Is OPA1 p.Ile40Val (c.118A>G) pathogenic?

OPA1 p.Ile40Val (c.118A>G) is classified Uncertain significance in OPA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-14). AlphaMissense: likely benign (0.0678); Very rare (popmax 8.52e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Ile40Val (c.118A>G)?

OPA1 p.Ile40Val (c.118A>G) is associated with Inborn genetic diseases (ClinVar).

How common is OPA1 p.Ile40Val (c.118A>G) in the general population?

OPA1 p.Ile40Val (c.118A>G) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about OPA1 p.Ile40Val (c.118A>G)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

OPA1 p.Ile40Val

c.118A>G · rs1728765767 · VCV2975469

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.82, phastCons 1
Overall
CADD	13.96	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 8.52e-05% European (non-Finnish) · 1/1,173,398 alleles

Overall 6.22e-05% 1/1,606,604 alleles · very rare exomes 0/1,454,768 · genomes 1/151,836 · 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: OPA1
Protein: p.Ile40Val
Coding: c.118A>G
MANE Select: NM_130837
dbSNP: rs1728765767
Type: single nucleotide variant
Location: chr3:193614808 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 40: a UniProt-annotated variant site (in opa1)

Full OPA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OPA1 c.1608+5G>A Uncertain significance ★★ same condition
OPA1 p.Ala364Val Uncertain significance ★★ ⚠ same condition
OPA1 p.Ala758Val Uncertain significance ★★ ⚠ same condition
OPA1 p.Arg216Cys Uncertain significance ★★ ⚠ same condition
OPA1 p.Arg639Leu Uncertain significance ★★ ⚠ same condition
OPA1 p.Arg682Lys Uncertain significance ★★ ⚠ same condition
OPA1 p.Asn654Ser Uncertain significance ★★ same condition
OPA1 p.Asn783Ser 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/opa1-p-ile40val (accessed [today's date]).

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