (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

3-methylglutaconic aciduria type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: optic atrophy 3

For 3-methylglutaconic aciduria type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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
OPA3 c.*677C>T 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-ala117 (accessed [today's date]).

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