Is TEK p.Pro417Thr (c.1249C>A) pathogenic?

TEK p.Pro417Thr (c.1249C>A) is classified Uncertain significance in TEK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0731); Ultra-rare (popmax 0.0333%, afr); Associated with Inborn genetic diseases.

What condition is associated with TEK p.Pro417Thr (c.1249C>A)?

TEK p.Pro417Thr (c.1249C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TEK p.Pro417Thr (c.1249C>A) in the general population?

TEK p.Pro417Thr (c.1249C>A) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about TEK p.Pro417Thr (c.1249C>A)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

TEK p.Pro417Thr

c.1249C>A · rs149712446 · VCV2394983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -2.55	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 1.4	GERP -1, phastCons 0.61
Regional constraint	o/e 0.81	unconstrained · MANE · 76 kb · p 8.9e-06 · regional, not allelic
Overall
CADD	15.45	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% African / African-American · 25/74,990 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00483% 78/1,613,842 alleles · ultra-rare exomes 66/1,461,598 · genomes 12/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,000
East Asian	0.0223%	4,487
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0128%	7,812
South Asian	0.00329%	30,359
European (non-Finnish)	0.00263%	38,059

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.Pro417Thr
Coding: c.1249C>A
MANE Select: NM_000459
dbSNP: rs149712446
Type: single nucleotide variant
Location: chr9:27185551 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 17 PDB
Residue 417: an α-helix; the ig-like c2-type 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TEK p.Pro417Ala Uncertain significance ★ ⚠ same residue
TEK p.Ala621Ser Uncertain significance ★★ ⚠ same condition
TEK p.Ala945Thr Uncertain significance ★★ ⚠ same condition
TEK p.Arg119His Uncertain significance ★★ ⚠ same condition
TEK p.Arg673His Uncertain significance ★★ ⚠ same condition
TEK p.Asn299Asp Uncertain significance ★★ ⚠ same condition
TEK p.Gly743Arg Uncertain significance ★★ ⚠ same condition
TEK p.His234Arg Uncertain significance ★★ ⚠ 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-pro417thr (accessed [today's date]).

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