Is OPA3 p.Leu71Pro (c.212T>C) pathogenic?

OPA3 p.Leu71Pro (c.212T>C) is classified Uncertain significance in OPA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-09). AlphaMissense: likely pathogenic (0.9656); Absent from gnomAD v4.1; Associated with 3-methylglutaconic aciduria type 3.

What condition is associated with OPA3 p.Leu71Pro (c.212T>C)?

OPA3 p.Leu71Pro (c.212T>C) is associated with 3-methylglutaconic aciduria type 3, optic atrophy 3 (ClinVar).

How common is OPA3 p.Leu71Pro (c.212T>C) in the general population?

OPA3 p.Leu71Pro (c.212T>C) is absent from gnomAD v4.1 (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.Leu71Pro (c.212T>C)?

AlphaMissense predicts likely pathogenic (score 0.9656) — an in-silico prediction, not a clinical call.

OPA3 p.Leu71Pro

c.212T>C · rs2513824588 · VCV1719130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9656 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylglutaconic aciduria type 3

Computational evidence

Protein change
AlphaMissense	0.9656	likely pathogenic · top 10% in OPA3
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.19 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OPA3
Protein: p.Leu71Pro
Coding: c.212T>C
MANE Select: NM_025136
dbSNP: rs2513824588
Type: single nucleotide variant
Location: chr19:45553842 (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.Leu71= 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-leu71pro (accessed [today's date]).

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