Is TEK p.Val486Ile (c.1456G>A) pathogenic?

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.

What condition is associated with TEK p.Val486Ile (c.1456G>A)?

TEK p.Val486Ile (c.1456G>A) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

What do computational predictors say about TEK p.Val486Ile (c.1456G>A)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

TEK p.Val486Ile

Q: How common is TEK p.Val486Ile (c.1456G>A) in the general population?

TEK p.Val486Ile (c.1456G>A) is common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1456G>A · rs1334811 · VCV366425

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple cutaneous and mucosal venous malformations

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 21 kb · p 0.78 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.8% African / African-American · 9,588/74,966 alleles

Filtering AF 12.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.5%

Overall 4.81% 77,618/1,613,842 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.8%	8
South Asian	12.2%	8
Middle Eastern	10.4%	10
Ashkenazi Jewishnot grpmax-eligible	6.46%	15
Remaining individualsnot grpmax-eligible	5.48%	18
European (non-Finnish)	3.95%	25
Admixed American	3.68%	27
Amishnot grpmax-eligible	2.63%	38
Finnishnot grpmax-eligible	2.04%	49
East Asian	1.85%	54

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.Val486Ile
Coding: c.1456G>A
MANE Select: NM_000459
dbSNP: rs1334811
Type: single nucleotide variant
Location: chr9:27190657 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 486: the fibronectin type-iii 1 domain; a UniProt-annotated variant site (in)

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-val486ile (accessed [today's date]).

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