# NM_000459.5(TEK):c.1284del (p.Val429fs)

https://sugi.bio/variant/tek-p-val429fs

## Summary

**TEK p.Val429fs (c.1284del)** is classified **Likely pathogenic** in TEK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). Associated with glaucoma 3, primary congenital, E.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TEK gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to glaucoma 3, primary congenital, 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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018227/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TEK](https://sugi.bio/atlas/gene/TEK/) |
| Protein change (HGVS p.) | p.Val429fs |
| Coding change (HGVS c.) | c.1284del |
| MANE Select transcript | [NM_000459](https://www.ncbi.nlm.nih.gov/nuccore/NM_000459) |
| Variant type | Deletion |
| Location | chr9:27185586-27185586 (GRCh38) |
| ClinVar | [VCV4813690](https://www.ncbi.nlm.nih.gov/clinvar/variation/4813690/) |

**All HGVS expressions:** `NC_000009.11:g.27185584del`, `NC_000009.12:g.27185586del`, `NG_011828.1:g.81438del`, `NG_011828.2:g.81447del`, `NM_000459.5:c.1284del`, `NM_001290077.2:c.1155del`, `NM_001290078.2:c.843del`, `NM_001375475.1:c.1284del`, `NM_001375476.1:c.1155del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 7.627, GERP 2, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.368, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**TEK** population constraint: LOEUF 0.368, pLI 1, missense-Z 2.8927. *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):

- **TEK-related primary glaucoma** — Definitive (AD)

## Protein context {#protein}

Residue **429** lies in the ig-like c2-type 2 domain.

AlphaFold model confidence (whole protein): pLDDT 84.37, 50% of residues very-high.

**17 experimental structure(s)** (PDB): [1FVR](https://www.rcsb.org/structure/1FVR), [2GY5](https://www.rcsb.org/structure/2GY5), [2GY7](https://www.rcsb.org/structure/2GY7), [2OO8](https://www.rcsb.org/structure/2OO8), [2OSC](https://www.rcsb.org/structure/2OSC), [2P4I](https://www.rcsb.org/structure/2P4I).

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

*Describes the biological roles of TEK (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:** TEK's established molecular role includes transmembrane receptor protein tyrosine kinase activity. p.Val429fs falls in the ig-like c2-type 2 domain.


### Pathways affected {#pathways}

TEK participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Tie2 Signaling](https://reactome.org/content/detail/R-HSA-210993) | electronic |

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

**Molecular function:** transmembrane receptor protein tyrosine kinase activity, transmembrane receptor protein kinase activity, identical protein binding.

**Biological process:** angiogenesis, sprouting angiogenesis, cell surface receptor signaling pathway, cell surface receptor protein tyrosine kinase signaling pathway, positive regulation of endothelial cell migration, negative regulation of angiogenesis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-03.

**Submitter consensus:** unanimous (1/1 Likely Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Variantyx, Inc. | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-03 |

## Associated conditions {#conditions}

[glaucoma 3, primary congenital, E](https://sugi.bio/atlas/disease/glaucoma-3-primary-congenital-e/).

**Reported phenotype names (ClinVar):** Glaucoma 3, primary congenital, E.

## Similar variants {#similar}

Related TEK variant pages (same residue, condition, or type): [TEK p.Lys145fs](/variant/tek-p-lys145fs), [TEK p.Tyr193fs](/variant/tek-p-tyr193fs), [TEK p.Gln518Ter](/variant/tek-p-gln518ter), [TEK p.Leu444fs](/variant/tek-p-leu444fs), [TEK p.Arg1076Trp](/variant/tek-p-arg1076trp), [TEK c.2209+17A>G](/variant/tek-c-2209-plus-17a-g), [TEK c.3063-49C>T](/variant/tek-c-3063-minus-49c-t), [TEK c.761-40C>T](/variant/tek-c-761-minus-40c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4813690). 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.*