Is ITK p.Arg562Gln (c.1685G>A) pathogenic?

ITK p.Arg562Gln (c.1685G>A) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-03). AlphaMissense: likely benign (0.1719); Ultra-rare (popmax 0.0163%, nfe); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Arg562Gln (c.1685G>A)?

ITK p.Arg562Gln (c.1685G>A) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Arg562Gln (c.1685G>A) in the general population?

ITK p.Arg562Gln (c.1685G>A) is ultra-rare (popmax 0.0163%, nfe) (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.Arg562Gln (c.1685G>A)?

AlphaMissense predicts likely benign (score 0.1719) — an in-silico prediction, not a clinical call.

ITK p.Arg562Gln

c.1685G>A · rs142618425 · VCV578820

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0163%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1719	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -11.87	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP -0.006, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 4,483 bp · p 2.1e-06 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0163% European (non-Finnish) · 192/1,179,866 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0133% 214/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,681
European (non-Finnish)grpmax	0.0163%	6,145
Finnishnot grpmax-eligible	0.00937%	10,671
Admixed American	0.005%	20,006
African / African-American	0.00133%	75,038
South Asian	0.0011%	91,082

Remaining individuals 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.Arg562Gln
Coding: c.1685G>A
MANE Select: NM_005546
dbSNP: rs142618425
Type: single nucleotide variant
Location: chr5:157248901 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 562: 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

For Combined immunodeficiency due to ITK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

ITK p.Arg562= Likely benign ★ same residue
ITK p.Arg562Ter Pathogenic/Likely pathogenic ★★ 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

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-arg562gln (accessed [today's date]).

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