# NM_001008212.2(OPTN):c.1243T>G (p.Ser415Ala)

https://sugi.bio/variant/optn-p-ser415ala

## Summary

**OPTN p.Ser415Ala (c.1243T>G)** is classified **Uncertain significance** in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: likely benign (0.0623); Absent from gnomAD v4.1; Associated with Glaucoma 1, open angle, E.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 3 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the OPTN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Glaucoma 1, open angle, E.

*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:** [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.Ser415Ala |
| Coding change (HGVS c.) | c.1243T>G |
| MANE Select transcript | [NM_001008212](https://www.ncbi.nlm.nih.gov/nuccore/NM_001008212) |
| Variant type | single nucleotide variant |
| Location | chr10:13127745-13127745 (GRCh38) |
| ClinVar | [VCV3757549](https://www.ncbi.nlm.nih.gov/clinvar/variation/3757549/) |

**All HGVS expressions:** `NC_000010.10:g.13169745T>G`, `NC_000010.11:g.13127745T>G`, `NG_012876.1:g.32664T>G`, `NM_001008211.1:c.1243T>G`, `NM_001008212.2:c.1243T>G`, `NM_001008213.1:c.1243T>G`, `NM_021980.4:c.1243T>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0623)
- REVEL 0.175 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.479 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.111, GERP 0.57, phastCons 1 — weakly conserved position
- CADD: **PHRED 15.55**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (13,109,123–13,136,863), spanning 27,740 bp. Chi-square p 0.058. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, T>A, IS in the release and scores Δ0.27 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **415** lies in the 'interaction with hd' region; the 'interaction with myo6' 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.Ser415Ala falls in the interaction with hd 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-06 |

## Associated conditions {#conditions}

[Glaucoma 1, open angle, E](https://sugi.bio/atlas/disease/glaucoma-1-open-angle-e/), [amyotrophic lateral sclerosis type 12](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-12/), [OPTN-related open angle glaucoma](https://sugi.bio/atlas/disease/optn-related-open-angle-glaucoma/).

**Reported phenotype names (ClinVar):** Glaucoma 1, open angle, E, Amyotrophic lateral sclerosis type 12, Primary open angle glaucoma, AMYOTROPHIC LATERAL SCLEROSIS 12 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA, OPTN-related open angle glaucoma.

## 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 3757549). 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.*