Is ITK p.Val587Ile (c.1759G>A) pathogenic?

ITK p.Val587Ile (c.1759G>A) is classified Benign/Likely benign in ITK (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0656); Rare (popmax 0.362%, sas); Associated with autoinflammatory syndrome.

What condition is associated with ITK p.Val587Ile (c.1759G>A)?

ITK p.Val587Ile (c.1759G>A) is associated with autoinflammatory syndrome, lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Val587Ile (c.1759G>A) in the general population?

ITK p.Val587Ile (c.1759G>A) is rare (popmax 0.362%, sas) (gnomAD).

What do computational predictors say about ITK p.Val587Ile (c.1759G>A)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

ITK p.Val587Ile

c.1759G>A · rs56005928 · VCV522219

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.362%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -2.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -3
Regional constraint	o/e 1.08	unconstrained · MANE · 3,753 bp · p 0.52 · regional, not allelic
Overall
CADD	4.758	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 0.362% South Asian · 330/91,076 alleles

Filtering AF 0.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.318%

Overall 0.277% 4,466/1,613,900 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.87%	54
Ashkenazi Jewishnot grpmax-eligible	0.615%	163
South Asiangrpmax	0.362%	276
Middle Eastern	0.33%	303
Remaining individualsnot grpmax-eligible	0.24%	417
European (non-Finnish)	0.212%	471
Admixed American	0.0733%	1,364
East Asian	0.0579%	1,726
African / African-American	0.0213%	4,690

Finnish 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.Val587Ile
Coding: c.1759G>A
MANE Select: NM_005546
dbSNP: rs56005928
Type: single nucleotide variant
Location: chr5:157248975 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 587: a UniProt-annotated variant site (in); the protein kinase domain; an α-helix

Full ITK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lymphoproliferative syndrome 1

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-val587ile (accessed [today's date]).

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