Is OPTN p.Ala253= (c.759A>C) pathogenic?

OPTN p.Ala253= (c.759A>C) is classified Likely benign in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-23). Very rare (popmax 0.000169%, nfe); Associated with Glaucoma 1, open angle, E.

What condition is associated with OPTN p.Ala253= (c.759A>C)?

OPTN p.Ala253= (c.759A>C) is associated with Glaucoma 1, open angle, E, amyotrophic lateral sclerosis type 12, OPTN-related open angle glaucoma (ClinVar).

How common is OPTN p.Ala253= (c.759A>C) in the general population?

OPTN p.Ala253= (c.759A>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

OPTN p.Ala253=

c.759A>C · rs147991854 · VCV2079402

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Glaucoma 1, open angle, E

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.028	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.56	GERP -5.8
Overall
CADD	2.295	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,024 alleles · very rare exomes 1/1,461,842 · genomes 1/152,182 · 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.Ala253=
Coding: c.759A>C
MANE Select: NM_001008212
dbSNP: rs147991854
Type: single nucleotide variant
Location: chr10:13119020 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB

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

Disease context

Glaucoma 1, open angle, E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 12 OPTN-related open angle glaucoma

Similar variants

OPTN c.1149-2A>G Likely pathogenic ★★ same condition
OPTN c.626+1G>A Likely pathogenic ★★ same condition
OPTN c.780-2A>C Likely pathogenic ★★ same condition
OPTN p.Gln165Ter Pathogenic/Likely pathogenic ★★ same condition
OPTN p.Gln335Ter Pathogenic ★★ same condition
OPTN p.Gln79Ter Pathogenic/Likely pathogenic ★★ same condition
OPTN p.Glu135Ter Pathogenic ★★ same condition
OPTN p.Glu399Ter 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/optn-p-ala253 (accessed [today's date]).

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