# NM_000459.5(TEK):c.1456G>A (p.Val486Ile)

https://sugi.bio/variant/tek-p-val486ile

## Summary

**TEK p.Val486Ile (c.1456G>A)** is classified **Benign** in TEK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0726); Common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with multiple cutaneous and mucosal venous malformations.

**At a glance:** Benign · review: Multiple submitters · rsID rs1334811 · 7 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the TEK gene that is classified as benign — not considered disease-causing, submitted by 7 submitters, and is linked to multiple cutaneous and mucosal venous malformations.

*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/0016600/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.Val486Ile |
| Coding change (HGVS c.) | c.1456G>A |
| MANE Select transcript | [NM_000459](https://www.ncbi.nlm.nih.gov/nuccore/NM_000459) |
| dbSNP | [rs1334811](https://www.ncbi.nlm.nih.gov/snp/rs1334811/) |
| Variant type | single nucleotide variant |
| Location | chr9:27190657-27190657 (GRCh38) |
| ClinVar | [VCV366425](https://www.ncbi.nlm.nih.gov/clinvar/variation/366425/) |

**All HGVS expressions:** `NC_000009.11:g.27190655G>A`, `NC_000009.12:g.27190657G>A`, `NG_011828.1:g.86509G>A`, `NG_011828.2:g.86518G>A`, `NM_000459.4:c.1456G>A`, `NM_000459.5:c.1456G>A`, `NM_001290077.2:c.1327G>A`, `NM_001290078.2:c.1015G>A`, `NM_001375475.1:c.1456G>A`, `NM_001375476.1:c.1327G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0726)
- REVEL 0.1 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.661 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.471, GERP 1.73, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.6**. 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 1.01** across the covering region of the MANE Select transcript (27,185,605–27,206,700), spanning 21,095 bp. Chi-square p 0.78. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **12.8%** (afr) · FAF95 12.6% · FAF99 12.5% · 9,588/74,966 in the highest group · 77,618/1,613,842 alleles overall — common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 12.8% | 8 |
| South Asian | 12.2% | 8 |
| Middle Eastern | 10.4% | 10 |
| Ashkenazi Jewish (not grpmax-eligible) | 6.46% | 15 |
| Remaining individuals (not grpmax-eligible) | 5.48% | 18 |
| European (non-Finnish) | 3.95% | 25 |
| Admixed American | 3.68% | 27 |
| Amish (not grpmax-eligible) | 2.63% | 38 |
| Finnish (not grpmax-eligible) | 2.04% | 49 |
| East Asian | 1.85% | 54 |

*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 **486** lies in the fibronectin type-iii 1 domain; a UniProt-annotated variant site (in).

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.Val486Ile falls in the fibronectin type-iii 1 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-27.

**Submitter consensus:** unanimous (7/7 Benign).

**Submission history:** 7 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-05-05 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-04-26 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-07 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-27 |

## Associated conditions {#conditions}

[multiple cutaneous and mucosal venous malformations](https://sugi.bio/atlas/disease/multiple-cutaneous-and-mucosal-venous-malformations/).

**Reported phenotype names (ClinVar):** Multiple cutaneous and mucosal venous malformations, not provided, not specified, none provided, AllHighlyPenetrant, TEK-Related Multiple Cutaneous and Mucosal Venous Malformations (VMCM).

## Similar variants {#similar}

Related TEK variant pages (same residue, condition, or type): [TEK p.Arg1099Ter](/variant/tek-p-arg1099ter), [TEK p.Arg849Trp](/variant/tek-p-arg849trp), [TEK p.Arg915Cys](/variant/tek-p-arg915cys), [TEK p.Arg915His](/variant/tek-p-arg915his), [TEK p.Arg918Cys](/variant/tek-p-arg918cys), [TEK p.Gln518Ter](/variant/tek-p-gln518ter), [TEK p.Tyr897Asn](/variant/tek-p-tyr897asn), [TEK p.Tyr897Cys](/variant/tek-p-tyr897cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 366425). 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.*