Is TEK p.Leu634Phe (c.1900C>T) pathogenic?

TEK p.Leu634Phe (c.1900C>T) is classified Benign/Likely benign in TEK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-04-28). AlphaMissense: likely benign (0.0989); Rare (popmax 0.297%, mid); Associated with multiple cutaneous and mucosal venous malformations.

What condition is associated with TEK p.Leu634Phe (c.1900C>T)?

TEK p.Leu634Phe (c.1900C>T) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

How common is TEK p.Leu634Phe (c.1900C>T) in the general population?

TEK p.Leu634Phe (c.1900C>T) is rare (popmax 0.297%, mid) (gnomAD).

What do computational predictors say about TEK p.Leu634Phe (c.1900C>T)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

TEK p.Leu634Phe

c.1900C>T · rs35378598 · VCV366433

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.297%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple cutaneous and mucosal venous malformations

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -3.93	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 21 kb · p 0.78 · regional, not allelic
Overall
CADD	20.9	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 0.297% Middle Eastern · 18/6,058 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.128% 2,072/1,613,834 alleles · rare exomes 1,936/1,461,688 · genomes 136/152,146 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.297%	337
European (non-Finnish)	0.151%	660
Remaining individualsnot grpmax-eligible	0.13%	772
South Asian	0.112%	893
Ashkenazi Jewishnot grpmax-eligible	0.0811%	1,234
African / African-American	0.0453%	2,206
Admixed American	0.0367%	2,726
Finnishnot grpmax-eligible	0.00625%	16,001

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.Leu634Phe
Coding: c.1900C>T
MANE Select: NM_000459
dbSNP: rs35378598
Type: single nucleotide variant
Location: chr9:27197590 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 634: the fibronectin type-iii 2 domain; an α-helix; a UniProt-annotated variant site (in)

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-leu634phe (accessed [today's date]).

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