Is TEK p.Pro447Leu (c.1340C>T) pathogenic?

TEK p.Pro447Leu (c.1340C>T) is classified Uncertain significance in TEK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.7004); Absent from gnomAD v4.1; Associated with TEK-related disorder.

What condition is associated with TEK p.Pro447Leu (c.1340C>T)?

TEK p.Pro447Leu (c.1340C>T) is associated with TEK-related disorder (ClinVar).

How common is TEK p.Pro447Leu (c.1340C>T) in the general population?

TEK p.Pro447Leu (c.1340C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TEK p.Pro447Leu (c.1340C>T)?

AlphaMissense predicts likely pathogenic (score 0.7004) — an in-silico prediction, not a clinical call.

TEK p.Pro447Leu

c.1340C>T · rs2131183122 · VCV2633325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7004 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TEK-related disorder

Computational evidence

Protein change
AlphaMissense	0.7004	likely pathogenic
REVEL	0.281	benign-leaning
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 21 kb · p 0.78 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TEK
Protein: p.Pro447Leu
Coding: c.1340C>T
MANE Select: NM_000459
dbSNP: rs2131183122
Type: single nucleotide variant
Location: chr9:27190541 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 447: 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

TEK-related disorder

Similar variants

TEK p.Arg849Trp Pathogenic ★★ ⚠ same condition
TEK p.Glu1109Ter Pathogenic/Likely pathogenic ★★ same condition
TEK p.Arg107Ter Likely pathogenic ★ same condition
TEK p.Cys1040Arg Likely pathogenic ★ ⚠ same condition
TEK p.Glu893Val Likely pathogenic ★ ⚠ same condition
TEK p.Thr1037Lys Likely pathogenic ★ ⚠ same condition
TEK p.Thr1037Ile Conflicting classifications of pathogenicity ★ ⚠ same condition
TEK p.Tyr611Cys Uncertain significance ★ ⚠ 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-pro447leu (accessed [today's date]).

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