Is OPA3 p.Ile41Val (c.121A>G) pathogenic?

OPA3 p.Ile41Val (c.121A>G) is classified Uncertain significance in OPA3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-04). AlphaMissense: likely benign (0.0692); Very rare (popmax 0.00167%, amr); Associated with 3-methylglutaconic aciduria type 3.

What condition is associated with OPA3 p.Ile41Val (c.121A>G)?

OPA3 p.Ile41Val (c.121A>G) is associated with 3-methylglutaconic aciduria type 3, optic atrophy 3 (ClinVar).

How common is OPA3 p.Ile41Val (c.121A>G) in the general population?

OPA3 p.Ile41Val (c.121A>G) is very rare (popmax 0.00167%, amr) (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.Ile41Val (c.121A>G)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

OPA3 p.Ile41Val

c.121A>G · rs766584469 · VCV2160881

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria type 3

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -3.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.084	GERP -1.4, phastCons 0.57
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.19 · regional, not allelic
Overall
CADD	13.15	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000558% 9/1,614,010 alleles · very rare exomes 7/1,461,882 · genomes 2/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
African / African-American	0.00133%	74,910
South Asian	0.0011%	91,086
European (non-Finnish)	0.000508%	196,671

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.Ile41Val
Coding: c.121A>G
MANE Select: NM_025136
dbSNP: rs766584469
Type: single nucleotide variant
Location: chr19:45584644 (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.Ile41Met Conflicting classifications of pathogenicity ★ ⚠ same residue
OPA3 p.Ile41Ser Uncertain significance ★ ⚠ same residue
OPA3 p.Ile41= 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

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-ile41val (accessed [today's date]).

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