Is TEK p.Tyr992= (c.2976T>C) pathogenic?

TEK p.Tyr992= (c.2976T>C) is classified Benign in TEK (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Common (popmax 22.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with multiple cutaneous and mucosal venous malformations.

What condition is associated with TEK p.Tyr992= (c.2976T>C)?

TEK p.Tyr992= (c.2976T>C) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

TEK p.Tyr992=

Q: How common is TEK p.Tyr992= (c.2976T>C) in the general population?

TEK p.Tyr992= (c.2976T>C) is common (popmax 22.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2976T>C · rs3737188 · VCV366447

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 22.1%, eas) — too common for a highly-penetrant pathogenic allele

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	<0.2	all four deltas below 0.2 · T>G here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1	GERP -2.4, phastCons 0.005
Overall
CADD	3.751	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.1% East Asian · 9,915/44,820 alleles

Filtering AF 21.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.8%

Overall 20.8% 334,646/1,611,766 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	23.9%	4
East Asiangrpmax	22.1%	5
European (non-Finnish)	21.9%	5
Remaining individualsnot grpmax-eligible	20.3%	5
Ashkenazi Jewishnot grpmax-eligible	18.5%	5
Amishnot grpmax-eligible	18.3%	5
Admixed American	16.5%	6
Middle Eastern	16.3%	6
South Asian	16.3%	6
African / African-American	9.37%	11

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.Tyr992=
Coding: c.2976T>C
MANE Select: NM_000459
dbSNP: rs3737188
Type: single nucleotide variant
Location: chr9:27213582 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 992: the protein kinase domain; a modified residue (phosphotyrosine; by autocatalysis)

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-tyr992 (accessed [today's date]).

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