Is ITK p.Arg451Trp (c.1351C>T) pathogenic?

ITK p.Arg451Trp (c.1351C>T) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: ambiguous (0.3954); Ultra-rare (popmax 0.099%, mid); Associated with Inborn genetic diseases.

What condition is associated with ITK p.Arg451Trp (c.1351C>T)?

ITK p.Arg451Trp (c.1351C>T) is associated with Inborn genetic diseases, lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Arg451Trp (c.1351C>T) in the general population?

ITK p.Arg451Trp (c.1351C>T) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about ITK p.Arg451Trp (c.1351C>T)?

AlphaMissense predicts ambiguous (score 0.3954) — an in-silico prediction, not a clinical call.

ITK p.Arg451Trp

c.1351C>T · rs200331133 · VCV575120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3954 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3954	ambiguous
REVEL	0.388	indeterminate
SaProt	LLR -13.04	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.055	GERP 0.04, phastCons 0.8
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	23.9	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 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00787% 127/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Admixed American	0.0567%	1,765
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.0107%	9,376
South Asian	0.00549%	18,213
European (non-Finnish)	0.00542%	18,436

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.Arg451Trp
Coding: c.1351C>T
MANE Select: NM_005546
dbSNP: rs200331133
Type: single nucleotide variant
Location: chr5:157244380 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 451: a UniProt-annotated variant site (in a gastric adenocarcinoma sample; somatic mutation); the protein kinase domain; a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lymphoproliferative syndrome 1

Similar variants

ITK p.Arg451= Likely benign ★ same residue
ITK p.Arg451Gln 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

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-arg451trp (accessed [today's date]).

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