# NM_000459.5(TEK):c.376C>T (p.Pro126Ser)

https://sugi.bio/variant/tek-p-pro126ser

## Summary

**TEK p.Pro126Ser (c.376C>T)** is classified **Uncertain significance** in TEK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.9815); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

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

## For patients & families {#patients}

This is a change in the TEK gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [TEK](https://sugi.bio/atlas/gene/TEK/) |
| Protein change (HGVS p.) | p.Pro126Ser |
| Coding change (HGVS c.) | c.376C>T |
| MANE Select transcript | [NM_000459](https://www.ncbi.nlm.nih.gov/nuccore/NM_000459) |
| Variant type | single nucleotide variant |
| Location | chr9:27168506-27168506 (GRCh38) |
| ClinVar | [VCV3966991](https://www.ncbi.nlm.nih.gov/clinvar/variation/3966991/) |

**All HGVS expressions:** `NC_000009.11:g.27168504C>T`, `NC_000009.12:g.27168506C>T`, `NG_011828.1:g.64358C>T`, `NG_011828.2:g.64367C>T`, `NM_000459.5:c.376C>T`, `NM_001290077.2:c.376C>T`, `NM_001290078.2:c.64C>T`, `NM_001375475.1:c.376C>T`, `NM_001375476.1:c.376C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9815)
- REVEL 0.617 (indeterminate)
- SaProt LLR -7.723 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 7.677, GERP 1.69, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.9**. 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 0.81** across the covering region of the MANE Select transcript (27,109,591–27,185,604), spanning 76,013 bp. Chi-square p 8.9e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.24 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}

**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 **126** lies in a UniProt-annotated variant site (in glc3e; formation of protein aggregates).

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.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-10 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related TEK variant pages (same residue, condition, or type): [TEK p.Ala621Ser](/variant/tek-p-ala621ser), [TEK p.Ala945Thr](/variant/tek-p-ala945thr), [TEK p.Arg119His](/variant/tek-p-arg119his), [TEK p.Arg673His](/variant/tek-p-arg673his), [TEK p.Asn299Asp](/variant/tek-p-asn299asp), [TEK p.Gly743Arg](/variant/tek-p-gly743arg), [TEK p.His234Arg](/variant/tek-p-his234arg), [TEK p.His458Pro](/variant/tek-p-his458pro).

### 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 2026-10-14); 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 3966991). 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.*