Is TEK p.Ser654= (c.1962A>G) pathogenic?

TEK p.Ser654= (c.1962A>G) is classified Benign in TEK (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Common (popmax 51.3%, amr) — too common for a highly-penetrant pathogenic allele; Associated with glaucoma 3, primary congenital, E.

What condition is associated with TEK p.Ser654= (c.1962A>G)?

TEK p.Ser654= (c.1962A>G) is associated with glaucoma 3, primary congenital, E, multiple cutaneous and mucosal venous malformations (ClinVar).

TEK p.Ser654=

Q: How common is TEK p.Ser654= (c.1962A>G) in the general population?

TEK p.Ser654= (c.1962A>G) is common (popmax 51.3%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1962A>G · rs639225 · VCV366434

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 51.3%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

glaucoma 3, primary congenital, E

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 -4.4	GERP -3.4
Overall
CADD	0.358	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 51.3% Admixed American · 30,805/59,998 alleles

Filtering AF 50.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.7%

Overall 47.5% 767,226/1,613,684 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	62.6%	2
Admixed Americangrpmax	51.3%	2
Amishnot grpmax-eligible	50.1%	2
European (non-Finnish)	48.7%	2
Remaining individualsnot grpmax-eligible	46.4%	2
Middle Eastern	39%	3
Ashkenazi Jewishnot grpmax-eligible	38.8%	3
East Asian	38.6%	3
South Asian	38%	3
African / African-American	36.3%	3

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.Ser654=
Coding: c.1962A>G
MANE Select: NM_000459
dbSNP: rs639225
Type: single nucleotide variant
Location: chr9:27202872 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 654: the fibronectin type-iii 3 domain

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

Disease context

glaucoma 3, primary congenital, E — 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-ser654 (accessed [today's date]).

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