Is ITK p.Arg581Trp (c.1741C>T) pathogenic?

ITK p.Arg581Trp (c.1741C>T) is classified Conflicting classifications of pathogenicity in ITK (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-24). AlphaMissense: ambiguous (0.3753); Rare (popmax 0.448%, eas); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Arg581Trp (c.1741C>T)?

ITK p.Arg581Trp (c.1741C>T) is associated with lymphoproliferative syndrome 1, autoinflammatory syndrome (ClinVar).

How common is ITK p.Arg581Trp (c.1741C>T) in the general population?

ITK p.Arg581Trp (c.1741C>T) is rare (popmax 0.448%, eas) (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.Arg581Trp (c.1741C>T)?

AlphaMissense predicts ambiguous (score 0.3753) — an in-silico prediction, not a clinical call.

ITK p.Arg581Trp

c.1741C>T · rs34482255 · VCV352476

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3753 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.448%, eas)

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3753	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -9.83	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 3,753 bp · p 0.52 · regional, not allelic
Overall
CADD	27.8	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 0.448% East Asian · 201/44,882 alleles

Filtering AF 0.397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.378%

Overall 0.0395% 637/1,613,884 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.638%	157
East Asiangrpmax	0.448%	223
Remaining individualsnot grpmax-eligible	0.101%	992
Admixed American	0.0317%	3,158
South Asian	0.0242%	4,140
Middle Eastern	0.0165%	6,054
European (non-Finnish)	0.0118%	8,488
Finnishnot grpmax-eligible	0.00312%	32,011
African / African-American	0.00133%	75,036

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.Arg581Trp
Coding: c.1741C>T
MANE Select: NM_005546
dbSNP: rs34482255
Type: single nucleotide variant
Location: chr5:157248957 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 581: a UniProt-annotated variant site (in); the protein kinase 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

Also linked: autoinflammatory syndrome

For Combined immunodeficiency due to ITK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

ITK p.Arg581Gln Uncertain significance ★ ⚠ same residue
ITK p.Arg581Gly Uncertain significance ★ ⚠ same residue
ITK p.Arg581= Likely benign ★ 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

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-arg581trp (accessed [today's date]).

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