Is OPA1 p.Ala799Ser (c.2395G>T) pathogenic?

OPA1 p.Ala799Ser (c.2395G>T) is classified Uncertain significance in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: ambiguous (0.4542); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with OPA1 p.Ala799Ser (c.2395G>T)?

OPA1 p.Ala799Ser (c.2395G>T) is associated with Inborn genetic diseases (ClinVar).

How common is OPA1 p.Ala799Ser (c.2395G>T) in the general population?

OPA1 p.Ala799Ser (c.2395G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about OPA1 p.Ala799Ser (c.2395G>T)?

AlphaMissense predicts ambiguous (score 0.4542) — an in-silico prediction, not a clinical call.

OPA1 p.Ala799Ser

c.2395G>T · VCV3410057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4542 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4542	ambiguous
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -8.49	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Overall
CADD	28.3	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 A744S vs ClinVar A799S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,852 alleles

Overall 6.2e-05% 1/1,613,910 alleles · very rare exomes 1/1,461,602 · genomes 0/152,308 · 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.Ala799Ser
Coding: c.2395G>T
MANE Select: NM_130837
Type: single nucleotide variant
Location: chr3:193658950 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 744 UniProt numbering: 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.Ala799Thr Uncertain significance ★★ ⚠ same residue
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

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-ala799ser (accessed [today's date]).

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