Is OPA3 p.Pro144fs (c.431del) pathogenic?

OPA3 p.Pro144fs (c.431del) is classified Uncertain significance in OPA3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-03-01). Very rare (popmax 8.48e-05%, nfe); Associated with 3-methylglutaconic aciduria type 3.

What condition is associated with OPA3 p.Pro144fs (c.431del)?

OPA3 p.Pro144fs (c.431del) is associated with 3-methylglutaconic aciduria type 3 (ClinVar).

How common is OPA3 p.Pro144fs (c.431del) in the general population?

OPA3 p.Pro144fs (c.431del) is very rare (popmax 8.48e-05%, 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.Pro144fs

c.431del · rs1205708262 · VCV556964

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

3-methylglutaconic aciduria type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -13	GERP -2.8
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,688 alleles

Overall 6.22e-05% 1/1,607,328 alleles · very rare exomes 0/1,455,114 · genomes 1/152,214 · 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.Pro144fs
Coding: c.431del
MANE Select: NM_025136
dbSNP: rs1205708262
Type: Deletion
Location: chr19:45553623 (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

For 3-methylglutaconic aciduria type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

OPA3 p.Pro144Arg Uncertain significance ★★ ⚠ same residue
OPA3 p.Pro144Gln Uncertain significance ★ ⚠ same residue
OPA3 p.Pro144Thr Uncertain significance ★ same residue
OPA3 p.Gly65fs Likely pathogenic ★★ same condition
OPA3 p.Leu149fs Uncertain significance ★★ same condition
OPA3 p.Ala5fs Likely pathogenic ★ same condition
OPA3 p.Arg103fs Likely pathogenic ★ same condition
OPA3 p.Cys96fs 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-pro144fs (accessed [today's date]).

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