Is TEK p.His684= (c.2052C>T) pathogenic?

TEK p.His684= (c.2052C>T) is classified Benign in TEK (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0615%, sas); Associated with multiple cutaneous and mucosal venous malformations.

What condition is associated with TEK p.His684= (c.2052C>T)?

TEK p.His684= (c.2052C>T) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

How common is TEK p.His684= (c.2052C>T) in the general population?

TEK p.His684= (c.2052C>T) is ultra-rare (popmax 0.0615%, sas) (gnomAD).

TEK p.His684=

c.2052C>T · rs35818764 · VCV366436

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0615%, sas)

Conditions

multiple cutaneous and mucosal venous malformations

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.8, phastCons 1
Overall
CADD	12.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0615% South Asian · 56/91,078 alleles

Filtering AF 0.0486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.044%

Overall 0.00483% 78/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0615%	1,626
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	59,974
European (non-Finnish)	0.00153%	65,556
African / African-American	0.00133%	74,908

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.His684=
Coding: c.2052C>T
MANE Select: NM_000459
dbSNP: rs35818764
Type: single nucleotide variant
Location: chr9:27202962 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 684: the fibronectin type-iii 3 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.His684Tyr Uncertain significance ★ ⚠ same residue
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

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-his684 (accessed [today's date]).

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