Is ITK p.Ala583Val (c.1748C>T) pathogenic?

ITK p.Ala583Val (c.1748C>T) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-19). AlphaMissense: ambiguous (0.4921); Ultra-rare (popmax 0.016%, afr); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Ala583Val (c.1748C>T)?

ITK p.Ala583Val (c.1748C>T) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Ala583Val (c.1748C>T) in the general population?

ITK p.Ala583Val (c.1748C>T) is ultra-rare (popmax 0.016%, 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.Ala583Val (c.1748C>T)?

AlphaMissense predicts ambiguous (score 0.4921) — an in-silico prediction, not a clinical call.

ITK p.Ala583Val

c.1748C>T · rs200077959 · VCV1514994

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.4921	ambiguous
REVEL	0.497	indeterminate
SaProt	LLR -11.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 3,753 bp · p 0.52 · regional, not allelic
Overall
CADD	24.5	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 0.016% African / African-American · 12/75,048 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00378% 61/1,613,918 alleles · ultra-rare exomes 50/1,461,592 · genomes 11/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,254
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0048%	20,831
European (non-Finnish)	0.00348%	28,776
East Asian	0.00223%	44,884

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.Ala583Val
Coding: c.1748C>T
MANE Select: NM_005546
dbSNP: rs200077959
Type: single nucleotide variant
Location: chr5:157248964 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 583: 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

For Combined immunodeficiency due to ITK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

ITK p.Ala583Ser Uncertain significance ★ ⚠ 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-ala583val (accessed [today's date]).

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