Is ITK p.Phe506= (c.1518C>T) pathogenic?

ITK p.Phe506= (c.1518C>T) is classified Likely benign in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0533%, amr); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Phe506= (c.1518C>T)?

ITK p.Phe506= (c.1518C>T) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Phe506= (c.1518C>T) in the general population?

ITK p.Phe506= (c.1518C>T) is ultra-rare (popmax 0.0533%, amr) (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.Phe506=

c.1518C>T · rs755630347 · VCV1136344

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, amr)

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -10	GERP -3.9
Overall
CADD	1.316	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0533% Admixed American · 32/60,010 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00298% 48/1,613,368 alleles · ultra-rare exomes 30/1,461,126 · genomes 18/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0533%	1,875
African / African-American	0.00133%	74,942
European (non-Finnish)	0.00119%	84,239
South Asian	0.0011%	91,078

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.Phe506=
Coding: c.1518C>T
MANE Select: NM_005546
dbSNP: rs755630347
Type: single nucleotide variant
Location: chr5:157245884 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 506: the protein kinase domain; an α-helix

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 p.Phe506Leu Uncertain significance ★ ⚠ same residue
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
ITK p.Ala525Thr 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-phe506 (accessed [today's date]).

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