Is OPA3 p.Ala30Val (c.89C>T) pathogenic?

OPA3 p.Ala30Val (c.89C>T) is classified Uncertain significance in OPA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-14). AlphaMissense: ambiguous (0.3444); Very rare (popmax 0.000169%, nfe); Associated with 3-methylglutaconic aciduria type 3.

What condition is associated with OPA3 p.Ala30Val (c.89C>T)?

OPA3 p.Ala30Val (c.89C>T) is associated with 3-methylglutaconic aciduria type 3, optic atrophy 3 (ClinVar).

How common is OPA3 p.Ala30Val (c.89C>T) in the general population?

OPA3 p.Ala30Val (c.89C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is 3-methylglutaconic aciduria type 3 inherited?

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

What do computational predictors say about OPA3 p.Ala30Val (c.89C>T)?

AlphaMissense predicts ambiguous (score 0.3444) — an in-silico prediction, not a clinical call.

OPA3 p.Ala30Val

c.89C>T · rs913275853 · VCV2097531

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3444 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

3-methylglutaconic aciduria type 3

Computational evidence

Protein change
AlphaMissense	0.3444	ambiguous
REVEL	0.297	indeterminate
SaProt	LLR -7.86	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP 0.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.19 · regional, not allelic
Overall
CADD	22.7	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 0.000169% European (non-Finnish) · 2/1,180,042 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,198 alleles · very rare exomes 2/1,461,882 · genomes 0/152,316 · joint denominator

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.Ala30Val
Coding: c.89C>T
MANE Select: NM_025136
dbSNP: rs913275853
Type: single nucleotide variant
Location: chr19:45584676 (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 p.Ala30= Likely benign ★ 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-ala30val (accessed [today's date]).

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