Is OPTN p.Gln42Pro (c.125A>C) pathogenic?

OPTN p.Gln42Pro (c.125A>C) is classified Uncertain significance in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely pathogenic (0.5777); Very rare (popmax 0.000424%, nfe); Associated with Glaucoma 1, open angle, E.

What condition is associated with OPTN p.Gln42Pro (c.125A>C)?

OPTN p.Gln42Pro (c.125A>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.Gln42Pro (c.125A>C) in the general population?

OPTN p.Gln42Pro (c.125A>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about OPTN p.Gln42Pro (c.125A>C)?

AlphaMissense predicts likely pathogenic (score 0.5777) — an in-silico prediction, not a clinical call.

OPTN p.Gln42Pro

c.125A>C · VCV3750398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Glaucoma 1, open angle, E

Computational evidence

Protein change
AlphaMissense	0.5777	likely pathogenic
REVEL	0.569	indeterminate
SaProt	LLR -10.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP -3.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,902 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,918 alleles · very rare exomes 5/1,461,712 · genomes 0/152,206 · 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.Gln42Pro
Coding: c.125A>C
MANE Select: NM_001008212
Type: single nucleotide variant
Location: chr10:13109247 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 42: an α-helix

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-gln42pro (accessed [today's date]).

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