Is TEK p.Val86Ile (c.256G>A) pathogenic?

TEK p.Val86Ile (c.256G>A) is classified Uncertain significance in TEK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-08). AlphaMissense: likely benign (0.1703); Very rare (popmax 0.00203%, nfe); Associated with multiple cutaneous and mucosal venous malformations.

What condition is associated with TEK p.Val86Ile (c.256G>A)?

TEK p.Val86Ile (c.256G>A) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

How common is TEK p.Val86Ile (c.256G>A) in the general population?

TEK p.Val86Ile (c.256G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about TEK p.Val86Ile (c.256G>A)?

AlphaMissense predicts likely benign (score 0.1703) — an in-silico prediction, not a clinical call.

TEK p.Val86Ile

c.256G>A · rs759283621 · VCV2260009

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple cutaneous and mucosal venous malformations

Computational evidence

Protein change
AlphaMissense	0.1703	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 76 kb · p 8.9e-06 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,994 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.0018% 29/1,614,074 alleles · very rare exomes 29/1,461,882 · genomes 0/152,192 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	0.00203%	49,166
African / African-American	0.00133%	75,004

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TEK
Protein: p.Val86Ile
Coding: c.256G>A
MANE Select: NM_000459
dbSNP: rs759283621
Type: single nucleotide variant
Location: chr9:27158034 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 86: a UniProt-annotated variant site (in glc3e; formation of protein aggregates); the ig-like c2-type 1 domain; a β-strand

Full TEK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple cutaneous and mucosal venous malformations — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TEK p.Arg1099Ter Pathogenic ★★ same condition
TEK p.Arg849Trp Pathogenic ★★ ⚠ same condition
TEK p.Arg915Cys Pathogenic/Likely pathogenic ★★ same condition
TEK p.Arg915His Pathogenic/Likely pathogenic ★★ same condition
TEK p.Arg918Cys Pathogenic/Likely pathogenic ★★ same condition
TEK p.Gln518Ter Pathogenic/Likely pathogenic ★★ same condition
TEK p.Tyr897Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
TEK p.Tyr897Cys Pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tek-p-val86ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown