Is OPA1 p.Pro668Ser (c.2002C>T) pathogenic?

OPA1 p.Pro668Ser (c.2002C>T) is classified Uncertain significance in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: ambiguous (0.4297); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Pro668Ser (c.2002C>T)?

OPA1 p.Pro668Ser (c.2002C>T) is associated with Inborn genetic diseases (ClinVar).

How common is OPA1 p.Pro668Ser (c.2002C>T) in the general population?

OPA1 p.Pro668Ser (c.2002C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OPA1 p.Pro668Ser (c.2002C>T)?

AlphaMissense predicts ambiguous (score 0.4297) — an in-silico prediction, not a clinical call.

OPA1 p.Pro668Ser

c.2002C>T · VCV3410059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4297 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4297	ambiguous
REVEL	0.646	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 2.2, phastCons 1
Overall
CADD	25.6	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 P613S vs ClinVar P668S) — verify the residue.

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: OPA1
Protein: p.Pro668Ser
Coding: c.2002C>T
MANE Select: NM_130837
Type: single nucleotide variant
Location: chr3:193648861 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 613 UniProt numbering: the 'stalk 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 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-pro668ser (accessed [today's date]).

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