Is ITK p.Trp209del (c.622TGG[1]) pathogenic?

ITK p.Trp209del (c.622TGG[1]) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-04). Very rare (popmax 0.00134%, afr); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Trp209del (c.622TGG[1])?

ITK p.Trp209del (c.622TGG[1]) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Trp209del (c.622TGG[1]) in the general population?

ITK p.Trp209del (c.622TGG[1]) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Combined immunodeficiency due to ITK deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ITK p.Trp209del

c.622TGG[1] · rs757871566 · VCV352465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP 0.048, phastCons 1
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,880 alleles

Overall 0.000744% 12/1,613,950 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,961
African / African-Americangrpmax	0.00134%	74,880
European (non-Finnish)	8.47e-05%	1,180,022

Ashkenazi Jewish 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: ITK
Protein: p.Trp209del
Coding: c.622TGG[1]
MANE Select: NM_005546
dbSNP: rs757871566
Type: Microsatellite
Location: chr5:157222989 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 209: the sh3 domain; a β-strand

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

Disease context

lymphoproliferative syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to ITK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

ITK c.1061-19CT[8] Benign ★ same condition
ITK c.244-17TG[4] Likely benign ★ same condition
ITK c.851+5G>A Uncertain significance ★★ same condition
ITK p.Ala191Thr Uncertain significance ★★ ⚠ same condition
ITK p.Ala261Thr Uncertain significance ★★ ⚠ same condition
ITK p.Ala308Ser Uncertain significance ★★ ⚠ same condition
ITK p.Ala345Val Uncertain significance ★★ ⚠ same condition
ITK p.Ala471Thr 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/itk-p-trp209del (accessed [today's date]).

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