Is OPA1 p.Ala758Val (c.2273C>T) pathogenic?

OPA1 p.Ala758Val (c.2273C>T) is classified Uncertain significance in OPA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-19). AlphaMissense: ambiguous (0.3455); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Ala758Val (c.2273C>T)?

OPA1 p.Ala758Val (c.2273C>T) is associated with Inborn genetic diseases (ClinVar).

How common is OPA1 p.Ala758Val (c.2273C>T) in the general population?

OPA1 p.Ala758Val (c.2273C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about OPA1 p.Ala758Val (c.2273C>T)?

AlphaMissense predicts ambiguous (score 0.3455) — an in-silico prediction, not a clinical call.

OPA1 p.Ala758Val

c.2273C>T · rs1714055995 · VCV2300593

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3455 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3455	ambiguous
REVEL	0.77	pathogenic-leaning
SaProt	LLR -6.92	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.3, phastCons 1
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A703V vs ClinVar A758V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,830 alleles

Overall 6.84e-05% 1/1,461,606 alleles · very rare

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.Ala758Val
Coding: c.2273C>T
MANE Select: NM_130837
dbSNP: rs1714055995
Type: single nucleotide variant
Location: chr3:193657174 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 758: the 'stalk region' region; the 'paddle region' region

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 p.Ala758= Benign ★★ same residue
OPA1 c.1608+5G>A Uncertain significance ★★ same condition
OPA1 p.Ala364Val 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-ala758val (accessed [today's date]).

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