Is TEK p.Asn449Ser (c.1346A>G) pathogenic?

TEK p.Asn449Ser (c.1346A>G) is classified Benign/Likely benign in TEK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0773); Low-frequency (popmax 1.09%, afr); Associated with multiple cutaneous and mucosal venous malformations.

What condition is associated with TEK p.Asn449Ser (c.1346A>G)?

TEK p.Asn449Ser (c.1346A>G) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

How common is TEK p.Asn449Ser (c.1346A>G) in the general population?

TEK p.Asn449Ser (c.1346A>G) is low-frequency (popmax 1.09%, afr) (gnomAD).

What do computational predictors say about TEK p.Asn449Ser (c.1346A>G)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

TEK p.Asn449Ser

c.1346A>G · rs149684174 · VCV716945

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.09%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple cutaneous and mucosal venous malformations

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -5.17	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 4.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 21 kb · p 0.78 · regional, not allelic
Overall
CADD	16.24	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 1.09% African / African-American · 816/75,044 alleles

Filtering AF 1.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 1%

Overall 0.0625% 1,009/1,614,016 alleles · low-frequency exomes 507/1,461,726 · genomes 502/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.09%	92
Remaining individualsnot grpmax-eligible	0.115%	868
Admixed American	0.115%	870
Middle Eastern	0.0825%	1,212
European (non-Finnish)	0.00398%	25,104

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.Asn449Ser
Coding: c.1346A>G
MANE Select: NM_000459
dbSNP: rs149684174
Type: single nucleotide variant
Location: chr9:27190547 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 449: 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

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-asn449ser (accessed [today's date]).

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