Is TEK p.Ala226Val (c.677C>T) pathogenic?

TEK p.Ala226Val (c.677C>T) is classified Benign/Likely benign in TEK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.1011); Ultra-rare (popmax 0.0984%, nfe); Associated with multiple cutaneous and mucosal venous malformations.

What condition is associated with TEK p.Ala226Val (c.677C>T)?

TEK p.Ala226Val (c.677C>T) is associated with multiple cutaneous and mucosal venous malformations (ClinVar).

How common is TEK p.Ala226Val (c.677C>T) in the general population?

TEK p.Ala226Val (c.677C>T) is ultra-rare (popmax 0.0984%, nfe) (gnomAD).

What do computational predictors say about TEK p.Ala226Val (c.677C>T)?

AlphaMissense predicts likely benign (score 0.1011) — an in-silico prediction, not a clinical call.

TEK p.Ala226Val

c.677C>T · rs35814893 · VCV366396

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1011 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0984%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple cutaneous and mucosal venous malformations

Computational evidence

Protein change
AlphaMissense	0.1011	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -5.98	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 0.058	GERP -3.1
Regional constraint	o/e 0.81	unconstrained · MANE · 76 kb · p 8.9e-06 · regional, not allelic
Overall
CADD	4.344	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 0.0984% European (non-Finnish) · 1,161/1,179,716 alleles

Filtering AF 0.0937% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0917%

Overall 0.0776% 1,252/1,613,758 alleles · ultra-rare exomes 1,178/1,461,460 · genomes 74/152,298 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0984%	1,016
Remaining individualsnot grpmax-eligible	0.0816%	1,225
African / African-American	0.02%	5,002
Admixed American	0.0167%	6,000
South Asian	0.0154%	6,506
Finnishnot grpmax-eligible	0.00156%	64,018

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.Ala226Val
Coding: c.677C>T
MANE Select: NM_000459
dbSNP: rs35814893
Type: single nucleotide variant
Location: chr9:27172664 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 226: a UniProt-annotated variant site (in); the egf-like 1 domain

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

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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-ala226val (accessed [today's date]).

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