Is OPA1 p.Ala8Ser (c.22G>T) pathogenic?

OPA1 p.Ala8Ser (c.22G>T) is classified Uncertain significance in OPA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-16). AlphaMissense: likely benign (0.1149); No allele count reported in gnomAD v4.1 (AN 1,547,420); Associated with autosomal dominant optic atrophy, classic form.

What condition is associated with OPA1 p.Ala8Ser (c.22G>T)?

OPA1 p.Ala8Ser (c.22G>T) is associated with autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Ala8Ser (c.22G>T) in the general population?

OPA1 p.Ala8Ser (c.22G>T) is no allele count reported in gnomAD v4.1 (AN 1,547,420) (gnomAD).

How is Autosomal dominant optic atrophy, classic form inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about OPA1 p.Ala8Ser (c.22G>T)?

AlphaMissense predicts likely benign (score 0.1149) — an in-silico prediction, not a clinical call.

OPA1 p.Ala8Ser

c.22G>T · rs794726939 · VCV193386

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1149 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,547,420)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant optic atrophy, classic form

Computational evidence

Protein change
AlphaMissense	0.1149	likely benign
REVEL	0.622	indeterminate
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.1, phastCons 1
Overall
CADD	17.93	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

No allele count reported in gnomAD v4.1 (AN 1,547,420). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: OPA1
Protein: p.Ala8Ser
Coding: c.22G>T
MANE Select: NM_130837
dbSNP: rs794726939
Type: single nucleotide variant
Location: chr3:193593399 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 8: a UniProt-annotated variant site (in opa1; uncertain significance)

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

Disease context

autosomal dominant optic atrophy, classic form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant optic atrophy, classic form (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

OPA1 p.Ala8Val Uncertain significance ★ ⚠ same residue
OPA1 c.1035+5G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1149+1G>T Likely pathogenic ★★ same condition
OPA1 c.1230+5G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1681+1G>T Pathogenic ★★ same condition
OPA1 c.1935+1G>C Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2778+1G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2779-9A>G Pathogenic/Likely pathogenic ★★ 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-ala8ser (accessed [today's date]).

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