Is ITK p.Pro521Leu (c.1562C>T) pathogenic?

ITK p.Pro521Leu (c.1562C>T) is classified Uncertain significance in ITK (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-23). AlphaMissense: likely pathogenic (0.9747); Very rare (popmax 0.004%, afr); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Pro521Leu (c.1562C>T)?

ITK p.Pro521Leu (c.1562C>T) is associated with lymphoproliferative syndrome 1, vitiligo-associated multiple autoimmune disease susceptibility 1 (ClinVar).

How common is ITK p.Pro521Leu (c.1562C>T) in the general population?

ITK p.Pro521Leu (c.1562C>T) is very rare (popmax 0.004%, 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.

What do computational predictors say about ITK p.Pro521Leu (c.1562C>T)?

AlphaMissense predicts likely pathogenic (score 0.9747) — an in-silico prediction, not a clinical call.

ITK p.Pro521Leu

c.1562C>T · rs759932471 · VCV1481575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9747	likely pathogenic
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -15.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.73 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 4,483 bp · p 2.1e-06 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00149% 24/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,977
European (non-Finnish)	0.00169%	59,001
South Asian	0.0011%	91,084

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.Pro521Leu
Coding: c.1562C>T
MANE Select: NM_005546
dbSNP: rs759932471
Type: single nucleotide variant
Location: chr5:157245928 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 521: 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: vitiligo-associated multiple autoimmune disease susceptibility 1

For Combined immunodeficiency due to ITK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

ITK p.Pro521= Conflicting classifications of pathogenicity ★ 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-pro521leu (accessed [today's date]).

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