Is OPTN p.Asp445fs (c.1318_1334dup) pathogenic?

OPTN p.Asp445fs (c.13181334dup) is classified Pathogenic in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Very rare (popmax 0.00329%, sas); Associated with OPTN-related open angle glaucoma.

What condition is associated with OPTN p.Asp445fs (c.1318_1334dup)?

OPTN p.Asp445fs (c.1318_1334dup) is associated with OPTN-related open angle glaucoma, amyotrophic lateral sclerosis type 12 (ClinVar).

How common is OPTN p.Asp445fs (c.1318_1334dup) in the general population?

OPTN p.Asp445fs (c.1318_1334dup) is very rare (popmax 0.00329%, sas) (gnomAD).

OPTN p.Asp445fs

c.1318_1334dup · rs2539070896 · VCV2928942

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

OPTN-related open angle glaucoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.45	GERP -3.4, phastCons 0.031

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,613,990 alleles · very rare exomes 3/1,461,856 · genomes 0/152,134 · 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: OPTN
Protein: p.Asp445fs
Coding: c.1318_1334dup
MANE Select: NM_001008212
dbSNP: rs2539070896
Type: Duplication
Location: chr10:13127819 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 445: an α-helix; the 'interaction with hd' region; the 'interaction with myo6' region

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

Disease context

Also linked: amyotrophic lateral sclerosis type 12

Similar variants

OPTN p.Asp445His Uncertain significance ★ ⚠ same residue
OPTN p.Ala436fs Pathogenic/Likely pathogenic ★★ same condition
OPTN p.Asn401fs Pathogenic ★ same condition
OPTN p.Gln151fs Pathogenic ★ same condition
OPTN p.Glu293fs Likely pathogenic ★ same condition
OPTN p.Lys55fs Pathogenic ★ same condition
OPTN p.Arg520fs Uncertain significance ★ same condition
OPTN c.1402-11dup Benign ★ 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/optn-p-asp445fs (accessed [today's date]).

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