Is TEK p.Arg522Leu (c.1565G>T) pathogenic?

TEK p.Arg522Leu (c.1565G>T) is classified Benign/Likely benign in TEK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-12). AlphaMissense: likely benign (0.1399); Ultra-rare (popmax 0.0352%, nfe); Associated with multiple cutaneous and mucosal venous malformations.

What condition is associated with TEK p.Arg522Leu (c.1565G>T)?

TEK p.Arg522Leu (c.1565G>T) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

How common is TEK p.Arg522Leu (c.1565G>T) in the general population?

TEK p.Arg522Leu (c.1565G>T) is ultra-rare (popmax 0.0352%, nfe) (gnomAD).

What do computational predictors say about TEK p.Arg522Leu (c.1565G>T)?

AlphaMissense predicts likely benign (score 0.1399) — an in-silico prediction, not a clinical call.

TEK p.Arg522Leu

c.1565G>T · rs138894008 · VCV366426

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1399 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0352%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple cutaneous and mucosal venous malformations

Computational evidence

Protein change
AlphaMissense	0.1399	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -4.46	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 6.8	GERP -0.19, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 21 kb · p 0.78 · regional, not allelic
Overall
CADD	18.41	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 0.0352% European (non-Finnish) · 415/1,179,962 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.0289% 466/1,613,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.05%	2,000
European (non-Finnish)grpmax	0.0352%	2,843
Remaining individualsnot grpmax-eligible	0.0192%	5,206
Admixed American	0.00834%	11,998
African / African-American	0.00134%	74,902
South Asian	0.0011%	91,078

Finnish 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.Arg522Leu
Coding: c.1565G>T
MANE Select: NM_000459
dbSNP: rs138894008
Type: single nucleotide variant
Location: chr9:27192564 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 522: the fibronectin type-iii 1 domain

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-arg522leu (accessed [today's date]).

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