# NM_001008212.2(OPTN):c.12A>G (p.Gln4=)

https://sugi.bio/variant/optn-p-gln4

## Summary

**OPTN p.Gln4= (c.12A>G)** is classified **Conflicting classifications of pathogenicity** in OPTN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-10). Very rare (popmax 8.47e-05%, nfe); Associated with OPTN-related open angle glaucoma.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 2 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the OPTN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to OPTN-related open angle glaucoma.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026277/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OPTN](https://sugi.bio/atlas/gene/OPTN/) |
| Protein change (HGVS p.) | p.Gln4= |
| Coding change (HGVS c.) | c.12A>G |
| MANE Select transcript | [NM_001008212](https://www.ncbi.nlm.nih.gov/nuccore/NM_001008212) |
| Variant type | single nucleotide variant |
| Location | chr10:13109134-13109134 (GRCh38) |
| ClinVar | [VCV3379944](https://www.ncbi.nlm.nih.gov/clinvar/variation/3379944/) |

**All HGVS expressions:** `NC_000010.10:g.13151134A>G`, `NC_000010.11:g.13109134A>G`, `NG_012876.1:g.14053A>G`, `NG_051826.1:g.690A>G`, `NM_001008211.1:c.12A>G`, `NM_001008212.2:c.12A>G`, `NM_001008213.1:c.12A>G`, `NM_021980.4:c.12A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.39) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.121, GERP 0.615, phastCons 0.004 — weakly conserved position
- CADD: **PHRED 15.82**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.32**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,976 in the highest group · 1/1,613,852 alleles overall — very rare (popmax 8.47e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**OPTN** population constraint: LOEUF 0.877, pLI 9.8571e-10, missense-Z 1.2212. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **amyotrophic lateral sclerosis type 12** — Definitive (SD)
- **glaucoma, normal tension, susceptibility to** — Definitive (AD)

## Protein context {#protein}

Residue **4** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.90, 53% of residues very-high.

**14 experimental structure(s)** (PDB): [2LO4](https://www.rcsb.org/structure/2LO4), [2LUE](https://www.rcsb.org/structure/2LUE), [3VTV](https://www.rcsb.org/structure/3VTV), [3VTW](https://www.rcsb.org/structure/3VTW), [5AAZ](https://www.rcsb.org/structure/5AAZ), [5B83](https://www.rcsb.org/structure/5B83) — incl. mutant structure 5EOA.

## What this gene does {#gene-function}

*Describes the biological roles of OPTN (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** OPTN's established molecular role includes protein-macromolecule adaptor activity. p.Gln4= falls in the disordered region.


### Pathways affected {#pathways}

OPTN participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)](https://reactome.org/content/detail/R-HSA-936964) | curated |
| [PINK1-PRKN Mediated Mitophagy](https://reactome.org/content/detail/R-HSA-5205685) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 ](https://reactome.org/content/detail/R-HSA-9824878) | curated |
| [Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation](https://reactome.org/content/detail/R-HSA-9828211) | curated |
| [Regulation of TNFR1 signaling](https://reactome.org/content/detail/R-HSA-5357905) | curated |
| [TBC/RABGAPs](https://reactome.org/content/detail/R-HSA-8854214) | curated |
| [TICAM1-dependent activation of IRF3/IRF7](https://reactome.org/content/detail/R-HSA-9013973) | curated |
| [TNFR1-induced NF-kappa-B signaling pathway](https://reactome.org/content/detail/R-HSA-5357956) | curated |
| [TNFR1-induced proapoptotic signaling](https://reactome.org/content/detail/R-HSA-5357786) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein-macromolecule adaptor activity, polyubiquitin modification-dependent protein binding, identical protein binding.

**Biological process:** negative regulation of receptor recycling, Golgi organization, positive regulation of autophagy, protein localization to Golgi apparatus, cellular response to unfolded protein, Golgi to plasma membrane protein transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-05-10.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-10 |

## Associated conditions {#conditions}

[OPTN-related open angle glaucoma](https://sugi.bio/atlas/disease/optn-related-open-angle-glaucoma/), [amyotrophic lateral sclerosis type 12](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-12/).

**Reported phenotype names (ClinVar):** Primary open angle glaucoma, not provided, Amyotrophic lateral sclerosis type 12, Glaucoma 1, open angle, E, none provided, OPTN-related open angle glaucoma, AMYOTROPHIC LATERAL SCLEROSIS 12 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA.

## Similar variants {#similar}

Related OPTN variant pages (same residue, condition, or type): [OPTN c.1149-2A>G](/variant/optn-c-1149-minus-2a-g), [OPTN c.626+1G>A](/variant/optn-c-626-plus-1g-a), [OPTN c.780-2A>C](/variant/optn-c-780-minus-2a-c), [OPTN p.Gln165Ter](/variant/optn-p-gln165ter), [OPTN p.Gln335Ter](/variant/optn-p-gln335ter), [OPTN p.Gln79Ter](/variant/optn-p-gln79ter), [OPTN p.Glu135Ter](/variant/optn-p-glu135ter), [OPTN p.Glu399Ter](/variant/optn-p-glu399ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3379944). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*