Is ITK p.Leu426= (c.1276C>T) pathogenic?

ITK p.Leu426= (c.1276C>T) is classified Conflicting classifications of pathogenicity in ITK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-02). Rare (popmax 0.325%, afr); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Leu426= (c.1276C>T)?

ITK p.Leu426= (c.1276C>T) is associated with lymphoproliferative syndrome 1, autoinflammatory syndrome (ClinVar).

How common is ITK p.Leu426= (c.1276C>T) in the general population?

ITK p.Leu426= (c.1276C>T) is rare (popmax 0.325%, 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.Leu426=

c.1276C>T · rs145991142 · VCV352473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.325%, 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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1, phastCons 1
Overall
CADD	11.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.325% African / African-American · 244/75,034 alleles

Filtering AF 0.292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.279%

Overall 0.0177% 285/1,614,168 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.325%	308
Admixed American	0.0416%	2,401
Remaining individualsnot grpmax-eligible	0.0224%	4,465
European (non-Finnish)	0.000169%	590,019

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.Leu426=
Coding: c.1276C>T
MANE Select: NM_005546
dbSNP: rs145991142
Type: single nucleotide variant
Location: chr5:157244305 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 426: the protein kinase domain

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

Also linked: autoinflammatory syndrome

For Combined immunodeficiency due to ITK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

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
ITK p.Ala583Val 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-leu426 (accessed [today's date]).

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