Is ITK p.Arg96Cys (c.286C>T) pathogenic?

ITK p.Arg96Cys (c.286C>T) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-12). AlphaMissense: likely benign (0.1636); Ultra-rare (popmax 0.024%, afr); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Arg96Cys (c.286C>T)?

ITK p.Arg96Cys (c.286C>T) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Arg96Cys (c.286C>T) in the general population?

ITK p.Arg96Cys (c.286C>T) is ultra-rare (popmax 0.024%, 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.Arg96Cys (c.286C>T)?

AlphaMissense predicts likely benign (score 0.1636) — an in-silico prediction, not a clinical call.

ITK p.Arg96Cys

c.286C>T · rs372181411 · VCV840048

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1636	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -7.39	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 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.024% African / African-American · 18/74,896 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00211% 34/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,161
East Asian	0.00223%	44,894
South Asian	0.0022%	45,539
Admixed American	0.00167%	60,002
European (non-Finnish)	0.00102%	98,328

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.Arg96Cys
Coding: c.286C>T
MANE Select: NM_005546
dbSNP: rs372181411
Type: single nucleotide variant
Location: chr5:157211329 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 96: the ph 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.Arg96His Uncertain significance ★★ ⚠ same residue
ITK p.Arg96Pro Uncertain significance ★★ ⚠ same residue
ITK p.Arg96Gly Uncertain significance ★ ⚠ same residue
ITK p.Arg96Ser 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

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-arg96cys (accessed [today's date]).

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