Is TEK p.Ile463Val (c.1387A>G) pathogenic?

TEK p.Ile463Val (c.1387A>G) is classified Conflicting classifications of pathogenicity in TEK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1158); Ultra-rare (popmax 0.0135%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TEK p.Ile463Val (c.1387A>G)?

TEK p.Ile463Val (c.1387A>G) is associated with Inborn genetic diseases, multiple cutaneous and mucosal venous malformations (ClinVar).

How common is TEK p.Ile463Val (c.1387A>G) in the general population?

TEK p.Ile463Val (c.1387A>G) is ultra-rare (popmax 0.0135%, nfe) (gnomAD).

What do computational predictors say about TEK p.Ile463Val (c.1387A>G)?

AlphaMissense predicts likely benign (score 0.1158) — an in-silico prediction, not a clinical call.

TEK p.Ile463Val

c.1387A>G · rs200857533 · VCV366423

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1158	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -6.39	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 5.9	GERP -0.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 21 kb · p 0.78 · regional, not allelic
Overall
CADD	16.74	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 0.0135% European (non-Finnish) · 159/1,179,950 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0123% 199/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0562%	1,779
European (non-Finnish)grpmax	0.0135%	7,421
Remaining individualsnot grpmax-eligible	0.0048%	20,826
African / African-American	0.00133%	74,940

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.Ile463Val
Coding: c.1387A>G
MANE Select: NM_000459
dbSNP: rs200857533
Type: single nucleotide variant
Location: chr9:27190588 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 463: the fibronectin type-iii 1 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple cutaneous and mucosal venous malformations

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-ile463val (accessed [today's date]).

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