Is OPA1 p.Val997fs (c.2990_2993del) pathogenic?

OPA1 p.Val997fs (c.29902993del) is classified Pathogenic/Likely pathogenic in OPA1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-03-17). Very rare (popmax 9.09e-05%, nfe); Associated with OPA1-related disorder.

What condition is associated with OPA1 p.Val997fs (c.2990_2993del)?

OPA1 p.Val997fs (c.2990_2993del) is associated with OPA1-related disorder, optic atrophy, autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Val997fs (c.2990_2993del) in the general population?

OPA1 p.Val997fs (c.2990_2993del) is very rare (popmax 9.09e-05%, nfe) (gnomAD).

OPA1 p.Val997fs

c.2990_2993del · rs879255560 · VCV5083

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 9.09e-05%, nfe)

Conditions

OPA1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 30 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.09e-05% European (non-Finnish) · 1/1,100,704 alleles

Overall 0.000132% 2/1,512,388 alleles · very rare exomes 2/1,360,024 · genomes 0/152,364 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00351%	28,500
European (non-Finnish)grpmax	9.09e-05%	1,100,705

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val997fs
Coding: c.2990_2993del
MANE Select: NM_130837
dbSNP: rs879255560
Type: Deletion
Location: chr3:193692067 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB

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

Disease context

OPA1-related disorder

Also linked: optic atrophy autosomal dominant optic atrophy, classic form

Similar variants

OPA1 c.1377_1377+4del Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2012+4_2012+7del Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2873_2876del Pathogenic/Likely pathogenic ★★ same condition
OPA1 p.Asp266fs Pathogenic ★★ same condition
OPA1 p.Gln714fs Likely pathogenic ★★ same condition
OPA1 p.His686fs Pathogenic ★★ same condition
OPA1 p.Lys267fs Pathogenic ★★ same condition
OPA1 p.Phe772fs 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-val997fs (accessed [today's date]).

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