Is ITK p.Arg96His (c.287G>A) pathogenic?

ITK p.Arg96His (c.287G>A) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-02). AlphaMissense: likely benign (0.1019); Very rare (popmax 0.00445%, eas); Associated with ITK-related disorder.

What condition is associated with ITK p.Arg96His (c.287G>A)?

ITK p.Arg96His (c.287G>A) is associated with ITK-related disorder, lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Arg96His (c.287G>A) in the general population?

ITK p.Arg96His (c.287G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about ITK p.Arg96His (c.287G>A)?

AlphaMissense predicts likely benign (score 0.1019) — an in-silico prediction, not a clinical call.

ITK p.Arg96His

c.287G>A · rs751865122 · VCV934494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ITK-related disorder

Computational evidence

Protein change
AlphaMissense	0.1019	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	24.9	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 0.00445% East Asian · 2/44,898 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00167% 27/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,449
European (non-Finnish)	0.00203%	49,165
South Asian	0.0011%	91,080

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.Arg96His
Coding: c.287G>A
MANE Select: NM_005546
dbSNP: rs751865122
Type: single nucleotide variant
Location: chr5:157211330 (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

ITK-related disorder

Also linked: lymphoproliferative syndrome 1

Similar variants

ITK p.Arg96Cys 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-arg96his (accessed [today's date]).

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